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Purpose: For men with intermediate-risk prostate cancer treated with definitive therapy, the addition of androgen deprivation therapy (ADT) reduces the risk of distant metastasis and cancer-related mortality. However, the absolute benefit of ADT varies by baseline cancer risk. Estimates of prognosis have improved over time, and little is known about ADT decision making in the modern era. We sought to characterize variability and identify factors associated with intended ADT use within the Michigan Radiation Oncology Quality Consoritum (MROQC)., Materials and Methods: Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from June 9, 2020, to June 26, 2023 (n = 815). Prospective data were collected using standardized patient, physician, and physicist forms. Intended ADT use was prospectively defined and was the primary outcome. Associations with patient, tumor, and practice-related factors were tested with multivariable analyses. Random intercept modeling was used to estimate facility-level variability., Results: Five hundred seventy patients across 26 facilities were enrolled with intermediate-risk disease. ADT was intended for 46% of men (n = 262/570), which differed by National Comprehensive Cancer Network favorable intermediate-risk (23.5%, n = 38/172) versus unfavorable intermediate-risk disease (56.3%, n = 224/398; P < .001). After adjusting for the statewide case mix, the predicted probability of intended ADT use varied significantly across facilities, ranging from 15.4% (95% CI, 5.4%-37.0%) to 71.7% (95% CI, 57.0%-82.9%), with P < .01. Multivariable analyses showed that grade group 3 (OR, 4.60 [3.20-6.67]), ≥50% positive cores (OR, 2.15 [1.43-3.25]), and prostate-specific antigen 10 to 20 (OR, 1.87 [1.24-2.84]) were associated with ADT use. Area under the curve was improved when incorporating MRI adverse features (0.76) or radiation treatment variables (0.76), but there remained significant facility-level heterogeneity in all models evaluated (P < .05)., Conclusions: Within a state-wide consortium, there is substantial facility-level heterogeneity in intended ADT use for men with intermediate-risk prostate cancer. Future efforts are necessary to identify patients who will benefit most from ADT and to develop strategies to standardize appropriate use., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Approximately 40% of adults living with HIV experience cognitive deficits. Little is known about the risk factors for cognitive impairment and its association with myelin content in young adults living with perinatally acquired HIV (YApHIV), which is assessed in our cross-sectional study., Design: A prospective, observational cohort study., Methods: All participants underwent an 11-test cognitive battery and completed medical and social history surveys. Cognitive impairment was defined as Z scores falling at least 1.5 SD below the mean in at least two domains. Twelve participants underwent myelin water imaging. Neuroimaging data were compared to age and sex-matched HIV-uninfected controls. Regression analyses were used to evaluate for risk factors of lower cognitive domain scores and association between myelin content and cognition in YApHIV., Results: We enrolled 21 virally suppressed YApHIV across two sites in the United States. Ten participants (48%) met criteria for cognitive impairment. Participants with any non-HIV related medical comorbidity scored lower across multiple cognitive domains compared to participants without comorbidities. Myelin content did not differ between YApHIV and controls after adjusting for years of education. Lower cognitive scores were associated with lower myelin content in the cingulum and corticospinal tract in YApHIV participants after correcting for multiple comparisons., Conclusion: Poor cognition in YApHIV may be exacerbated by non-HIV related comorbidities as noted in older adults with horizontally acquired HIV. The corticospinal tract and cingulum may be vulnerable to the legacy effect of untreated HIV in infancy. Myelin content may be a marker of cognitive reserve in YApHIV., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, t-Tau, or p-Tau, published in PubMed/EMBASE up to April 10th, 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g., ICP monitoring), thus we focused on blood biomarkers' temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Out of the 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19, and p-Tau in seven. Data in rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham) with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers' trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Abstract: Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The C. elegans nervous system is compact and well described, ideal for identifying genetic programs that drive neuron-specific development, function, and connectivity. Here, we present a protocol for isolating specific neuron types for gene expression profiling by bulk or single-cell RNA sequencing. We describe steps for worm synchronization, dissociation, and fluorescence-activated cell sorting (FACS) isolation. We then detail procedures for RNA extraction and preparing cells for single-cell sequencing. This protocol is applicable to the isolation of individual cell types from larval and adult animals. For additional details on the use and execution of this protocol, see Taylor et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults have been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when over-activated. The aim of this study is to explore the role of hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP., Methods: CP was induced in mice by repeated injections of L-arginine or Caerulein in two separate models. Mice were administered with the FDA approved pharmacological hedgehog pathway inhibitor, Vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease., Results: Our study shows that hedgehog signaling was over-activated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already established fibrosis. Additionally, inhibition of hedgehog signaling resulted in reversal of pancreatic stellate cell activation ex vivo. Conclusions: Findings from our study justify conducting clinical trials using Vismodegib against CP and thus, could lead to development of novel therapeutic strategy for the treatment of CP.

We report the synthesis and characterization of the macrocyclic californium derivative Na[Cf(H 2 O)(DOTA)] (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), 1-Cf , which was studied in comparison to its dysprosium counterpart, Na[Dy(H 2 O)(DOTA)], 1-Dy . Divergent spectroscopic and magnetic behaviors were observed between 1-Cf and 1-Dy . Based upon spectroscopic measurements, we propose that accessible 5f → 6d transitions (potentially operating in tandem with charge-transfer transitions) are the major contributors to the observed broadband photoluminescence in 1-Cf . Dc magnetic susceptibility data for 1-Cf revealed lower magnetic moments than those previously observed for 1-Dy and expected for an f 9 free ion, which calculations suggest is the result of greater ligand field effects. Notably, 1-Cf displays slow magnetic relaxation on the time scale of ac susceptibility measurements, making it the first example of a californium-based single-molecule magnet. A side-by-side comparison of the ac susceptibility data reveals magnetic relaxation properties that widely differ between 1-Cf and 1-Dy . This divergent relaxation behavior is attributed mainly to the inherent difference in spin-orbit coupling between Dy 3+ and Cf 3+ .

Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal progenitors (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis and ChIP sequencing analysis of PDGFRα+ OPCs sorted from neonatal and adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac histone mark as enriched in the aOPCs. We detect increased occupancy of the H4K8ac activating mark at chromatin locations corresponding to genes related to the progenitor state (e.g., Hes5, Gpr17), metabolic processes (e.g., Txnip, Ptdgs), and myelin components (e.g., Cnp, Mog). aOPCs showed higher levels of transcripts related to lipid metabolism and myelin, and lower levels of transcripts related to cell cycle and proliferation compared with nOPCs. In addition, pharmacological inhibition of histone acetylation decreased the expression of the H4K8ac target genes in aOPCs and decreased their proliferation. Overall, this study identifies acetylation of the histone H4K8 as a regulator of the proliferative capacity of aOPCs., (© 2024 Dansu et al.)

Background: Learning Health Networks (LHN) have evolved within medicine over the past two decades, but their integration into transplantation has been more recent., Objectives and Methods: In this paper, we describe three LHNs in end-stage organ disease/transplantation, their common and unique features, and how their "actor-oriented" architecture allowed for rapid adaptation to meet the needs of their patients and practitioners during the recent COVID-19 pandemic., Result: The structure and focus of the Improving Renal Outcomes Collaborative (IROC), Starzl Network for Excellence in Pediatric Transplantation (SNEPT), and the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) are reviewed. We discuss the critical role of patient and family engagement, focusing on collaboration with Transplant Families. Finally, we review challenges common to the LHN concept and potential common areas of alignment to achieve the goal of more rapid and sustained progress to improve health in pediatric transplantation., Conclusion: LHN in transplantation are essential to accelerate knowledge dissemination and improve outcomes., (© 2024 Wiley Periodicals LLC.)

Objective: The scientific literature reports on how social media potentially influences eating disorders, although there is a large gap in the specific case of TikToks influence of adolescent's recovery from anorexia nervosa (AN). Our study uses in-depth interviews with female adolescents primarily suffering from AN to explore how they perceive the social media platform TikTok in relation to their recovery., Method: A total of 14 interviews with female adolescents recovering from AN were conducted and analyzed with reflexive thematic analysis., Results: We developed four distinct main themes: social connectivity, algorithmic engagement, regulation and adaptation, and personal agency and recovery pathways. Our findings indicate both potential benefits and harm by TikTok use when in recovery from AN, depending on a complex interplay of individual and contextual factors., Discussion: The study adds nuance to the on-going scientific debate on the role that TikTok plays in recovery from AN in general from the perspective provided by female adolescents. Suggestions are made for clinical implications at adolescent AN outpatient care including parental or professional support in TikTok adaptations and advice on how to discern when use may be triggering or supportive. Future research would benefit from longitudinal designs and inclusion of how individual differences, such as gender and personality, influence the effects on recovery and TikTok use., (© 2024 The Author(s). International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Key Points: This follow-up dual-institutional and longitudinal study further evaluated for underlying gender biases in LORs for rhinology fellowship. Explicit and implicit linguistic gender bias was found, heavily favoring male applicants., (© 2024 ARS‐AAOA, LLC.)

Background: Sinonasal malignancy surveillance paradigms are often based on Head and Neck National Comprehensive Cancer Network guidelines, which do not recommend standard surveillance imaging beyond 6 months without concerning symptomatology or physical examination findings., Methods: This was a retrospective analysis of all patients who underwent resection of sinonasal malignancy at a tertiary care center over a 20-year period from 2000 to 2020, with an ensuing surveillance period demonstrating recurrence., Results: Fifty-two patients with sinonasal malignancy recurrence were included, with an average time to recurrence of 30.9 months and a follow-up period of over 60 months. Recurrence was diagnosed by routine imaging or endoscopy in asymptomatic patients in a majority (60%) of cases, while the remaining minority of diagnoses followed new symptomatology. Asymptomatic recurrence was associated with perineural spread of tumor at initial resection (p = 0.025), but not with age (p = 0.85) or stage at diagnosis (p = 0.68). Expectedly, positron emission tomography/computed tomography (CT) more often detected regional or distant recurrence, while structural imaging (CT/magnetic resonance imaging) demonstrated more frequent detection of recurrence in those with perineural spread of tumor (p = 0.01)., Conclusions: Our findings support high rates of asymptomatic recurrence in sinonasal malignancy, with the majority of recurrences diagnosed by routine endoscopy or imaging. Tailored and extended surveillance guidelines are necessary relative to those utilized for other head and neck mucosal cancers, and are especially appropriate when features such as perineural spread are present., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Purpose: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell (PBSC) transplantation for non-Hodgkin lymphoma (NHL). Previous studies report an association between clonal hematopoiesis (CH) in PBSC and risk of t-MN, but small samples precluded examination of risk within specific subpopulations., Methods: Targeted DNA sequencing was performed to identify CH mutations in PBSC from a retrospective cohort of 984 patients with NHL (median age at transplant, 57 years; range, 18-78). Fine-Gray proportional subdistribution hazard regression models estimated association between number of CH mutations and t-MN, adjusting for demographic, clinical, and therapeutic variables. Secondary analyses evaluated the association between CH and t-MN among males and females., Results: CH was identified in PBSC from 366 patients (37.2%). t-MN developed in 60 patients after a median follow-up of 5 years. Presence of ≥2 mutations conferred increased t-MN risk (adjusted hazard ratio [aHR], 2.10; 95% CI [1.08 to 4.11]; P = .029). CH was associated with increased t-MN risk among males (aHR, 1.83 [95% CI, 1.01 to 3.31]) but not females (aHR, 0.56 [95% CI, 0.15 to 2.09]). Although the prevalence and type of CH mutations in PBSC were comparable, the 8-year cumulative incidence of t-MN was higher among males vs. females with CH (12.4% v 3.6%) but was similar between males and females without CH (4.9% v 3.9%). Expansion of CH clones from PBSC to t-MN was seen only among males., Conclusion: presence of CH mutations in PBSC confers increased risk of t-MN after autologous transplantation in male but not female patients with NHL. Factors underlying sex-based differences in risk of CH progression to t-MN merit further investigation.

Odorant transport is of fundamental and applied importance. Using computational simulations, we studied odorant transport in an anatomically accurate model of the nasal passage of a hagfish (probably Eptatretus stoutii). We found that ambient water is sampled widely, with a significant ventral element. Additionally, there is a bilateral element to olfactory flow, which enters the single nostril in two narrow, laminar streams that are then split prior to the nasal chamber by the anterior edge of the central olfactory lamella. An appendage on this lamella directs a small portion (10-14%) of the overall nasal flow to the olfactory sensory channels. Much of the remaining flow is diverted away from the sensory channels by two peripheral channels. The anterior edge of the central olfactory lamella, together with a jet-impingement mechanism, disperses flow over the olfactory surfaces. Diffusion of odorant from bulk water to the olfactory surfaces is facilitated by the large surface area:volume ratio of the sensory channels, and by a resistance-based hydrodynamic mechanism that leads to long residence times (up to 4.5 s) in the sensory channels. With increasing volumetric flow rate, the rate of odorant transfer to the olfactory surfaces increases, but the efficiency of odorant uptake decreases, falling in the range 2-6%. Odorant flux decreases caudally across the olfactory surfaces, suggesting in vivo a preponderance of olfactory sensory neurons on the anterior part of each olfactory surface. We conclude that the hagfish has a subtle anatomy for locating and capturing odorant molecules., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

High-grade endometrioid carcinomas occasionally demonstrate solid basaloid morphology with geographic necrosis (SB-GN). This pattern is among the defining features of pilomatrix-like high-grade endometrioid carcinoma (PiMHEC), a recently proposed tumor type which is additionally characterized by the presence of shadow cells, abnormal beta-catenin/CTNNB1 mutations, strong CDX2 expression, and poor outcomes. Clinicopathologic overlap between PiMHEC and other high-grade endometrial cancers with SB-GN has not been established. We screened 300 endometrial carcinomas on tissue microarray for SB-GN histology and performed a detailed whole-section morphologic review, immunohistochemical analysis, and next-generation sequencing on all cases bearing this pattern. Four (1.3%) demonstrated SB-GN. All 3 with clinical follow-up had extremely aggressive behavior despite being MMR-deficient; in contrast, only 27% of other MMR-deficient high-grade carcinomas recurred. One SB-GN case met most of the previously outlined diagnostic criteria for PiMHEC including abnormal beta-catenin/CTNNB1 (p.S37P variant) and strong CDX2 expression; notably, however, shadow cells were absent. This case also demonstrated a KRAS p.A59T pathogenic variant. The other 3 cases also lacked shadow cells; the 2 with sequencing data bore no CTNNB1 abnormalities but showed likely oncogenic variants involving the pilomatrixoma-associated gene FGFR2. All 3 cases with molecular results also bore somatic Notch pathway (NOTCH1/NOTCH2/NOTCH3) variants. The single case treated with immunotherapy showed complete and sustained response with regression of bone metastases despite abnormal beta-catenin/CTNNB1, which has been associated with immunotherapeutic resistance. These data suggest that the SB-GN pattern may connote a poor prognosis even in the absence of overt pilomatrix-like differentiation, and that novel molecular events may have implications for the treatment of these tumors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Background: Children and young people (CYP) with asthma in the UK are at higher risk of poor outcomes compared with other high-income European countries due to factors including poor access to high-quality asthma reviews, diagnostic testing and inconsistent postattack reviews. The Leicester Integrated Care Board funded the first UK pilot asthma hub for CYP, to investigate the feasibility and effectiveness of hubs, in providing postattack reviews along with providing asthma education, the opportunity to carry out diagnostic lung function tests and optimise treatment., Methods: Clinical pilot study including CYP aged 4-17 years referred to the hub with uncontrolled asthma or postattack from November 2021 to April 2022. CYP received a structured clinical assessment including National Institute for Health and Care Excellence (NICE) first-line diagnostic investigations for asthma including spirometry, bronchodilator reversibility (BDR) and fraction of exhaled nitric oxide (FeNO)., Results: Of 312 CYP referred (mean age 8.6±3.2 years; 42% women), 266 (85.3%) attended their appointment. Median time from referral to review was 2 days (IQR 1-3). Three CYP (1.1%) were severely unwell at review and required further hospital treatment. In the 231 CYP who completed first-line tests, asthma was confirmed for 73 (31.6%) based on NICE diagnostic criteria for CYP. Twenty-two per cent of children with normal baseline spirometry had ≥12% BDR., Conclusion: Paediatric asthma hubs are a feasible model of care to deliver CYP postasthma attack reviews and identify high-risk patients requiring further treatment. Spirometry, BDR and FeNO testing allowed diagnostic confirmation in a significant proportion of CYP., Competing Interests: Competing interests: EAG: none relating to this manuscript. Unrelated to this manuscript, consultancy work for Boehringer Ingelheim with money paid to the institution (University of Leicester). Investigator led research grants from Circassia Group, Gilead Sciences, Chiesi Limited and Propeller Health. Research collaboration with AstraZeneca, Helicon Health and Adherium (NZ) Limited. Speaker fees Circassia Group and Sanofi. MIA: Children’s and Young people clinical lead at Leicester, Leicestershire and Rutland Integrated Care Board. National Webinar for Proveca Limited., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Chylothorax after pediatric cardiac surgery is associated with increased morbidity and mortality. Poor understanding exists regarding inflammation within the pleural fluid. Our aim was to determine the relationship between proinflammatory markers and chylothorax., Methods: This is a single-center prospective observational cohort study. Pediatric patients after cardiac surgery with >20 mL/kg/day of chest tube output were included from January 2022 through January 2023. The pleural fluid was tested for 13 cytokine concentrations using a multiplexed immunoassay and for albumin and C-Reactive Protein (CRP) levels. Bivariable comparisons and Spearman's rank correlations were made., Results: Out of 63 patients, chylothorax occurred in 20 (32 %), of which 10 (50 %) were neonates. Cytokine concentrations, CRP, and albumin levels were not different between chylothorax and non-chylothorax patients. Higher levels of four proinflammatory cytokines (IL-1β, IL-5, IL-8, IL-13) correlated with longer chest tube drainage (r = 0.29, 0.43, 0.28, 0.39 respectively). There were higher concentrations of IL-1β, IL-5, IL-8 and IL-13 in each progressively longer quartile of days to resolution. The longest quartile of days to resolution (12-50 days) showed the highest median cytokine levels., Conclusions: The 13 cytokines tested were not associated with the diagnosis of chylothorax. However, higher IL-1β, IL-5, IL-8, and IL-13 concentrations were correlated with longer days to resolution. These findings demonstrate an inflammatory component to effusion resolution and may indicate an inflammatory phenotype that is distinct from chylothorax., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Wheat stem sawfly (WSS), Cephus cinctus Norton (Hymenoptera: Cephidae), is a major pest of cereal crops throughout the Northern Great Plains of North America. Native parasitoids, Bracon cephi (Gahan) and B. lissogaster Muesebeck (Hymenoptera: Braconidae), play a key role in suppressing WSS populations and limiting associated damage. Smooth brome grass (Bromus inermis Leyss.) serves as a potential trap reservoir for WSS when grown in areas surrounding wheat (Triticum aestivum L.) fields in Montana. Its unique biology allows it to support high WSS infestation while promoting significant larval mortality throughout the growing season. Late-season WSS survivors can then serve as hosts for WSS parasitoids. Our study investigated smooth brome as a host refuge for WSS parasitoids. We measured WSS larval infestation and survival rate inside smooth brome grown within WSS-inclusion cages, finding a maximum infestation of 66.5% and an end-of-year WSS survival of 5.7%. In addition, we collected stems from sites in central and north-central Montana to measure the WSS infestation and parasitoid prevalence in wheat and adjacent smooth brome. WSS infestation was high in both Big Sandy (64.5% smooth brome, 65.7% adjacent wheat) and Moccasin, MT (50.6%, 38.6%). Year-end WSS larval mortality was 43.6% greater in smooth brome compared to adjacent wheat at both field sites, but both hosted similar numbers of WSS parasitoids. This research underscores the importance of smooth brome in providing a sustainable host refuge for WSS parasitoids and highlights its significant role in supporting the economics of wheat cultivation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America.)

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The tumor microenvironment (TME) plays a major regulatory role in TNBC progression and is highly infiltrated by suppressive immune cells that reduce anti-tumor immune activity. Although regulatory B cells (Bregs) are a key TME component, knowledge of their function in TNBC is limited. CD84 is a homophilic adhesion molecule that promotes the survival of blood tumors. In the current study, we followed the role of CD84 in the regulation of the TME in TNBC. We demonstrate that CD84 induces a cascade in Bregs that involves the β-catenin and Tcf4 pathway, which induces the transcription of interleukin-10 by binding to its promoter and the promoter of its regulator, AhR. This leads to the expansion of Bregs, which in turn control the activity of other immune cells and immune suppression. Accordingly, we suggest CD84 as a therapeutic target for breaking immune tolerance in TNBC., Competing Interests: Declaration of interests S.T.R. and I.S. have stock options as founders in SLAMBio. This potential conflict of interest has been reviewed and managed by the Weizmann and COH Conflict of Interest in Research Committees., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gram-positive bacteria utilize a Fatty Acid Kinase (FAK) complex to harvest fatty acids from the environment. This complex consists of the fatty acid kinase, FakA, and an acyl carrier protein, FakB, and is known to impact virulence and disease outcomes. Despite some recent studies, there remains many outstanding questions as to the enzymatic mechanism and structure of FAK . To better address this gap in knowledge, we used a combination of modeling, biochemical, and cell-based approaches to build on prior proposed models and identify critical details of FAK activity. Using bio-layer interferometry, we demonstrated nanomolar affinity between FakA and FakB that also indicates that FakA is dimer when binding FakB. Additionally, targeted mutagenesis of the FakA Middle domain demonstrates it possesses a metal binding pocket that is critical for FakA dimer stability and FAK function in vitro and in vivo. Lastly, we solved structures of the apo and ligand-bound FakA kinase domain to capture the molecular changes in the protein following ATP binding and hydrolysis. Together, these data provide critical insight into the structure and function of the FAK complex which is essential for understanding its mechanism., Competing Interests: Conflict of interest Authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). We studied a Grn knockout (Grn-KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9-encoded regulatory subunit of the "K + ATP" channel that is well-tolerated in humans. Aged (13 months) Grn-KO and wild-type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral performance, neuropathology, and gene expression. Mortality was significantly higher for aged Grn-KO mice (particularly females), but there was a conspicuous improvement in survival for both sexes treated with nicorandil. Grn-KO mice performed worse on some cognitive tests than WT mice, but Morris Water Maze performance was improved with nicorandil treatment. Neuropathologically, Grn-KO mice had significantly increased levels of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytosis but not ionized calcium binding adaptor molecule 1 (IBA-1)-immunoreactive microgliosis, indicating cell-specific inflammation in the brain. Expression of several astrocyte-enriched genes, including Gfap, were also elevated in the Grn-KO brain. Nicorandil treatment was associated with a subtle shift in a subset of detected brain transcript levels, mostly related to attenuated inflammatory markers. Nicorandil treatment improved survival outcomes, cognition, and inflammation in aged Grn-KO mice., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Graph neural networks (GNNs) have emerged as powerful tools for quantum chemical property prediction, leveraging the inherent graph structure of molecular systems. GNNs depend on an edge-to-node aggregation mechanism for combining edge representations into node representations. Unfortunately, existing learnable edge-to-node aggregation methods substantially increase the number of parameters and, thus, the computational cost relative to simple sum aggregation. Worse, as we report here, they often fail to improve predictive accuracy. We therefore propose a novel learnable edge-to-node aggregation mechanism that aims to improve the accuracy and parameter efficiency of GNNs in predicting molecular properties. The new mechanism, called "patch aggregation", is inspired by the Multi-Head Attention and Mixture of Experts machine learning techniques. We have incorporated the patch aggregation method into the specialized, state-of-the-art GNN models SchNet, DimeNet++, SphereNet, TensorNet, and VisNet and show that patch aggregation consistently outperforms existing learnable and nonlearnable aggregation techniques (sum, multilayer perceptron, softmax, and set transformer aggregation) in the prediction of molecular properties such as QM9 thermodynamic properties and MD17 molecular dynamics trajectory energies and forces. We also find that patch aggregation not only improves prediction accuracy but also is parameter-efficient, making it an attractive option for practical applications for which computational resources are limited. Further, we show that Patch aggregation can be applied across different GNN models. Overall, Patch aggregation is a powerful edge-to-node aggregation mechanism that improves the accuracy of molecular property predictions by GNNs.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD., (© 2024 Federation of European Biochemical Societies.)

Centrosomes have critical roles in microtubule organization, ciliogenesis, and cell signaling. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 Centrosomal alterations also contribute to diseases, including microcephaly, cancer, and ciliopathies. 9 , 10 , 11 , 12 , 13 To date, over 150 centrosomal proteins have been identified, including several kinases and phosphatases that control centrosome biogenesis, function, and maintenance. 2 , 3 , 4 , 5 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 However, the regulatory mechanisms that govern centrosome function are not fully defined, and thus how defects in centrosomal regulation contribute to disease is incompletely understood. Using a systems genetics approach, we find here that PPP2R3C, a poorly characterized PP2A phosphatase subunit, is a distal centriole protein and functional partner of centriolar proteins CEP350 and FOP. We further show that a key function of PPP2R3C is to counteract the kinase activity of MAP3K1. In support of this model, MAP3K1 knockout suppresses growth defects caused by PPP2R3C inactivation, and MAP3K1 and PPP2R3C have opposing effects on basal and microtubule stress-induced JNK signaling. Illustrating the importance of balanced MAP3K1 and PPP2R3C activities, acute overexpression of MAP3K1 severely inhibits centrosome function and triggers rapid centriole disintegration. Additionally, inactivating PPP2R3C mutations and activating MAP3K1 mutations both cause congenital syndromes characterized by gonadal dysgenesis. 22 , 23 , 24 , 25 , 26 , 27 , 28 As a syndromic PPP2R3C variant is defective in centriolar localization and binding to centriolar protein FOP, we propose that imbalanced activity of this centrosomal kinase-phosphatase pair is the shared cause of these disorders. Thus, our findings reveal a new centrosomal phospho-regulatory module, shed light on disorders of gonadal development, and illustrate the power of systems genetics to identify previously unrecognized gene functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Contemporary surgical practices for traumatic brain injury (TBI) remain unclear. We describe the clinical profile of an 18-centre US TBI cohort with cranial surgery., Methods: The prospective, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (2014-2018; ClinicalTrials.gov #NCT02119182) enrolled subjects who presented to trauma centre and received head computed tomography within 24-h (h) post-TBI. We performed a secondary data analysis in subjects aged ≥17-years with hospitalisation. Clinical characteristics, surgery type/timing, hospital and six-month outcomes were reported., Findings: Of 2032 subjects (age: mean = 41.4-years, range = 17-89-years; male = 71% female = 29%), 260 underwent cranial surgery, comprising 65% decompressive craniectomy, 23% craniotomy, 12% other surgery. Subjects with surgery (vs. without surgery) presented with worse neurological injury (median Glasgow Coma Scale = 6 vs. 15; midline shift ≥5 mm: 48% vs. 2%; cisternal effacement: 61% vs. 4%; p < 0.0001). Median time-to-craniectomy/craniotomy was 1.8 h (interquartile range = 1.1-5.0 h), and 67% underwent intracranial pressure monitoring. Seventy-three percent of subjects with decompressive craniectomy and 58% of subjects with craniotomy had ≥3 intracranial lesion types. Decompressive craniectomy (vs. craniotomy) was associated with intracranial injury severity (median Rotterdam Score = 4 vs. 3, p < 0.0001), intensive care length of stay (median = 13 vs. 4-days, p = 0.0002), and six-month unfavourable outcome (62% vs. 30%; p = 0.0001). Earlier time-to-craniectomy was associated with intracranial injury severity., Interpretation: In a large representative cohort of patients hospitalised with TBI, surgical decision-making and time-to-surgery aligned with intracranial injury severity. Multifocal TBIs predominated in patients with cranial surgery. These findings summarise current TBI surgical practice across US trauma centres and provide the foundation for analyses in targeted subpopulations., Funding: National Institute of Neurological Disorders and Stroke; US Department of Defense; Neurosurgery Research and Education Foundation., Competing Interests: AMD declares: grant funding from the Mercatus Center at George Mason University (not related to the current work). DKM declares: grant funding from United Kingdom National Institute for Health Research (not related to the current work). KKWW declares: is a shareholder of Gryphon Bio, Inc. (not related to the current work). All other authors declare no conflict of interest., (© 2024 The Author(s).)

Background: The prevalence of cardiometabolic diseases is escalating in sub-Saharan Africa (SSA) alongside the prevailing high burden of communicable diseases. Although many countries in SSA, including Rwanda, have existing data on the prevalence of individual components of the MetS, many SSA countries have insufficient data to guide policy makers on the magnitude of MetS. This study sought to determine the magnitude of MetS and its associated risk factors by sex at a referral teaching hospital in Rwanda., Methods: A cross-sectional, study was conducted among adults aged 35 to 65 years presenting at Ruhengeri Referral Teaching Hospital, Rwanda. We collected socio-clinicodemographic data using the World Health Organization (WHO) STEPwise tool for non-communicable diseases. We used the National Cholesterol Education Program Adult Treatment Panel III criteria for MetS., Results: Overall, 99 (23.5%) males and 322 (76.5%) female participants with mean ± SD age 47.5 ± 8.2 years were enrolled. The overall frequency of MetS was 51.9% (95% CI: 47.0-56.8) and was significantly higher (p < 0.001) in females 193 (59.4%) compared to males 26 (26.3%). Significant differences by sex were also noted in the proportions of visceral obesity; 70.4% vs 7.1% (p < 0.001), hypoalphalipoproteinaemia 36.1% vs 69.7% (p < 0.0001), type 2 diabetes mellitus; 18.4% vs 31.6% (p = 0.020) and body mass index 25.9 ± 15.6 vs 28.2 ± 6.4 (p = 0.032). On multivariate logistic regression, older age (odds ratio (OR) 1.05; 95% confidence interval ((CI) 1.01-1.10)), higher body weight (OR 1.06; 95% CI 1.04-1.08) and higher total cholesterol (1.25; 95% CI 1.05 -1.74) were significantly associated with MetS in females; whereas only higher body weight (OR1.10; 95% CI 1.04-1.18) was significantly associated with MetS in males., Conclusion: A high frequency of MetS was observed in the present study, which was higher among females. Our findings emphasize the need for tailored prevention and intervention strategies to mitigate the long-term impact of MetS., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Gafirita et al.)

We describe a case of severe symptomatic tumoral calcinosis in a young man with end stage kidney disease secondary to antineutrophil cytoplasmic antibodies-associated vasculitis with longstanding hyperphosphatemia and secondary hyperparathyroidism while on several years of peritoneal dialysis. The use of intravenous sodium thiosulfate, optimization of clearance with five times weekly hemodialysis, and intradialytic nutrition were used to treat his inoperable tumoral calcinosis. Over 3 months, he had a remarkable reduction in the size of his calcified masses and associated improvement in pain. He subsequently received a living donor kidney transplant., (© 2024 International Society for Hemodialysis.)

The androgen receptor signaling inhibitor apalutamide is used successfully for the treatment of prostate cancer. An increased risk of hypothyroidism, mostly subclinical, has been reported in the SPARTAN and TITAN trials. We present three cases of subacute deterioration of previously known but well-controlled hypothyroidism treated with levothyroxine, occurring shortly after the initiation of treatment with apalutamide, resulting in severe hypothyroidism. These cases highlight the importance of awareness of thyroid dysfunction during treatment with apalutamide, particularly in patients with pre-existing thyroid disease, common in the general population. We provide practice recommendations for thyroid management prior to and during apalutamide treatment as well as after the interruption of this therapy.

Widespread vaccination and natural infection have resulted in greatly decreased rates of severe disease, hospitalization and death after subsequent infection or reinfection with SARS-CoV-2. New vaccine formulations are based on circulating strains of virus, which have tended to evolve to more readily transmit human to human and to evade the neutralizing antibody response. An assumption of this approach is that ancestral strains of virus will not recur. Recurrence of these strains could be a problem for individuals not previously exposed to ancestral spike protein by vaccination or infection. Here, we addressed this question by infecting mice with recent SARS-CoV-2 variants and then challenging them with a highly pathogenic mouse-adapted virus closely related to the ancestral Wuhan-1 strain (SARS2-N501YMA30). We found that challenged mice were protected from death and substantial weight loss, even though they generally had low or no neutralizing antibody response to SARS2-N501YMA30 at the time of reinfection. T cell depletion from the previously infected mice did not diminish infection against clinical disease, although it did result in delayed kinetics of virus clearance in the nasal turbinate and in some cases, in the lungs. Levels of tissue resident memory T cells were significantly elevated in the nasal turbinate of previously infected mice compared to mice that had no previous exposure to SARS-CoV-2. However, this phenotype was not seen in lung tissues. Together, these results indicate that the immune response to newly circulating variants afforded protection against re-infection with the ancestral virus that was at least in part T cell based.

The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation. This includes (i) pig von Willebrand Factor (vWF) interaction with human platelets, which can induce abnormal clotting responses, heightening the risk of graft failure, (ii) the inefficiency of pig thrombomodulin in activating human protein C, which emphasizes the species-specific variations that aggravate coagulation challenges, and (iii) the development of thrombotic microangiopathy in the pig grafts and the occurrence of systemic consumptive coagulopathy in the recipients. Indeed, coagulation dysregulation largely results from differences in endothelial cell response and incompatibilities between pig and human coagulation-anticoagulation pathways. These barriers can be resolved by modifications to pig vWF and the expression of human thrombomodulin and endothelial protein C receptors in pig cells, serving as strategic interventions to align the coagulation systems of the two species more closely. These coagulation challenges have clinical implications in how they affect graft survival and patient outcome. Genetic engineering of the organ-source pig and the administration of various drugs have assisted in correcting this coagulation dysregulation. Hence, comprehending and controlling coagulation dysregulation is crucial for progress in xenotransplantation as a viable option for treating patients with terminal kidney disease., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Groundnut (Arachis hypogaea L.) is one of the most important climate-resilient oil crops in sub-Saharan Africa. There is a significant yield gap for groundnut in Africa because of poor soil fertility, low agricultural inputs, biotic and abiotic stresses. Cross-country evaluations of promising breeding lines can facilitate the varietal development process. The objective of our study was to characterize popular test environments in Uganda (Serere and Nakabango) and Malawi (Chitala and Chitedze) and identify genotypes with stable superior yields for potential future release. Phenotypic data were generated for 192 breeding lines for yield-related traits, while genotypic data were generated using skim-sequencing. We observed significant variation (p < 0.001; p < 0.01; p < 0.05) across genotypes for all yield-related traits: days to flowering (DTF), pod yield (PY), shelling percentage, 100-seed weight, and grain yield within and across locations. Nakabango, Chitedze, and Serere were clustered as one mega-environment with the top five most stable genotypes being ICGV-SM 01709, ICGV-SM 15575, ICGV-SM 90704, ICGV-SM 15576, and ICGV-SM 03710, all Virginia types. Population structure analysis clustered the genotypes in three distinct groups based on market classes. Eight and four marker-trait associations (MTAs) were recorded for DTF and PY, respectively. One of the MTAs for DTF was co-localized within an uncharacterized protein on chromosome 13, while another one (TRv2Chr.11&#95;3476885) was consistent across the two countries. Future studies will need to further characterize the candidate genes as well as confirm the stability of superior genotypes across seasons before recommending them for release., (© 2024 The Author(s). The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Background: Respiratory viral infections are common and are a major cause of morbidity and mortality. We evaluated the impact of universal masking implemented during the coronavirus disease 2019 (COVID-19) pandemic on other healthcare-associated respiratory viral infections (HA-RIs) in an academic medical center., Methods: A retrospective cohort study was performed among all inpatients aged ≥18 years admitted between 1 May 2019 and 30 June 2022. Universal masking was implemented in May 2020 at our hospital and state-level mask mandates had been lifted by May 2021. We evaluated and compared the HA-RI rates, adjusted for monthly community-onset viral infections, during the premasking period, universal masking period, and post-community mandate period., Results: We identified 3015 patients (median age, 58 years; 48.0% males) with a positive respiratory viral test within 14 days prior to, or during, their hospitalization; 441 (14.6%) patients had an HA-RI. Rhinovirus/enterovirus (51.0%), parainfluenza virus (14.3%), coronaviruses (229E, OC43, HKU1, and NL63; 13.2%) and influenza (10.0%) were the predominant HA-RI viruses detected. The monthly HA-RI rate decreased 34.9% (95% confidence interval, 8.8%-51.8%) after the implementation of universal masking (0.71 premasking period vs 0.19 universal masking period vs 0.35 infections per 1000 patient-days in the post-community mandate period) while accounting for a drop in the community-onset respiratory viral infections using a structural time-series model analysis ( P < .001), with no significant change in HA-RI rates with the relaxation of community masking mandate., Conclusions: Implementation of universal masking at our hospital was associated with a significantly reduced incidence of HA-RIs., Competing Interests: Potential conflicts of interest. All authors: No potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dunai, Hetherington, Boardman, Clark, Sharma, Subramaniam, Tharmaratnam, Needham, Williams, Huang, Wood, Collie, Fower, Fox, Ellul, Held, Egbe, Griffiths, Solomon, Breen, Kipar, Cavanagh, Irani, Vincent, Stewart, Taams, Menon and Michael.)

Purpose: Bladder cancer is 1 of the most costly cancers, however there is limited research on medical care costs by type of urinary diversion. The objective of our study was to compare medical care costs of the 2 most common urinary diversions in the year following radical cystectomy., Methods: The Bladder Cancer Quality of Life Study included patients diagnosed with bladder cancer who underwent radical cystectomy and received an ileal conduit (IC, n = 821) or neobladder (NB, n = 181) in 3 integrated health systems. Medical care costs per patient per quarter were estimated for the year following cystectomy. Multivariable generalized linear models with a gamma distribution and log link were used to estimate mean monthly medical care costs (2022 USD$), adjusted for patient demographic and clinical characteristics., Results: In multivariable analysis, mean monthly costs per quarter were not significantly different between IC and NB patients in the 12 months following cystectomy. Overall, mean monthly costs in IC and NB patients were highest during the first quarter and decreased thereafter. Factors associated with higher mean costs across all quarters included presence of any complications and advanced tumor stage at cystectomy (all P < 0.001)., Conclusion: Our study addresses an important knowledge gap by quantifying the medical costs of bladder cancer patients by urinary diversion type and comparing costs of different treatment approaches. Studies that assess patient-reported outcomes and out-of-pocket costs, by urinary diversion type, are warranted to inform treatment decision-making and cost conversations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A two-component low-molecular-weight gelator (LMWG) formed from a modified amino acid and an aldehyde was formulated with active pharmaceutical ingredients (APIs). Basic APIs (propranolol, atropine) can be mixed with the LMWG prior to gel assembly while acidic APIs (naproxen, rosuvastatin) inhibit assembly by disrupting the LMWG imine bond and were loaded by diffusion after gel assembly. For diffusion-loaded gels, the API in the liquid-like phase was rapidly released, with the remainder, interacting with gel fibres, retained in the gel. Rosuvastatin release was particularly low with Saturation Transfer Difference (STD) NMR indicating interactions between the aromatic ring and the self-assembled gel network. Propranolol also interacted with the gel via its aromatic unit, and its release led to gel erosion. Using agarose as a polymer gelator additive reinforced the gel, restricting erosion. In contrast, atropine was readily released over a period of hours - it is primarily in the liquid-like phase with STD NMR indicating no interactions with the gel network. The atropine-loaded gel retained its thixotropic properties. Overall, APIs must be carefully chosen to optimise formulation/release. Of the APIs investigated, atropine has most potential for further development. Atropine has applications in treating myopia, and our results suggest potential ophthalmic applications of supramolecular gels., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: Endovascular therapy (EVT) has revolutionized the treatment of acute stroke, but large vessel recanalization does not always result in tissue-level reperfusion. Cerebral blood flow (CBF) is not routinely monitored during EVT. We aimed to leverage diffuse correlation spectroscopy (DCS), a novel transcranial optical imaging technique, to assess the relationship between microvascular CBF and post-EVT outcomes., Methods: Frontal lobe CBF was monitored by DCS in 40 patients undergoing EVT. Baseline CBF deficit was calculated as the percentage of CBF impairment on pre-EVT CT perfusion. Microvascular reperfusion was calculated as the percentage increase in DCS-derived CBF that occurred with recanalization. The adequacy of reperfusion was defined by persistent CBF deficit, calculated as: baseline CBF deficit - microvascular reperfusion. A good functional outcome was defined as 90-day modified Rankin Scale score ≤2., Results: Thirty-six of 40 patients achieved successful recanalization, in whom microvascular reperfusion in itself was not associated with infarct volume or functional outcome. However, patients with good functional outcomes had a smaller persistent CBF deficit (median 1% (IQR -11%-16%)) than patients with poor outcomes (median 28% (IQR 2-50%)) (p=0.02). Smaller persistent CBF deficit was also associated with smaller infarct volume (p=0.004). Multivariate models confirmed that persistent CBF deficit was independently associated with infarct volume and functional outcome., Conclusions: CBF augmentation alone does not predict post-EVT outcomes, but when microvascular reperfusion closely matches the baseline CBF deficit, patients experience favorable clinical and radiographic outcomes. By recognizing inadequate reperfusion, bedside CBF monitoring may provide opportunities to personalize post-EVT care aimed at CBF optimization., Competing Interests: Competing interests: AGY has three patents potentially relevant to this work that do not currently generate income (United States patents 10,342,488; 10,827,976; and 6,076,010). JAD and AGY have one additional patent potentially relevant to this work that does not currently generate income (United States patent 8,082,015); CGF received an investigator initiated grant from OpenWater, not directly related to this study., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

White matter (WM) brain age, a neuroimaging-derived biomarker indicating WM microstructural changes, helps predict dementia and neurodegenerative disorder risks. The cumulative effect of chronic stress on WM brain aging remains unknown. In this study, we assessed cumulative stress using a multi-system composite allostatic load (AL) index based on inflammatory, anthropometric, respiratory, lipidemia, and glucose metabolism measures, and investigated its association with WM brain age gap (BAG), computed from diffusion tensor imaging data using a machine learning model, among 22 951 European ancestries aged 40 to 69 (51.40% women) from UK Biobank. Linear regression, Mendelian randomization, along with inverse probability weighting and doubly robust methods, were used to evaluate the impact of AL on WM BAG adjusting for age, sex, socioeconomic, and lifestyle behaviors. We found increasing one AL score unit significantly increased WM BAG by 0.29 years in association analysis and by 0.33 years in Mendelian analysis. The age- and sex-stratified analysis showed consistent results among participants 45-54 and 55-64 years old, with no significant sex difference. This study demonstrated that higher chronic stress was significantly associated with accelerated brain aging, highlighting the importance of stress management in reducing dementia and neurodegenerative disease risks., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The wetsalts tiger beetle, Cicindelidia haemorrhagica (LeConte) (Coleoptera: Cicindelidae), is found in several active thermal hot spring areas in Yellowstone National Park (YNP) where substrate surface temperatures can exceed 50 °C. However, relationships between surface temperatures and the time adults spend on them remain poorly understood. Therefore, we characterized thermal profiles of Dragon Spring and Rabbit Creek, 2 thermally active research sites containing C. haemorrhagica in YNP, to quantify the time adults spend at different surface temperatures. We took 58 thermal video recordings of adults over 6 total days of observation ranging from 10 to 15 min for each adult. Thermal video analysis results indicated a positive relationship between the total time adult beetles spent on surface temperatures from Dragon Spring and Rabbit Creek as temperatures increased from 20 °C. Once surface temperatures exceeded 40 °C, the total time spent at those surface temperatures declined. Adults were recorded on substrates exceeding 50 °C at one of the 2 research locations. Rabbit Creek had substantially more instances of adults present with surface temperatures exceeding 40 °C, including one individual on a surface temperature of 61.5 °C. There were 3 instances of beetles spending more than 4 min at a particular surface temperature, all within the preferred range of 30-40 °C. Our thermal profile results and previous behavioral observations suggest that adults may be resistant to the heat produced from the thermal waters that influence the substrate temperatures but may not be subject to high surface temperatures as previously reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

High-level disinfection and sterilization are complex processes, requiring initial and ongoing training of frontline staff. 1 A key component of appropriate disinfection and sterilization is point-of-use pre-cleaning performed by front-line staff. Our facility implemented an annual hospital-wide education and competency program for staff that perform pre-cleaning of reusable medical devices., Competing Interests: Declaration of Competing Interest No relevant conflict of interest. Dr. Warren reports personal fees from Mölnlycke Health Care AB, outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in non-structural protein 3. Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the glycine-isoleucine-phenylalanine motif. While we previously demonstrated the importance of the glycine residue for CoV replication and pathogenesis, the impact of the isoleucine and phenylalanine residues remains unknown. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that correlated with attenuated replication and pathogenesis of F-A mutant MERS-CoV and SARS-CoV-2 viruses in cell culture and mice. In contrast, the I-A mutant proteins had normal enzyme activity and enhanced ADP-ribose binding. Despite only demonstrating increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 viruses were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication., Importance: The conserved coronavirus (CoV) macrodomain (Mac1) counters the activity of host ADP-ribosyltransferases and is critical for CoV replication and pathogenesis. As such, Mac1 is a potential therapeutic target for CoV-induced disease. However, we lack a basic knowledge of how several residues in its ADP-ribose binding pocket contribute to its biochemical and virological functions. We engineered mutations into two highly conserved residues in the ADP-ribose binding pocket of Mac1, both as recombinant proteins and viruses for Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Interestingly, a Mac1 isoleucine-to-alanine mutant protein had enhanced ADP-ribose binding which proved to be detrimental for virus replication, indicating that this isoleucine controls ADP-ribose binding and is beneficial for virus replication and pathogenesis. These results provide unique insight into how macrodomains control ADP-ribose binding and will be critical for the development of novel inhibitors targeting Mac1 that could be used to treat CoV-induced disease.

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7-3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227-0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235-0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141-0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524-2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted.

Post-mortem studies have shown that patients dying from severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection frequently have pathological changes in their CNS, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized coronavirus disease 2019 (COVID-19) patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on MRI is inconclusive. We therefore used ultra-high field (7 T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7 T QSM data from 30 patients, scanned 93-548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients' QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-dimer and platelet levels), functional recovery (modified Rankin scale), depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7). In COVID-19 survivors, the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. This study contributes to understanding the long-term effects of COVID-19 and recovery. Using non-invasive ultra-high field 7 T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Cirrhosis affects all structures of the kidney, in particular the tubules, which are responsible for secretion of protein-bound metabolites and electrolyte/water homeostasis. Yet, prevailing assessments of kidney function focus solely on glomerular filtration rate (GFR), which may incompletely reflect these processes. We sought to characterize markers of tubular function, injury, and viability in patients with and without cirrhosis., Methods: We recruited outpatients undergoing liver transplantation evaluation for a collection of plasma and 24-hour urine, matching by GFR to control participants without cirrhosis. We measured urinary kidney injury molecule-1, a marker of proximal tubular injury, as well as epidermal growth factor (EGF), a marker of viability necessary for tubular epithelial cell proliferation after injury. We also estimated secretory clearance by measuring several highly secreted endogenous metabolites in urine and plasma., Results: We recruited 39 patients with cirrhosis (mean model for end-stage liver disease 17 ± 4, Child-Pugh 8 ± 2, estimated glomerular filtration rate 66 ± 20 mL/min/1.73 m 2 ) and 58 GFR-matched controls without cirrhosis (estimated glomerular filtration rate 66 ± 21 mL/min/1.73 m 2 ). Urinary kidney injury molecule-1 was 4.4-fold higher than controls (95% confidence interval: 2.9-6.5), and EGF averaged 7.41-fold higher than controls (95% confidence interval: 2.15-25.53). We found that of 8 solutes, 5 had significantly greater kidney clearance in cirrhosis (1.3-2.1-fold higher): indoxyl sulfate, p-cresol sulfate, pyridoxic acid, tiglylglycine, and xanthosine., Discussion: Cirrhosis was characterized by molecular signs of tubular injury in stable outpatients without acute kidney injury, accompanied by largely preserved tubular secretory clearance and greater signs of tubular viability. Within the limitations of the study, this suggests a phenotype of chronic ischemic injury but with initial preservation of tubular function in cirrhosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from genome-wide association studies with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease, schizophrenia (SCZ), major depressive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and autism spectrum disorder. Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian randomization to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" ( p = 0.0001), "Presynaptic nicotinic acetylcholine receptors" ( p = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" ( p = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" ( p = 0.0001), and "Acetylcholine binding and downstream events" pathways ( p = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and SCZ, suggesting possible pathophysiologic commonalities. In this study, we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcomes. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiological overlap with other neuropsychiatric diseases.

The federally endangered sister species, Eucyclogobius newberryi (northern tidewater goby) and E. kristinae (southern tidewater goby) comprise the California endemic genus Eucyclogobius, which historically occurred in all coastal California counties. Isolated lagoons that only intermittently connect to the sea are their primary habitat. Reproduction occurs during lagoon closure, minimizing marine dispersal and generating the most genetically subdivided vertebrate genus on the California coast. We present a new genome assembly for E. newberryi using HiFi long reads and Hi-C chromatin-proximity sequencing. The 980Mb E. newberryi reference genome has an N50 of 34Mb with 22 well-described scaffolds comprising 88% of the genome and a complete BUSCO score of 96.7%. This genome will facilitate studies addressing selection, drift, and metapopulation genetics in subdivided populations, as well as the persistence of the critically endangered E. kristinae, where reintroduction will be an essential element of conservation actions for recovery. It also provides tools critical to the recovery of the genetically distinct management units in the northern tidewater goby, as well as broader ecological and evolutionary studies of gobies, the most speciose family of fishes in the world., (© The American Genetic Association. 2024.)

Background: Open Hartmann's procedure has traditionally been the procedure of choice to treat complicated diverticulitis. We analyzed the ACS-NSQIP database to compare outcomes in patients who underwent emergent laparoscopic Hartmann's procedure (LHP) to those who had an open Hartmann's procedure (OHP)., Study Design: Data analyzed from 2015 to 2019 using ICD-10 codes. Patients were matched on several important covariates using a propensity score matching method (PSM). Patients were matched in a 4:1 ratio of controls to cases based on the propensity score., Results: We identified 5026, of which 456 had LHP and 4570 had OHP. PSM analysis yielded 369 LHP and 1476 OHP patients. LHP had lower rates of superficial surgical site infection (SSSI) compared to OHP (2.44% vs. 5.89%, p = 0.007). LHP had similar post-operative outcomes compared to OHP, including 30-day mortality (5.15% vs. 2.98%, p = 0.060), organ space surgical site infection (OSSSI) (14.36% vs. 12.60%, p = 0.161), wound disruption (1.36% vs. 2.44%, p = 0.349), median LOS (8 vs. 9 days, p = 0.252), readmission within 30 days (11.92% vs. 8.67%, p = 0.176), rate of reoperation (6.0 vs. 6.5%, p = 0.897), and discharge to home (76% vs. 77%, p = 0.992). LHP had longer operative times compared to OHP (median 129 vs. 118 min, p < 0.0001)., Conclusion: The LHP is associated with lower rates of SSSI. However, it is not associated with lower rates of mortality, OSSSI, readmissions and reoperations within 30 days. Surgical times are longer in LHP. More studies are needed to determine whether LHP offers advantages in the long-term, particularly in rates of incisional hernia and colostomy closure., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)