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Chemical studies usually consist of measurements made on large ensembles of molecules with data representing average values for the population. It has been shown that individual molecules of a given enzyme have different properties. Large-scale averaging has in the past masked these differences. Alkaline phosphatase has been used as a model to study this enzyme heterogeneity. The catalytic rates of the individual molecules have been found to differ by over 10-fold, and the activation energy of catalysis by more than two-fold. Differences in properties indicate that differences in structure must exist between the molecules. For alkaline phosphatase, the structural differences have been suggested to be differences in glycosylation, differences due to partial proteolysis, and due to some molecules containing mixtures of active and inactive subunits. The determination of the distribution of activities of populations of this enzyme within a sample has also been shown to be a useful tool in diagnostics. This review discusses the advent of single-molecule enzymology and summarizes its use in the study of alkaline phosphatase using capillary electrophoresis, microscopic well assays, and single-molecule tracking.

Several theoretical traditions posit that individual skills (or human capital) have become stronger predictors of life outcomes over time. To date, however, significant limitations have hindered a confident empirical assessment of this important idea. Using six nationally representative datasets, the authors find surprisingly little support for the notion that measurable skills are becoming more important over time. Instead, the results reveal a durable relationship between measurable skills and socioeconomic outcomes despite periods of significant societal change.

Although the ant genus Temnothorax is broadly distributed, extremely diverse, and contains multitudes of undescribed species, discovering new Temnothorax species in the eastern United States is rare due to the high concentration of taxonomic effort on this region. Here, we recognize and describe a new species that has consistently been misidentified in museum collections as Temnothorax ambiguus, a common inhabitant of acorn shells and leaf litter. Unlike T. ambiguus, T. caryaluteus sp. nov. nests primarily in arboreal microhabitats, especially within dead branches on live Carya and Quercus trees. We compare the morphology of T. caryaluteus sp. nov. against the congeners with similar appearance T. ambiguus and T. curvispinosus, and delineate diagnostic characters for T. caryaluteus sp. nov. Moreover, we provide an updated key to the Temnothorax species of the eastern United States.

We present waveguide cavity measurements used to evaluate several thin materials for use in radomes. In addition to the data on the materials, we show how these measurements can be performed with common laboratory equipment and simple calculations. We sought an approach that allowed candidate materials to be readily evaluated to deal with formerly selected materials becoming unavailable or cost-prohibitive. We used lengths of standard waveguide (WR650 and WR137 here) with readily manufactured irises and a vector network analyzer (Keysight N5225B here). To select the iris size and determine the limits of the simplifications in the equations used, we employed a full-wave 3D electromagnetic simulator (CST Microwave Studio). The equations required to calculate the dielectric properties of samples and their contribution to the equivalent system noise temperature from unloaded and loaded resonant frequencies and Q factors are shown. While these formulations can be found elsewhere, we did not find these assembled as conveniently in other studies in the literature. We also show that orienting the sample down the length of the cavity allows for higher-order modes to be fully utilized. We did not find this straightforward adaptation of the common cross-guide orientation in other works. Overall, the results allowed us to recommend three fabrics for use at the frequencies tested (1.7 and 5.6 GHz). The complete process is outlined to assist others in performing these measurements themselves.

Abstract Background Patients with advanced critical illness often receive more intensive treatment than they would choose for themselves, which contributes to high health care costs near the end of life. The purpose of this study was to determine whether a family support intervention delivered by the interprofessional ICU team decreases hospitalization costs and hospital readmissions among critically ill patients at high risk of death or severe functional impairment. Results We examined index hospitalization costs as well as post-discharge utilization of acute care hospitals, rehabilitation and skilled nursing facilities, and hospice services for the PARTNER trial, a multicenter, stepped-wedge, cluster randomized trial of an interprofessional ICU family support intervention. We determined patients’ total controllable and direct variable costs using a computerized accounting system. We determined post-discharge resource utilization (as defined above) by structured telephone interview at 6-month follow-up. We used multiple variable regression modelling to compare outcomes between groups. Compared to usual care, the PARTNER intervention resulted in significantly lower total controllable costs (geometric mean: $26,529 vs $32,105; log-linear coefficient: − 0.30; 95% CI − 0.49, − 0.11) and direct variable costs ($3912 vs $6034; − 0.33; 95% CI − 0.56, − 0.10). A larger cost reduction occurred for decedents ($20,304 vs. $26,610; − 0.66; 95% CI − 1.01, − 0.31) compared to survivors ($31,353 vs. $35,015; − 0.15; 95% CI − 0.35,0.05). A lower proportion in the intervention arm were re-admitted to an acute care hospital (34.9% vs 45.1%; 0.66; 95% CI 0.56, 0.77) or skilled nursing facility (25.3% vs 31.6%; 0.63; 95% CI 0.47, 0.84). Conclusions A family support intervention delivered by the interprofessional ICU team significantly decreased index hospitalization costs and readmission rates over 6-month follow-up. Trial registration Trial registration number: NCT01844492

Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition that is characterized by unresolved fatigue, post-exertion symptom exacerbation (PESE), cognitive dysfunction, orthostatic intolerance, and other symptoms. ME/CFS lacks established clinical biomarkers and requires further elucidation of disease mechanisms. A growing number of studies demonstrate signs of hematological and cardiovascular pathology in ME/CFS cohorts, including hyperactivated platelets, endothelial dysfunction, vascular dysregulation, and anomalous clotting processes. To build on these findings, and to identify potential biomarkers that can be related to pathophysiology, we measured differences in protein expression in platelet-poor plasma (PPP) samples from 15 ME/CFS study participants and 10 controls not previously infected with SARS-CoV-2, using DIA LC-MS/MS. We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated. Proteins related to clotting processes – thrombospondin-1 (important in platelet activation), platelet factor 4, and protein S – were differentially expressed in the ME/CFS group, suggestive of a dysregulated coagulation system and abnormal endothelial function. Complement machinery was also significantly downregulated, including C9 which forms part of the membrane attack complex. Additionally, we identified a significant upregulation of lactotransferrin, protein S100-A9, and an immunoglobulin variant. The findings from this experiment further implicate the coagulation and immune system in ME/CFS, and bring to attention the pathology of or imposed on the endothelium. This study highlights potential systems and proteins that require further research with regards to their contribution to the pathogenesis of ME/CFS, symptom manifestation, and biomarker potential, and also gives insight into the hematological and cardiovascular risk for ME/CFS individuals affected by diabetes mellitus. Graphical abstract

Culture-dependent and culture-independent microbiological methods are two approaches used to study microbial community composition. Culture-dependent methods have been the standard method used for many years but have limited utility with unculturable microorganisms. Culture-independent methods, including molecular techniques, enable direct analysis of microbial DNA without requiring cultivation. Both culture-dependent and -independent methods have roles in advancing our understanding of microbiology, and a combination of these approaches often yields a comprehensive depiction of the microbial diversity within a dynamic system. Bacterial activity reaction tests (BARTs) are a common culture-dependent test used to identify bacteria growing in industrial water samples. In this study, next-generation sequencing (NGS) was used to identify the taxa growing in BARTs and compared with the BART reaction patterns. Additionally, several water samples were analyzed by both BART and NGS analysis to determine whether the bacteria found in the water were also present in the BARTs. The results showed overall agreement between NGS and BARTs, though, in some cases, the most abundant taxa found in the water samples differed from those in the BARTs. This highlights the need for further study into the microbial community dynamics of culture-dependent tests to determine whether they are representative of the original sample.

Background: Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. Objective: We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. Results: In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. Limitations: A retrospective study. Conclusions: Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.

This article presents the position of the Society of Metabolic Health Practitioners (SMHP) regarding therapeutic carbohydrate reduction (TCR) nutrition interventions for type 1 diabetes mellitus (T1DM). A modified Delphi methodology was used to arrive at a consensus consisting of several focus groups, multiple rounds, and an anonymous survey. The field of endocrinology has seen many new advances for the treatment of T1DM including hybrid closed-loop insulin delivery systems and continuous glucose monitors for better glycaemic control, monoclonal antibodies to delay the onset of disease and increased access to paediatric endocrinologists, among many other noteworthy achievements. Despite these advancements, standard of care approaches to T1DM result in higher than acceptable morbidity and mortality, with a high prevalence of microvascular and macrovascular complications. Insulin resistance in type 1 diabetes is an independent risk factor for adverse outcomes even in well controlled type 1 diabetes. In 2021, only 21% of adults with T1DM in the United States achieved the American Diabetes Association’s (ADA’s) target haemoglobin A1C goal of 7.0%, while data in the paediatric and adolescent population have demonstrated worse glycaemic control. Supported by observational and interventional evidence, the SMHP advocates for the reevaluation of the prevailing nutritional therapy for T1DM with more broad consideration for TCR. The SMHP recommends open access and clinical support for TCR nutrition interventions for individuals with T1DM of all ages and calls upon the medical community to help foster more attention and research on TCR for T1DM.

Abstract Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12–1.64, P = 2×10−03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18–1.88, P = 9×10−04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07–4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Based on statistical analyses applied to official data from the Digital Atlas of Disasters in Brazil over the last 25 years, we evidenced a consistent intensification in the annual occurrence of natural disasters in the state of Pará, located in the eastern Brazilian Amazon. The quantitative comparison between the averages of the most intense period of disasters (2017 to 2023) and the earlier years (1999 to 2016) revealed a remarkable percentage increase of 473%. Approximately 81% of the state’s municipalities were affected, as indicated by disaster mapping. A clear seasonal pattern was observed, with Hydrological disasters (Inundations, Flash floods, and Heavy rainfall) peaking between February and May, while Climatological disasters (Droughts and Forest fires) were most frequent from August to October. The catastrophic impacts on people and the economy were documented, showing a significant rise in the number of homeless individuals and those directly affected, alongside considerable material damage and economic losses for both the public and private sectors. Furthermore, we conducted a comprehensive composite analysis on the tropical ocean–atmosphere dynamic structure that elucidated the various triggering mechanisms of disasters arising from Inundations, Droughts, and Forest fires (on seasonal scale), and Flash floods and Heavy rainfall (on sub-monthly scale) in Pará. The detailed characterization of disasters on a municipal scale is relevant in terms of the scientific contribution applied to the strategic decision-making, planning, and implementation of public policies aimed at early risk management (rather than post-disaster response), which is critical for safeguarding human well-being and strengthening the resilience of Amazonian communities vulnerable to climate change.

IntroductionRecent evidence has demonstrated that the microbiome is a driver of the underlying pathophysiological mechanisms of respiratory disease. Studies have indicated that bacterial metabolites produced in the gut and lung can impact lung inflammation and immune cell activity, affecting disease pathology. Despite asthma being a disease with marked sex differences, experimental work linking microbiomes and asthma has not considered the sex variable.MethodsTo test the hypothesis that the lung and gut microbial composition impacts allergic lung inflammation in a sex-specific manner, we evaluated lung and gut microbiome alterations in a mouse model of allergic inflammation and assessed their association with lung function and inflammation phenotypes. For this, we exposed male and female adult C57BL/6J mice intranasally to 25 µg of a house dust mite extract mix (HDM) daily, or phosphate-buffered saline (PBS) as control, for 5 weeks (n = 4–6/group). DNA from fecal pellets collected before and after the 5-week treatment, and from lung tissue collected at endpoint, was extracted using the ZymoBIOMICS®-96 MagBead DNA Kit and analyzed to determine the 16S microbiome via Targeted Metagenomic Sequencing.ResultsThe HDM treatment induced a sex-specific allergic inflammation phenotype with significantly higher neutrophilia, lymphocytosis, inflammatory gene expression, and histopathological changes in females than males following exposure to HDM, but higher airway hyperresponsiveness (AHR) in males than females. In addition, sex-specific lung gene expression and associated pathways were identified HDM mix after challenge. These changes corresponded to sex-specific alterations in the gut microbiome, where the Firmicutes to Bacteroidetes ratio (F:B) was significantly reduced in fecal samples from only male mice after HDM challenge, and alpha diversity was increased in males, but decreased in females, after 5-weeks of HDM treatment.DiscussionOverall, our findings indicate that intranasal allergen challenge triggers sex-specific changes in both gut and lung microbiomes, and induces sex-specific lung inflammation, AHR, and lung inflammatory gene expression pathways, suggesting a contribution of the lung-gut axis in allergic airway disease.

IntroductionSystemic lupus erythematosus is a multi-faceted autoimmune disorder of complex etiology. Pre-pubertal onset of pediatric systemic lupus erythematosus (pSLE) is uncommon and should raise suspicion for a genetic driver of disease. Autosomal recessive p40phox deficiency is a rare immunologic disorder characterized by defective but not abolished NADPH oxidase activity with residual production of reactive oxygen species (ROS) by phagocytic cells.Case presentationWe report the case of a now 18-year-old female with pSLE onset at 7 years of age. She presented with recurrent fever and malar rash. Aspects of her immune dysregulation over time have included typical pSLE features including production of autoantibodies, hematologic manifestations, and hypocomplementemia, as well as chronic suppurative skin lesions and recurrent infections. Genetic analysis revealed biallelic pathogenic variants in NCF4 resulting in p40phox deficiency. Comprehensive NADPH oxidase activity studies confirmed significantly decreased production of reactive oxygen species, confirming the cellular phenotype seen in p40phox deficient patients.ConclusionsHere, we present a patient with pSLE harboring biallelic variants in NCF4. Our patient represents a unique clinical presentation of severe onset autoimmunity in the setting of a rare inborn error of immunity affecting NADPH oxidase activity. This case underscores the need to consider genetic causes of pSLE in cases of pre-pubertal onset and atypical disease.

Abstract Silicon and Germanium oxide (SiOx and GeOx) nanostructures are promising materials for energy storage applications due to their potentially high energy density, large lithiation capacity (~10X carbon), low toxicity, low cost, and high thermal stability. This work reports a unique approach to achieving controlled synthesis of SiOx and GeOx nanostructures via photonic curing. Unlike conventional methods like rapid thermal annealing, quenching during pulsed photonic curing occurs rapidly (sub‐millisecond), allowing the trapping of metastable states to form unique phases and nanostructures. We explored the possible underlying mechanism of photonic curing by incorporating laws of photophysics, photochemistry, and simulated temperature profile of thin film. The results show that photonic curing of spray coated 0.1 M molarity Si and Ge Acetyl Acetate precursor solution, at total fluence 80 J cm−2 can yield GeOx and SiOx nanostructures. The as‐synthesized nanostructures are ester functionalized due to photoinitiated chemical reactions in thin film during photonic curing. Results also showed that nanoparticle size changes from ~48 nm to ~11 nm if overall fluence is increased by increasing the number of pulses. These results are an important contribution towards large‐scale synthesis of the Ge and Si oxide nanostructured materials which is necessary for next‐generation energy storage devices.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

BackgroundImmune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.MethodsPatients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry.ResultsA total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and –if required–second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4–1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.ConclusionInterestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Abstract Concerns about competition between pollinators are predicated on the assumption of floral resource limitation. Floral resource limitation, however, is a complex phenomenon involving the interplay of resource production by plants, resource demand by pollinators, and exogenous factors—like weather conditions—that constrain both plants and pollinators. In this study, we examined nectar limitation during the mass flowering of rosaceous fruit trees in early spring. Our study was set in the same region as a previous study that found severe nectar limitation in summer grasslands. We used this seasonal contrast to evaluate two alternative hypotheses concerning the seasonal dynamics of floral resource limitation: either (H1) rates of resource production and consumption are matched through seasonal time to maintain a consistent degree of resource limitation, or (H2) a mismatch of high floral resource production and low pollinator activity in early spring creates a period of relaxed resource limitation that intensifies later in the year. We found generally much lower depletion in our spring study compared to the near 100% depletion found in the summer study, but depletion rates varied markedly through diel time and across sampling days, with afternoon depletion rates sometimes exceeding 80%. In some cases, there were also pronounced differences in depletion rates across simultaneously sampled floral species, indicating different degrees of nectar exploitation. These findings generally support the seasonal mismatch hypothesis (H2) but underscore the complex contingency of nectar depletion. The challenge of future work is to discern how the fluctuation of resource limitation across diel, inter‐diel, and seasonal time scales translates into population‐level outcomes for pollinators.

Abstract Background Transfer of severely injured patients to trauma centers, either directly from the field or after evaluation at non-trauma centers, reduces preventable morbidity and mortality. Failure to transfer these patients appropriately (i.e., under-triage) remains common, and occurs in part because physicians at non-trauma centers make diagnostic errors when evaluating the severity of patients’ injuries. We developed Night Shift, a theory-based adventure video game, to recalibrate physician heuristics (intuitive judgments) in trauma triage and established its efficacy in the laboratory. We plan a type 1 hybrid effectiveness-implementation trial to determine whether the game changes physician triage decisions in real-life and hypothesize that it will reduce the proportion of patients under-triaged. Methods We will recruit 800 physicians who work in the emergency departments (EDs) of non-trauma centers in the US and will randomize them to the game (intervention) or to usual education and training (control). We will ask those in the intervention group to play Night Shift for 2 h within 2 weeks of enrollment and again for 20 min at quarterly intervals. Those in the control group will receive only usual education (i.e., nothing supplemental). We will then assess physicians’ triage practices for older, severely injured adults in the 1-year following enrollment, using Medicare claims, and will compare under-triage (primary outcome), 30-day mortality and re-admissions, functional independence, and over-triage between the two groups. We will evaluate contextual factors influencing reach, adoption, implementation, and maintenance with interviews of a subset of trial participants (n = 20) and of other key decision makers (e.g., patients, first responders, administrators [n = 100]). Discussion The results of the trial will inform future efforts to improve the implementation of clinical practice guidelines in trauma triage and will provide deeper understanding of effective strategies to reduce diagnostic errors during time-sensitive decision making. Trial registration ClinicalTrials.gov; NCT06063434 . Registered 26 September 2023.

Abstract Background Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of $$\text{ER}\alpha$$ ER α . These findings demonstrated that TrkB activation in the presence of $$\text{ER}\alpha$$ ER α comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of $$\text{ER}\alpha$$ ER α -dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period. Methods In this study, we used a unilateral hypoxic ischemic (HI) mouse model. $$\text{ER}\alpha$$ ER α +/+ or $$\text{ER}\alpha$$ ER α −/− mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry. Results Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking $$\text{ER}\alpha$$ ER α . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$\text{ER}\alpha$$ ER α -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$\text{ER}\alpha$$ ER α . When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of $$\text{ER}\alpha$$ ER α significantly reduced overall HI-associated mortality in both sexes. Conclusions These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are $$\text{ER}\alpha$$ ER α -associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner.

Abstract Infected wounds pose a major mortality risk in animals. Injuries are common in the ant Megaponera analis, which raids pugnacious prey. Here we show that M. analis can determine when wounds are infected and treat them accordingly. By applying a variety of antimicrobial compounds and proteins secreted from the metapleural gland to infected wounds, workers reduce the mortality of infected individuals by 90%. Chemical analyses showed that wound infection is associated with specific changes in the cuticular hydrocarbon profile, thereby likely allowing nestmates to diagnose the infection state of injured individuals and apply the appropriate antimicrobial treatment. This study demonstrates that M. analis ant societies use antimicrobial compounds produced in the metapleural glands to treat infected wounds and reduce nestmate mortality.

Abstract Background Vaccinations are a vital part of routine childhood and adolescent preventive care. We sought to identify current oncology provider practices, barriers, and attitudes towards vaccinating childhood and adolescent cancer patients and survivors. Methods We conducted a one-time online survey distributed from March-October 2018 to pediatric oncologists at nine institutions across the United States (N = 111, 68.8% participation rate). The survey included 32 items about vaccination practices, barriers to post-treatment vaccination, availability of vaccinations in oncology clinic, familiarity with vaccine guidelines, and attitudes toward vaccination responsibilities. Descriptive statistics were calculated in STATA 14.2. Results Participants were 54.0% female and 82.9% white, with 12.6% specializing in Bone Marrow Transplants. Influenza was the most commonly resumed vaccine after treatment (7030%). About 50%-60% were familiar with vaccine guidelines for immunocompromised patients. More than half (62.7%) recommended that patients restart most immunizations 6 months to 1 year after chemotherapy. Common barriers to providers recommending vaccinations included not having previous vaccine records for patients (56.8%) or lacking time to ascertain which vaccines are needed (32.4%). Of participants, 66.7% stated that vaccination should be managed by primary care providers, but with guidance from oncologists. Conclusions Many pediatric oncologists report being unfamiliar with vaccine guidelines for immunocompromised patients and almost all report barriers in supporting patients regarding vaccines after cancer treatment. Our findings show that further research and interventions are needed to help bridge oncology care and primary care regarding immunizations after treatment.

Abstract Background Bladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy. Methods The CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication. Discussion The CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC. Trial registration ClinicalTrials.gov, NCT03933826. Registered on May 1, 2019.

Abstract External factors such as exposure to a chemical, drug, or toxicant (CDT), or conversely, the lack of certain chemicals can cause many diseases. The ability to identify such causal CDTs based on changes in the gene expression profile is extremely important in many studies. Furthermore, the ability to correctly infer CDTs that can revert the gene expression changes induced by a given disease phenotype is a crucial step in drug repurposing. We present an approach for Predicting Upstream REgulators (PURE) designed to tackle this challenge. PURE can correctly infer a CDT from the measured expression changes in a given phenotype, as well as correctly identify drugs that could revert disease-induced gene expression changes. We compared the proposed approach with four classical approaches as well as with the causal analysis used in Ingenuity Pathway Analysis (IPA) on 16 data sets (1 rat, 5 mouse, and 10 human data sets), involving 8 chemicals or drugs. We assessed the results based on the ability to correctly identify the CDT as indicated by its rank. We also considered the number of false positives, i.e. CDTs other than the correct CDT that were reported to be significant by each method. The proposed approach performed best in 11 out of the 16 experiments, reporting the correct CDT at the very top 7 times. IPA was the second best, reporting the correct CDT at the top 5 times, but was unable to identify the correct CDT at all in 5 out of the 16 experiments. The validation results showed that our approach, PURE, outperformed some of the most popular methods in the field. PURE could effectively infer the true CDTs responsible for the observed gene expression changes and could also be useful in drug repurposing applications.

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS -WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease ( n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315–648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [ RET-PCM1 and FGFR2-POC1B ( N = 1 each)]; and one with a druggable EGFR ( EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR -altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

The exchange of small molecules between the cell and the environment happens through transporter proteins. Besides nutrients and native metabolic products, xenobiotic molecules are also transported, however it is not well understood which transporters are involved. In this study, by combining exo-metabolome screening in yeast with transporter characterization in Xenopus oocytes, we mapped the activity of 30 yeast transporters toward six small non-toxic substrates. Firstly, using LC–MS, we determined 385 compounds from a chemical library that were imported and exported by S. cerevisiae. Of the 385 compounds transported by yeast, we selected six compounds (viz. sn-glycero-3-phosphocholine, 2,5-furandicarboxylic acid, 2-methylpyrazine, cefadroxil, acrylic acid, 2-benzoxazolol) for characterization against 30 S. cerevisiae xenobiotic transport proteins expressed in Xenopus oocytes. The compounds were selected to represent a diverse set of chemicals with a broad interest in applied microbiology. Twenty transporters showed activity toward one or more of the compounds. The tested transporter proteins were mostly promiscuous in equilibrative transport (i.e., facilitated diffusion). The compounds 2,5-furandicarboxylic acid, 2-methylpyrazine, cefadroxil, and sn-glycero-3-phosphocholine were transported equilibratively by transporters that could transport up to three of the compounds. In contrast, the compounds acrylic acid and 2-benzoxazolol, were strictly transported by dedicated transporters. The prevalence of promiscuous equilibrative transporters of non-native substrates has significant implications for strain development in biotechnology and offers an explanation as to why transporter engineering has been a challenge in metabolic engineering. The method described here can be generally applied to study the transport of other small non-toxic molecules. The yeast transporter library is available at AddGene (ID 79999).

Abstract Aromatic compounds are used in pharmaceutical, food, textile and other industries. Increased demand has sparked interest in exploring biotechnological approaches for their sustainable production as an alternative to chemical synthesis from petrochemicals or plant extraction. These aromatic products may be toxic to microorganisms, which complicates their production in cell factories. In this study, we analysed the toxicity of multiple aromatic compounds in common production hosts. Next, we screened a subset of toxic aromatics, namely 2‐phenylethanol, 4‐tyrosol, benzyl alcohol, berberine and vanillin, against transporter deletion libraries in Escherichia coli and Saccharomyces cerevisiae. We identified multiple transporter deletions that modulate the tolerance of the cells towards these compounds. Lastly, we engineered transporters responsible for 2‐phenylethanol tolerance in yeast and showed improved 2‐phenylethanol bioconversion from L‐phenylalanine, with deletions of YIA6, PTR2 or MCH4 genes improving titre by 8–12% and specific yield by 38–57%. Our findings provide insights into transporters as targets for improving the production of aromatic compounds in microbial cell factories.

Abstract Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1 −/− ;Apc −/− organoids was reduced relative to Apc −/− organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.

Abstract Background Microbial dysbiosis has emerged as an important element in the development and progression of various cancers, including breast cancer. However, the microbial composition of the breast from healthy individuals, even relative to risk of developing breast cancer, remains unclear. Here, we performed a comprehensive analysis of the microbiota of the normal breast tissue, which was analyzed in relation to the microbial composition of the tumor and adjacent normal tissue. Methods The study cohorts included 403 cancer-free women (who donated normal breast tissue cores) and 76 breast cancer patients (who donated tumor and/or adjacent normal tissue samples). Microbiome profiling was obtained by sequencing the nine hypervariable regions of the 16S rRNA gene (V1V2, V2V3, V3V4, V4V5, V5V7, and V7V9). Transcriptome analysis was also performed on 190 normal breast tissue samples. Breast cancer risk score was assessed using the Tyrer-Cuzick risk model. Results The V1V2 amplicon sequencing resulted more suitable for the analysis of the normal breast microbiome and identified Lactobacillaceae (Firmicutes phylum), Acetobacterraceae, and Xanthomonadaceae (both Proteobacteria phylum) as the most abundant families in the normal breast. However, Ralstonia (Proteobacteria phylum) was more abundant in both breast tumors and histologically normal tissues adjacent to malignant tumors. We also conducted a correlation analysis between the microbiome and known breast cancer risk factors. Abundances of the bacterial taxa Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp. were associated with age (p

Abstract The discovery and development of novel treatments that harness the patient’s immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th–December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

Abstract We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)−6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible is thus highly desirable. We used a strategy in which a yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine to determine those transporters whose absence made it more resistant; we also recognised the structural similarity of the fluorescent dye safranin O (also known as safranin T) to clozapine, allowing it to be used as a surrogate marker. Strains lacking the mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance to clozapine. MDL1 overexpression also conferred extra sensitivity to clozapine and admitted a massive increase in the cellular and mitochondrial uptake of safranin O, as determined using flow cytometry and microscopically. Yeast lacking mitochondria showed no such unusual accumulation. Mitochondrial MDL1 is thus the main means of accumulation of clozapine in S. cerevisiae. The closest human homologue of S. cerevisiae MDL1 is ABCB10.

Ecological traits have flourished in insect-based studies, resulting in a substantial and growing list of measurable traits. One trait that will likely become more attractive as data quality and curation improve is the diel patterns of insect activities. Diel patterns in ants can help better understand vital ecological processes such as competition and invasion biology. Because diel activity has the potential to be an informative trait in ants, we assessed the diel designations of foraging ants across the literature to quantify and assess the variation and sampling extent of this particular trait. We collected diel designations from 104 peer-reviewed scientific articles and quantified these data across important and documented ecological traits. We found that a disproportionate amount of solitary foraging ants were primarily diurnal foragers relative to ants that cooperatively forage. Our data show that diel patterns in foraging vary widely within and across ant genera. Importantly, we highlight the undersampling of this crucial ecological trait, which currently limits its utility. Our efforts highlight the importance of assessing an ecologically important trait’s landscape of reported data.

Abstract The successes of introduced populations in novel habitats often provide powerful examples of evolution and adaptation. In the 1950s, opossum shrimp (Mysis diluviana) individuals from Clearwater Lake in Minnesota, USA were transported and introduced to Twin Lakes in Colorado, USA by fisheries managers to supplement food sources for trout. Mysis were subsequently introduced from Twin Lakes into numerous lakes throughout Colorado. Because managers kept detailed records of the timing of the introductions, we had the opportunity to test for evolutionary divergence within a known time interval. Here, we used reduced representation genomic data to investigate patterns of genetic diversity, test for genetic divergence between populations, and for evidence of adaptive evolution within the introduced populations in Colorado. We found very low levels of genetic diversity across all populations, with evidence for some genetic divergence between the Minnesota source population and the introduced populations in Colorado. There was little differentiation among the Colorado populations, consistent with the known provenance of a single founding population, with the exception of the population from Gross Reservoir, Colorado. Demographic modeling suggests that at least one undocumented introduction from an unknown source population hybridized with the population in Gross Reservoir. Despite the overall low genetic diversity we observed, FST outlier and environmental association analyses identified multiple loci exhibiting signatures of selection and adaptive variation related to elevation and lake depth. The success of introduced species is thought to be limited by genetic variation, but our results imply that populations with limited genetic variation can become established in a wide range of novel environments. From an applied perspective, the observed patterns of divergence between populations suggest that genetic analysis can be a useful forensic tool to determine likely sources of invasive species.

Abstract Purpose/Objectives Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. Materials/Methods Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine‐based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan–Meier method and compared between groups via the log‐rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. Results 121 patients were included with a median age of 62 years (37–86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving 60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19‐9 (p

This consensus conference report summarizes discussions on sleep apnea care and management. Our goal is to simplify the journey to optimize success for individuals at risk of obstructive sleep apnea and to facilitate diagnostics, monitoring and communication among the entire healthcare team including patients, primary care physicians, sleep specialists, sleep dentists and other key providers. The statement identifies five key problems or unmet needs and contemplates four potential future directions.

Immune checkpoint inhibitors (ICIs) have revolutionized the field of anti-cancer therapy over the last decade; they provide durable clinical responses against tumors by inhibiting immune checkpoint proteins that canonically regulate the T cell-mediated immune response. Despite their success in many primary tumors and soft tissue metastases, ICIs function poorly in patients with bone metastases, and these patients do not have the same survival benefit as patients with the same primary tumor type (e.g., non-small cell lung cancer [NSCLC], urothelial, renal cell carcinoma [RCC], etc.) that has not metastasized to the bone. Additionally, immune-related adverse events including rheumatologic and musculoskeletal toxicities, bone loss, and increased fracture risk develop after treatment with ICIs. There are few preclinical studies that investigate the interplay of the immune system in bone metastases; however, the current literature suggests a role for CD8+ T cells and myeloid cell subsets in bone homeostasis. As such, this review focuses on findings from the clinical and pre-clinical studies that have investigated immune checkpoint blockade in the bone metastatic setting and highlights the need for more comprehensive investigations into the relationship between immune cell subsets, ICIs, and the bone-tumor microenvironment.

Immune-related adverse events (irAEs) are side effects of immune checkpoint inhibitor therapy (ICI). While common irAEs have been well characterized, there are more limited data on rare immune related adverse events (RirAEs) due to low incidence. Lack of characterization of these entities has led to difficulties in accurate diagnosis and management. Here, we conducted a multi-institution analysis of all patients with stage III/IV melanoma who developed RirAEs after being treated with ICIs (anti-PD-1/L1, anti-CTLA-4, and combination PD-1/CTLA-4 blockade) at three institutions (Vanderbilt University Medical Center, Massachusetts General Hospital, and Melanoma Institute of Australia). RirAEs were defined as those occurring in approximately

The occurrence of defects in solar cells is intrinsically related to a reduction in the efficiency and reliability of these devices. Therefore, monitoring techniques, such as lock-in thermography, electroluminescence and the I-V characteristic curve are adopted in order to evaluate the integrity of the solar cells. In the present work, a novel experimental procedure for the lock-in thermography of solar cells is proposed, aiming to improve the detection capability of the assay. Conventional techniques use pulse width modulation to operate the cell at a fixed point on the I-V curve. Instead, we propose a methodology based on a sinusoidal electric current excitation in order to extend the range of operational points that are close to the maximum power point as the cell operates in the field. Some traditional image processing techniques (principal component analysis, the fast Fourier transform and the four-step phase-shifting method) have been used to analyze the thermal images captured by an infrared camera during steady-state operation mode of the solar cells using both sinusoidal electric current signal and standard pulse width modulation procedures. Comparison between the results of both procedures found that this novel approach provides smoother and clearer delimitation of the defects. Furthermore, the contrast of the phase images was found to exhibit significant changes between the defective and non-defective regions for different modulation frequencies and types of defects. From the achieved results, it was possible to obtain a satisfactory characterization of the existing defects.

Abstract Large language models (LLM) such as ChatGPT have gained public and scientific attention. The aim of this study is to evaluate ChatGPT as a support tool for breast tumor board decisions making. We inserted into ChatGPT-3.5 clinical information of ten consecutive patients presented in a breast tumor board in our institution. We asked the chatbot to recommend management. The results generated by ChatGPT were compared to the final recommendations of the tumor board. They were also graded independently by two senior radiologists. Grading scores were between 1–5 (1 = completely disagree, 5 = completely agree), and in three different categories: summarization, recommendation, and explanation. The mean age was 49.4, 8/10 (80%) of patients had invasive ductal carcinoma, one patient (1/10, 10%) had a ductal carcinoma in-situ and one patient (1/10, 10%) had a phyllodes tumor with atypia. In seven out of ten cases (70%), ChatGPT’s recommendations were similar to the tumor board’s decisions. Mean scores while grading the chatbot’s summarization, recommendation and explanation by the first reviewer were 3.7, 4.3, and 4.6 respectively. Mean values for the second reviewer were 4.3, 4.0, and 4.3, respectively. In this proof-of-concept study, we present initial results on the use of an LLM as a decision support tool in a breast tumor board. Given the significant advancements, it is warranted for clinicians to be familiar with the potential benefits and harms of the technology.

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.

Abstract Introduction COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. Methods Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. Results Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 – 1.39; targeted therapy OR 1.89, 95% CI 0.64 – 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 – 2.35). Conclusions Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.

Abstract Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.