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[CD8.sup.+] T cells destroy insulin-producing pancreatic [beta] cells in type 1 diabetes through HLA class I- restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24* healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease., Introduction Multiple lines of evidence show that type 1 diabetes (T1D) develops due to [CD8.sup.+] T cell-mediated destruction of insulin-producing pancreatic [beta] cells. Human leukocyte antigen class I (HLA-I), the [...]

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disruption of lung uptake of fatty acids, yet enhancement of uptake of arachidonic acid, a precursor of proinflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multiorgan metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue., Introduction Cystic fibrosis (CF) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) anion channel (1-4). The clinical phenotype is [...]

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similarly to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through combined effects on histone methylation and RNA [N.sup.6]- methyladenosine. The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high-L-2HG kidney cancers demonstrate reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high-L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors., Introduction Oncometabolites are small molecules that aberrantly accumulate within tumor cells. These small molecules can have either tumor-promoting or -suppressive effects, indicating that their impact on tumor biology is highly [...]

Context.--Because of restrictions as a result of the COVID-19 pandemic, medical educators rapidly transitioned to an online curriculum for pathology resident education. The benefits and challenges of the shift to online learning, as well as strategies to maximize learning, are yet to be fully elucidated. Objective.--To assess learner perception and satisfaction with the move to online learning. Understanding the benefits of online learning will allow future curricular changes to most effectively incorporate online learning. Understanding the common challenges will allow our current learning strategies to rapidly adapt and ideally mitigate these challenges as online learning is incorporated into medical education. Design.--This was a survey-based study distributed by email to pathology residents nationwide in Canada in anatomic pathology, general pathology, neuropathology, and hematopathology. Thirty residents participated, from anatomic pathology (n = 23; 76%), from general pathology (n = 5; 16%), and 1 participant each from hematopathology and neuropathology. Results.--All participants indicated that their program had transitioned to online learning at least in part. The majority of participants (n = 16; 53%) did not feel their pathology education was negatively affected by the transition to online learning; however, a significant minority (n = 6; 20%) felt their education had been negatively affected. Convenience and less intimidation were rated as benefits of online learning. Negative effects included technical issues and decreased engagement; we identified a number of strategies used by programs and pathology residents to mitigate these negative effects. Conclusions.--Our survey points to a need to use adaptations and best-practice recommendations to maximize the benefits of online learning moving forward. doi: 10.5858/arpa.2022-0208-EP, The rapidity with which online learning has been adopted and integrated into medical residency is a unique and unprecedented aspect of the COVID-19 pandemic. (1) The pandemic left programs swiftly [...]

Operation Button Up was the program to correct deficiencies in the design of the Minuteman launch facility Personnel Access System (PAS). The liquid propellant Atlas, Titan I and II systems [...]

The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic-ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI., Author(s): Ryan L. Hoiland [sup.1] [sup.2] [sup.3] [sup.4] [sup.5], Chiara Robba [sup.6] [sup.7], David K. Menon [sup.8], Giuseppe Citerio [sup.9], Claudio Sandroni [sup.10], Mypinder S. Sekhon [sup.1] [sup.4] [sup.5] [sup.11] [...]

Abstract.--A survey of Fundulus parvipinnis parvipinnis from coastal waters of Central and Southern California for Monogenea revealed two new species of Gyrodactylus Nordmann, 1832, Fundulotrema prolongis (Hargis, 1955) (both Gyrodactylidae), [...]

The Mesnard Quartzite of Paleoproterozoic age is believed to represent among the first preserved cratonal continental rocks in the Lake Superior region, was deposited above Archean basement in the Marquette structural trough and is estimated to contain more than 99% sandstone (now quartzite) beds. The Mesnard Quartzite is interpreted to have been deposited largely by tidal currents. Evidence of tidal current deposition includes lack of wave-influenced structures such as hummocky cross-beds, and presence of strongly unidirectional paleocurrents from cross-beds, mud-drapes on cross-bed foresets, evidence of current reversal including herringbone cross-bedding and sigmoidal cross-bedding. Sandstone bedding types include homogeneous or structureless beds, parallel-laminated beds, cross-beds, and symmetric ripple marks. Unidirectional paleocurrents from cross-beds are largely subparallel to the axis of the Marquette structural trough, leading to the interpretation that the trough was subsiding during deposition. Cross-bed set thickness and symmetric ripple marks both support the interpretation of shallow water marine deposition, likely only a few meters. Although the Mesnard Quartzite is on the order of 110 m thick, there is no evidence of internal sequence boundaries or flooding surfaces, and low accommodation during deposition is inferred. The climate during deposition is interpreted to be humid, and tropical to subtropical based on the quartz arenite composition. Deposition likely occurred in a failed rift basin or in an intracratonic extensional basin. Key words: tidal, sequence stratigraphy, sedimentology, depositional environments, Paleoproterozoic, Lake Superior, Introduction The Mesnard Quartzite is the basal sandstone interval in the Paleoproterozoic Chocolay Group of the Marquette Range Supergroup in northern Michigan (Cannon and Gair 1970; Cannon 1973). The Chocolay [...]

I was impressed with the C-130 from the first time I saw it. There was something about its appearance and deportment that conveyed a sense of strength, self-confidence, and grace. [...]

Background Fluid overload associates with poor outcomes after neonatal cardiac surgery, but consensus does not exist for the most clinically relevant method of measuring fluid balance (FB). While weight change-based FB (FB-W) is standard in neonatal intensive care units, weighing infants after cardiac surgery may be challenging. We aimed to identify characteristics associated with obtaining weights and to understand how intake/output-based FB (FB-IO) and FB-W compare in the early postoperative period in this population. Methods Observational retrospective study of 2235 neonates undergoing cardiac surgery from 22 hospitals comprising the NEonatal and Pediatric Heart and Renal Outcomes Network (NEPHRON) database. Results Forty-five percent (n = 998) of patients were weighed on postoperative day (POD) 2, varying from 2 to 98% among centers. Odds of being weighed were lower for STAT categories 4 and 5 (OR 0.72; 95% CI 0.53-0.98), cardiopulmonary bypass (0.59; 0.42-0.83), delayed sternal closure (0.27; 0.19-0.38), prophylactic peritoneal dialysis use (0.58; 0.34-0.99), and mechanical ventilation on POD 2 (0.23; 0.16-0.33). Correlation between FB-IO and FB-W was weak for every POD 1-6 and within the entire cohort (correlation coefficient 0.15; 95% CI 0.12-0.17). FB-W measured higher than paired FB-IO (mean bias 12.5%; 95% CI 11.6-13.4%) with wide 95% limits of agreement (- 15.4-40.4%). Conclusions Weighing neonates early after cardiac surgery is uncommon, with significant practice variation among centers. Patients with increased severity of illness are less likely to be weighed. FB-W and FB-IO have weak correlation, and further study is needed to determine which cumulative FB metric most associates with adverse outcomes. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information., Author(s): Tara M. Neumayr [sup.1] , Jeffrey A. Alten [sup.2] , David K. Bailly [sup.3] , Priya N. Bhat [sup.4] , Katie L. Brandewie [sup.2] , J. Wesley Diddle [sup.5] [...]

Author(s): Emanuele Rezoagli [sup.1] [sup.2], Matteo Petrosino [sup.3], Paola Rebora [sup.3], David K. Menon [sup.4], Stefania Mondello [sup.5], D. James Cooper [sup.6] [sup.7], Andrew I. R. Maas [sup.8], Eveline J. [...]

Background We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC). Methods Patient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test. Results From September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19. Conclusions Despite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in < 1% of COVID-19-positive patients and in less than < 0.1% of all transplant patients within the IROC cohort. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Charles Jr. Varnell [sup.1] [sup.2] , Lyndsay A. Harshman [sup.3] , Chunyan Liu [sup.1] , Laurie Smith [sup.1] , Samhar Al-Akash [sup.4] , Gina-Marie Barletta [sup.5] , Paul Brakeman [...]

Learning health systems (LHS) align science, informatics, incentives, and culture for continuous improvement and innovation. In this organizational system, best practices are seamlessly embedded in the delivery process, and new knowledge is captured as an integral byproduct of the care delivery experience aimed to transform clinical practice and improve patient outcomes. The objective of this review is to describe how building better health systems that integrate clinical care, improvement, and research as part of an LHS can improve care within pediatric nephrology. This review will provide real-world examples of how this system can be established in a single center and across multiple centers as learning health networks., Author(s): Charles D. Jr Varnell [sup.1] [sup.2] [sup.3] , Peter Margolis [sup.1] [sup.3] , Jens Goebel [sup.4] [sup.5] , David K. Hooper [sup.1] [sup.2] [sup.3] Author Affiliations: (1) grid.24827.3b, 0000 [...]

In late 1950s, designers of intercontinental ballistic missile launch facilities had to juggle hardening the facilities against nuclear weapon blast effects while maximizing reaction time and rapid force expenditure without [...]

Purpose The effect of high arterial oxygen levels and supplemental oxygen administration on outcomes in traumatic brain injury (TBI) is debated, and data from large cohorts of TBI patients are limited. We investigated whether exposure to high blood oxygen levels and high oxygen supplementation is independently associated with outcomes in TBI patients admitted to the intensive care unit (ICU) and undergoing mechanical ventilation. Methods This is a secondary analysis of two multicenter, prospective, observational, cohort studies performed in Europe and Australia. In TBI patients admitted to ICU, we describe the arterial partial pressure of oxygen (PaO.sub.2) and the oxygen inspired fraction (FiO.sub.2). We explored the association between high PaO.sub.2 and FiO.sub.2 levels within the first week with clinical outcomes. Furthermore, in the CENTER-TBI cohort, we investigate whether PaO.sub.2 and FiO.sub.2 levels may have differential relationships with outcome in the presence of varying levels of brain injury severity (as quantified by levels of glial fibrillary acidic protein (GFAP) in blood samples obtained within 24 h of injury). Results The analysis included 1084 patients (11,577 measurements) in the CENTER-TBI cohort, of whom 55% had an unfavorable outcome, and 26% died at a 6-month follow-up. Median PaO.sub.2 ranged from 93 to 166 mmHg. Exposure to higher PaO.sub.2 and FiO.sub.2 in the first seven days after ICU admission was independently associated with a higher mortality rate. A trend of a higher mortality rate was partially confirmed in the OzENTER-TBI cohort (n = 159). GFAP was independently associated with mortality and functional neurologic outcome at follow-up, but it did not modulate the outcome impact of high PaO.sub.2 and FiO.sub.2 levels, which remained independently associated with 6-month mortality. Conclusions In two large prospective multicenter cohorts of critically ill patients with TBI, levels of PaO.sub.2 and FiO.sub.2 varied widely across centers during the first seven days after ICU admission. Exposure to high arterial blood oxygen or high supplemental oxygen was independently associated with 6-month mortality in the CENTER-TBI cohort, and the severity of brain injury did not modulate this relationship. Due to the limited sample size, the findings were not wholly validated in the external OzENTER-TBI cohort. We cannot exclude the possibility that the worse outcomes associated with higher PaO.sub.2 were due to use of higher FiO.sub.2 in patients with more severe injury or physiological compromise. Further, these findings may not apply to patients in whom FiO.sub.2 and PaO.sub.2 are titrated to brain tissue oxygen monitoring (PbtO.sub.2) levels. However, at minimum, these findings support the need for caution with oxygen therapy in TBI, particularly since titration of supplemental oxygen is immediately applicable at the bedside., Author(s): Emanuele Rezoagli [sup.1] [sup.2], Matteo Petrosino [sup.3], Paola Rebora [sup.3], David K. Menon [sup.4], Stefania Mondello [sup.5], D. James Cooper [sup.6] [sup.7], Andrew I. R. Maas [sup.8], Eveline J. [...]

To the Editor: Long-term sequelae of SARS-CoV-2 infection, referred to as postacute sequelae of COVID-19 (PASC), involve many organs, including the cardiovascular, pulmonary, gastrointestinal, and neurological systems. The basis of [...]

The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete [Cl.sup.-] into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/[Cl.sup.-] channels in their basolateral membrane. Disrupting barttin/[Cl.sup.-] channel function impaired liquid absorption, and overexpressing barttin/[Cl.sup.-] channels increased absorption. Together, apical CFTR and basolateral barttin/[Cl.sup.-] channels provide an electrically conductive pathway for [Cl.sup.-] flow through ionocytes, and the transepithelial voltage generated by apical [Na.sup.+] channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption., Introduction Pulmonary ionocytes are a rare cell type accounting for approximately 1% of airway epithelial cells. Ionocytes have attracted attention because, although rare, in airway epithelia they contain about half [...]

The U.S. Army John F. Kennedy Special Warfare Center and School, Master Sgt. David K. Thuma Noncommissioned Officer Academy (NCOA) provides professional military education for active duty and select Reserve [...]

Young environmental activists often say that older generations are creating a future climate disaster. They argue that current generations are obligated to take decisive action against global warming now to [...]

Along with the 1947 decision to locate the first U. S. long-range ballistic missile test range at Cape Canaveral, Florida, came the need to accurately determine reentry vehicle impact location [...]

Background In patients with severe brain injury, withdrawal of life-sustaining measures (WLSM) is common in intensive care units (ICU). WLSM constitutes a dilemma: instituting WLSM too early could result in death despite the possibility of an acceptable functional outcome, whereas delaying WLSM could unnecessarily burden patients, families, clinicians, and hospital resources. We aimed to describe the occurrence and timing of WLSM, and factors associated with timing of WLSM in European ICUs in patients with traumatic brain injury (TBI). Methods The CENTER-TBI Study is a prospective multi-center cohort study. For the current study, patients with traumatic brain injury (TBI) admitted to the ICU and aged 16 or older were included. Occurrence and timing of WLSM were documented. For the analyses, we dichotomized timing of WLSM in early (< 72 h after injury) versus later ([greater than or equal to] 72 h after injury) based on recent guideline recommendations. We assessed factors associated with initiating WLSM early versus later, including geographic region, center, patient, injury, and treatment characteristics with univariable and multivariable (mixed effects) logistic regression. Results A total of 2022 patients aged 16 or older were admitted to the ICU. ICU mortality was 13% (n = 267). Of these, 229 (86%) patients died after WLSM, and were included in the analyses. The occurrence of WLSM varied between regions ranging from 0% in Eastern Europe to 96% in Northern Europe. In 51% of the patients, WLSM was early. Patients in the early WLSM group had a lower maximum therapy intensity level (TIL) score than patients in the later WLSM group (median of 5 versus 10) The strongest independent variables associated with early WLSM were one unreactive pupil (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.3-12.4) or two unreactive pupils (OR 5.8, CI 2.6-13.1) compared to two reactive pupils, and an Injury Severity Score (ISS) if over 41 (OR per point above 41 = 1.1, CI 1.0-1.1). Timing of WLSM was not significantly associated with region or center. Conclusion WLSM occurs early in half of the patients, mostly in patients with severe TBI affecting brainstem reflexes who were severely injured. We found no regional or center influences in timing of WLSM. Whether WLSM is always appropriate or may contribute to a self-fulfilling prophecy requires further research and argues for reluctance to institute WLSM early in case of any doubt on prognosis., Author(s): Ernest van Veen [sup.1] [sup.2], Mathieu van der Jagt [sup.2], Giuseppe Citerio [sup.3] [sup.4], Nino Stocchetti [sup.5] [sup.6], Diederik Gommers [sup.2], Alex Burdorf [sup.1], David K. Menon [sup.7], Andrew [...]

The Sports Revolution: How Texas Changed the Culture of American Athletics. By Frank Andre Guridy. Texas Bookshelf. (Austin: University of Texas Press, 2021. Pp. x, 418. $29.95, ISBN 978-1-4773-2183-6.) I [...]

Although few studies have established significant associations between cancer risk perception and smoking status, the evidence remains inconclusive. Therefore, the current study aimed to examine the association between risk perception for developing cancer and smoking status, controlling for sociodemographic factors. Data from the National Cancer Institute's Health Information National Trends Survey [HINTS 5, Cycle 1 (2017)] were utilized. Multivariable logistic regression analysis examined the association between cancer risk perception and smoking status in a sample of 2,232 adults with no history of cancer, adjusting for age, gender, race/ethnicity, education, marital status, employment and family history of cancer. Overall prevalence for current cigarette smoking was 14.75%. Relative to participants who reported lower perceived risk of developing cancer, those who reported higher perceived risk had significantly greater odds of being a current smoker (OR=2.60; 95% CI: 1.23-5.49) or former smoker (OR=1.69; 95% CI: 1.06-2.69). In a sub-group analysis, higher- and moderate-perceived risk of developing cancer were significantly associated with intention to quit smoking (OR=6.56; 95% CI: 1.93-22.28) and (OR=6.53; 95% CI: 1.78-23.89), respectively. Though an individual's perceived risk of developing cancer might predict intention to quit smoking, it is unlikely to be sufficient for inducing motivation to stop high-risk behaviors including smoking. Therefore, initiation and wider dissemination of proven strategies for both discouraging smoking initiation and sustaining smoking cessation are warranted. Keywords: risk perception, cigarette smoking, cancer, adults, INTRODUCTION Recent epidemiological estimations for the United States indicate that between 2010 and 2030 the number of new cancer cases will increase by approximately 45% (Smith et al., 2009). Critical, [...]

Background Nonadherence to immunosuppression is common among pediatric, adolescent, and young adult kidney transplant recipients and a leading cause of graft loss. Assessing barriers to medication adherence in clinical practice may identify patients at risk for rejection and provide therapeutic targets. Methods Kidney transplant patients and/or their caregivers were assessed for 14 barriers to medication adherence using the barriers assessment tool. We compared rejection rates between patients with at least one reported adherence barrier to those without reported adherence barriers using a Kaplan-Meier estimator and Cox proportional hazard models to adjust for other mediators of acute rejection at 2 years following barriers assessment. Results Ninety-eight patients were assessed for barriers to adherence. Over the 2-year observation period, 22 patients developed biopsy-proven acute rejection (BPAR). Kaplan-Meier estimates show that patients with an identified barrier to adherence were more likely to have BPAR (p = 0.02) than patients without an identified barrier in the 24 months following barriers assessment. The median time to rejection for patients who experienced acute rejection was 175.5 days (IQR 63-276 days) from the time of barriers assessment. An identified barrier to adherence remained the only statistically significant predictor of BPAR with Cox modeling (HR 2.6, p = 0.04), after accounting for age, sex, and race. Conclusions Pediatric and adolescent kidney transplant recipients with identified adherence barriers are at increased risk for acute rejection. Barriers to adherence provide a potentially modifiable therapeutic target that can be assessed in clinic to guide targeted interventions., Author(s): Charles D. Jr Varnell [sup.1] [sup.2] [sup.3] , Kristin L. Rich [sup.3] [sup.4] , Bin Zhang [sup.3] [sup.5] , Adam C. Carle [sup.2] [sup.6] , Ahna L. H. Pai [...]

Background Previous studies in non-critically ill hospitalized pediatric patients have shown that daily serum creatinine monitoring for the development of nephrotoxic medication-associated acute kidney injury decreases both the rate of high nephrotoxic medication exposure and associated acute kidney injury. Attempts to spread this successful screening program have been met with concerns that daily serum creatinine monitoring in critically ill neonates with high-risk nephrotoxic medication exposure would lead to iatrogenic anemia and an increase in blood transfusion requirements. Methods We measured blood transfusion rates while implementing a system of daily serum creatinine monitoring in critically ill neonates at risk for high nephrotoxic medication-associated acute kidney injury. Results There was no correlation between blood transfusion rates and serum creatinine monitoring rates. Conclusions We recommend that critically ill neonates identified as having high-risk nephrotoxic medication exposure undergo daily screening for the development of nephrotoxic medication-associated acute kidney injury., Author(s): Hailey W. Gavigan [sup.1] , Cara L. Slagle [sup.2] , Kelli A. Krallman [sup.1] , Brenda B. Poindexter [sup.2] , David K. Hooper [sup.1] , Stuart L. Goldstein [sup.1] [...]

Kobe Bryant was an extraordinarily gifted athlete who enjoyed a long and remarkable basketball career. Entering the National Basketball Association directly out of Lower Merion High School (PA) in 1996, Bryant played his entire 20-year career with the Los Angeles Lakers. He helped lead the Lakers to five league championships, became the first player in league history to score over 30,000 points and collect 6000 assists, was selected 12 times to the league's All-Defensive Team, was twice the league's scoring champion, and 18 times was chosen as an NBA All-Star. Importantly, in contrast to some athletes who have difficulties in transitioning out of sport, Bryant seemingly had no such problems as he embarked on a highly successful post-athletic career that witnessed his involvement in successful business ventures, important charity work, and a host of meaningful educational and entrepreneurial activities. By all accounts, he had settled into a life that was marked by much satisfaction and a commitment to helping care for the needs of underserved and under privileged communities. This essay not only details the many important initiatives that occupied Bryant's time during a post-athletic career tragically cut short in 2020, but assesses factors involved in his apparently seamless transition from basketball icon deluged with constant media attention and adulation to private citizen intent on doing good works., Author(s): David K. Wiggins [sup.1] Author Affiliations: (1) grid.22448.38, 0000 0004 1936 8032, George Mason University, , 22030, Fairfax, VA, USA 'Kobe was a legend on the court and just [...]

Symptomatic Subjects: Bodies, Medicine, and Causation in the Literature of Late Medieval England. By Julie Orlemanski. Philadelphia: University of Pennsylvania Press, 2019. Pp. x + 333. 4 illustrations. $69.95. Even [...]

Technologies that rely on quantum bits (qubits) require long coherence times and high-fidelity operations.sup.1. Superconducting qubits are one of the leading platforms for achieving these objectives.sup.2,3. However, the coherence of superconducting qubits is affected by the breaking of Cooper pairs of electrons.sup.4-6. The experimentally observed density of the broken Cooper pairs, referred to as quasiparticles, is orders of magnitude higher than the value predicted at equilibrium by the Bardeen-Cooper-Schrieffer theory of superconductivity.sup.7-9. Previous work.sup.10-12 has shown that infrared photons considerably increase the quasiparticle density, yet even in the best-isolated systems, it remains much higher.sup.10 than expected, suggesting that another generation mechanism exists.sup.13. Here we provide evidence that ionizing radiation from environmental radioactive materials and cosmic rays contributes to this observed difference. The effect of ionizing radiation leads to an elevated quasiparticle density, which we predict would ultimately limit the coherence times of superconducting qubits of the type measured here to milliseconds. We further demonstrate that radiation shielding reduces the flux of ionizing radiation and thereby increases the energy-relaxation time. Albeit a small effect for today's qubits, reducing or mitigating the impact of ionizing radiation will be critical for realizing fault-tolerant superconducting quantum computers. Ionizing radiation from environmental radioactivity and cosmic rays increases the density of broken Cooper pairs in superconducting qubits, reducing their coherence times, but can be partially mitigated by lead shielding., Author(s): Antti P. Vepsäläinen [sup.1] , Amir H. Karamlou [sup.1] , John L. Orrell [sup.2] , Akshunna S. Dogra [sup.1] [sup.4] , Ben Loer [sup.2] , Francisca Vasconcelos [sup.1] , [...]

The great majority of globally circulating pathogens go undetected, undermining patient care and hindering outbreak preparedness and response. To enable routine surveillance and comprehensive diagnostic applications, there is a need for detection technologies that can scale to test many samples.sup.1-3 while simultaneously testing for many pathogens.sup.4-6. Here, we develop Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (CARMEN), a platform for scalable, multiplexed pathogen detection. In the CARMEN platform, nanolitre droplets containing CRISPR-based nucleic acid detection reagents.sup.7 self-organize in a microwell array.sup.8 to pair with droplets of amplified samples, testing each sample against each CRISPR RNA (crRNA) in replicate. The combination of CARMEN and Cas13 detection (CARMEN-Cas13) enables robust testing of more than 4,500 crRNA-target pairs on a single array. Using CARMEN-Cas13, we developed a multiplexed assay that simultaneously differentiates all 169 human-associated viruses with at least 10 published genome sequences and rapidly incorporated an additional crRNA to detect the causative agent of the 2020 COVID-19 pandemic. CARMEN-Cas13 further enables comprehensive subtyping of influenza A strains and multiplexed identification of dozens of HIV drug-resistance mutations. The intrinsic multiplexing and throughput capabilities of CARMEN make it practical to scale, as miniaturization decreases reagent cost per test by more than 300-fold. Scalable, highly multiplexed CRISPR-based nucleic acid detection shifts diagnostic and surveillance efforts from targeted testing of high-priority samples to comprehensive testing of large sample sets, greatly benefiting patients and public health.sup.9-11. CRISPR-based nucleic acid detection is used in a platform that can simultaneously detect 169 human-associated viruses in multiple samples, providing scalable, multiplexed pathogen detection aimed at routine surveillance for public health., Author(s): Cheri M. Ackerman [sup.1] [sup.2] , Cameron Myhrvold [sup.1] [sup.3] , Sri Gowtham Thakku [sup.1] [sup.4] , Catherine A. Freije [sup.1] [sup.5] , Hayden C. Metsky [sup.1] [sup.6] , [...]

Tumor-associated peptide-human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface-expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents., Introduction The ability to selectively target tumor-specific antigens holds great promise for the development of specific cancer treatments, but their identification remains a key challenge. Peptide fragments presented on the [...]

Ways and Means: Lincoln and His Cabinet and the Financing of the Civil War. By Roger Lowenstein. (New York: Penguin Press, 2022. Pp. [xvi], 432. $30.00, ISBN 978-0-7352-2355-4.) Just days [...]

Author(s): Emanuele Rezoagli [sup.1], Matteo Petrosino [sup.2], David K. Menon [sup.3], Giuseppe Citerio [sup.1] [sup.4] Author Affiliations: (1) grid.7563.7, 0000 0001 2174 1754, School of Medicine and Surgery, University of [...]

Background Focal segmental glomerulosclerosis (FSGS) in pediatric patients is typically difficult to treat and will progress to end-stage renal disease (ESRD) in about 10% of cases. Following kidney transplantation, FSGS can recur in up to 56% of renal allografts-with a near 100% recurrence in subsequent transplants. Methods Four different pediatric centers across the USA and the UK employed a protocol using LDL-apheresis (LDL-A) and pulse solumedrol to treat recurrent FSGS after transplantation in seven patients. All the patients included in this series demonstrated immediate, or early, recurrence of FSGS, which clinically presented as nephrotic-range proteinuria within hours to days after implantation of the kidney. Results All patients experienced reductions in urinary protein to creatinine ratios resulting in partial or complete remission. All patients demonstrated improvements in their estimated GFRs at their most recent follow-up since LDL-A discontinuation. Conclusions This case series describes the successful treatment, across four different pediatric centers, of seven pediatric patients with recurrent post-transplant FSGS using the Liposorber® LA-15 in combination with pulse solumedrol., Author(s): Lokesh Shah [sup.1] , David K. Hooper [sup.2] , Daryl Okamura [sup.3] , Dean Wallace [sup.4] , Divya Moodalbail [sup.5] , Caroline Gluck [sup.5] , Ania Koziell [sup.6] , [...]

Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS- CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS- CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-[beta] treatment failed to effectively inhibit virus replication; increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs; and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-[alpha][beta] or combination therapy may need to be used cautiously to treat viral infections in clinical settings., Introduction Emerging and reemerging highly pathogenic zoonotic viruses are a significant threat to global public health (1-3). This threat is illustrated by the appearance of several highly pathogenic respiratory viruses [...]

Author(s): Mauro Oddo [sup.1], Paul Vespa [sup.2] [sup.3], David K. Menon [sup.4] [sup.5] Author Affiliations: (1) 0000 0001 0423 4662, grid.8515.9, Department of Intensive Care Medicine, Critical Care Clinical Research [...]