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Despite the high prevalence and economic burden of chronic kidney disease (CKD) in the United States, federal funding for kidney-related research, prevention, and education activities under the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) remains substantially lower compared to other chronic diseases. More federal support is needed to promote critical research that will expand knowledge of kidney health and disease, develop new and effective therapies, and reduce health disparities. In 2021, the National Kidney Foundation (NKF) convened 2 Research Roundtables (preclinical and clinical research), comprising nephrology leaders from prominent US academic institutions and the pharmaceutical industry, key bodies with expertise in research, and including individuals with CKD and their caregivers and kidney donors. The goal of these roundtables was to identify priorities for preclinical and clinical kidney-related research. The research priorities identified by the Research Roundtables and presented in this position statement outline attainable opportunities for groundbreaking and critically needed innovations that will benefit patients with kidney disease in the next 5-10 years. Research priorities fall within 4 preclinical science themes (expand data science capability, define kidney disease mechanisms and utilize genetic tools to identify new therapeutic targets, develop better models of human disease, and test cell-specific drug delivery systems and utilize gene editing) and 3 clinical science themes (expand number and inclusivity of clinical trials, develop and test interventions to reduce health disparities, and support implementation science). These priorities in kidney-related research, if supported by additional funding by federal agencies, will increase our understanding of the development and progression of kidney disease among diverse populations, attract additional industry investment, and lead to new and more personalized treatments.

This chapter summarizes primary care principles for recognizing psychologically traumatized patients and engaging them in treatment. Psychological trauma is a psychiatric injury that occurs in response to severely stressful events and can become chronic if not treated. Trauma-informed clinicians understand how psychological trauma changes how people feel, think, and behave. Recognizing and engaging a psychologically traumatized patient for diagnosis and treatment is one of the most satisfying clinical experiences in primary care, opening doors for both patient and provider. While posttraumatic stress disorder (PTSD) is a common psychiatric disorder, the condition tends to be under-recognized. PTSD recognition is challenging owing to stigma, the variety of presentations, the non-specific nature, and range of severity of PTSD symptoms, and high co-occurrence with other conditions. Patients can be reluctant to seek care, disclose traumatizing events, or remember events. PTSD is more prevalent in people with addictions, chronic physical health conditions, chronic pain, medically unexplained symptoms, other psychiatric disorders, and occupations such as military and public safety personnel. Fourteen diverse case examples demonstrate some of the many faces of PTSD in adults. Barriers and facilitators to recognizing PTSD in primary care and targeted use of screening tools are discussed.

Kidney disease is an important US public health problem because it affects over 37 million Americans, and Medicare expenditures for patients with chronic kidney disease now alone exceed $130 billion annually. Kidney disease is characterized by strong racial, ethnic, and socioeconomic disparities, and reducing kidney disease incidence will positively impact US health disparities. Due to the aging of the US population and an unabated obesity epidemic, the number of patients receiving treatment for kidney failure is anticipated to increase, which will escalate kidney disease health expenditures. The historical and current investment in kidney-related research via the National Institute of Diabetes and Digestive and Kidney Diseases has severely lagged behind ongoing expenditures for kidney disease care. Increasing research investment will identify, develop, and increase implementation of interventions to slow kidney disease progression, reduce incidence of kidney failure, enhance survival, and improve quality of life. This perspective states the urgent reasons why increasing investment in kidney-related research is important for US public health. The National Kidney Foundation and the American Society of Nephrology are working together to advocate for increased funding for the National Institute of Diabetes and Digestive and Kidney Diseases. The long-term goal is to reduce the burden of kidney disease in the US population and improve the quality of life of patients living with kidney disease.

Dropout is a popular tool employed in training neural networks for learning tasks. In shallow networks, a variety of recent works have provided a theoretical understanding of the regularizing effect of dropout. The case of deeper networks is, up to this point, only partially understood from a theoretical standpoint. This work studies the theory of dropout from a nonparametric viewpoint, which is considered a proxy for the deepest layers of a neural network. Utilizing ideas from the calculus of variations, it is shown that in the nonparametric limit, the simplest version of dropout has no regularizing effect. Quantified covering number bounds are given describing the failure of dropout to regularize, and simple numerical illustrations are also given to explore the effect of dropout during a transition towards nonparametric settings.

BackgroundT-cell lymphomas and leukemias are a class of diseases lacking durable effective therapies, where median survival for patients suffering from relapsed/refractory disease is often measured in months. Translation of B-cell targeting CAR-T therapeutic success to T-cell malignancies comes with significant challenges. Notably, the shared expression of target antigens on malignant T-cells and in the T-cell product itself results in CAR-T activation and fratricide during manufacturing. To overcome the challenges associated with creating CD5-targeting CAR-Ts, we developed a process to simultaneously base edit five target genes, including CD5 and PD1, to produce potency-enhanced allogeneic anti-CD5 CAR T-cells for use as an off-the-shelf treatment for T-cell malignancies.MethodsAnti-CD5 CAR-Ts were produced in a GMP-compatible process using T-cells isolated from healthy human donors. T-cells were modified using base editing technology to simultaneously knock-out five target genes in a single electroporation step. Edited T-cells were transduced with a lentivirus encoding a second-generation anti-CD5 CAR. Knockout frequencies were evaluated by flow cytometry and next-generation sequencing. Anti-CD5 CAR-Ts were then characterized for their specificity in vitro and potency in in vivo xenograft tumor models.ResultsSimultaneous base editing at five genomic loci resulted in anti-CD5 CAR-Ts edited with 94–98% efficiency at each target gene, greatly diminishing the likelihood of GvHD, CAR-T rejection, fratricide, and checkpoint inhibitor activation. In addition, CD5 has an established role as a negative regulator of TCR signaling, and T cells lacking CD5 have enhanced proliferative capacity.1 Anti-CD5 CAR T-cells with or without CD5 KO demonstrated equally potent cytotoxicity and cytokine production in vitro against CD5 expressing tumor lines. However, CD5 KO greatly improved in vivo efficacy of anti-CD5 CAR-Ts in a murine model of T-ALL against established tumor xenografts. Mice previously cleared of tumor underwent a second tumor challenge to assess the persistence of anti-CD5 CAR-T cells and were cleared of tumor a second time, indicating extended persistence of functional anti-CD5 CAR-T cells in vivo.ConclusionsOur approach addresses current technological limitations in developing and applying CAR-Ts that target T-cell malignancies and demonstrates that simultaneous multiplex base editing of up to five targets can create universally compatible, fratricide-resistant, therapeutically active anti-CD5 CAR-Ts. We further demonstrate that CD5 knockout produces CAR-T cells with enhanced potency capable of clearing multiple tumor challenges in vivo. We are progressing this CD5-targeting CAR-T cell product towards potential clinical development for the treatment of T cell malignancies and other CD5+ hematological tumors.ReferenceGuillaume V, Peredo G, Romain R. CD5, an Undercover Regulator of TCR Signaling. Frontiers in Immunology 2018;9:2900.Ethics ApprovalAll animal studies were performed according to the guidelines and approval of the Institutional Animal Care and Use Committee.

This paper discusses the model problem presented in "A model for system uncertainty in reinforcement learning", Systems and Control Letters, 2018, for certain tasks in reinforcement learning. The model provides a framework to deal with situations in which the system dynamics is not known and encodes the available information about the state dynamics as a measure on the space of functions. Such a measure is updated in time, taking into account all the previous measurements of the state variable and extracting new information from them. Here we will mainly focus on the differences between the present model and central algorithms used in reinforcement learning (i.e. value iteration and Thompson sampling).

Before the end of World War Two, many nations had implemented entitlements for veterans, such as disability pensions, health care, and vocational rehabilitation. However, the concept of disability has evolved since then, and some nations have modernized disability compensation. We examined how disability is assessed, how compensation is structured, and modern principles in designing and reforming veteran disability compensation for 11 nations through a survey, interviews with subject matter experts, and a literature review. While there are some similarities in these schemes, substantial differences were found in the components of the schemes and the context in which they operate. This makes best practices difficult to identify and limits the application of certain aspects of program design to other nations. As a result, this chapter presents five key interrelated guiding principles in designing effective compensation systems: adequacy of compensation for losses; program affordability; integration of rehabilitation; simplicity; and comprehensiveness as well as a description of modern concepts of disability. This provided a framework for developing five recommendations that can help guide nations without compensation schemes in their development and to guide reforms among nations with existing schemes.

Quantum dot comb sources integrated with silicon photonic ring-resonator filters and modulators enable the realization of optical sub-components and modules for both inter- and intra-data-center applications. Low-noise, multi-wavelength, single-chip, laser sources, PAM4 modulation and direct detection allow a practical, scalable, architecture for applications beyond 400 Gb/s. Multi-wavelength, single-chip light sources are essential for reducing power dissipation, space and cost, while silicon photonic ring resonators offer high-performance with space and power efficiency.

Objectives/Hypothesis To characterize the frequency and nature of readmissions to free standing pediatric hospitals after otolaryngologic procedures. Study Design Retrospective national database analysis. Methods Using the Pediatric Health Information Systems database, we examined 30-day inpatient readmissions in children less than 18 years old who underwent otolaryngology procedures between January 1, 2009, and December 31, 2011. Univariate and multivariate logistic regression analyses accounting for correlated structure of the data identified factors related to readmission rate. Reasons for readmission and the postoperative day at which readmission occurred were also examined. Results In the 24-month study period, a total of 493,507 procedures were performed, resulting in 11,574 (2.3%) 30-day readmissions. Readmission rates varied significantly based on the type of procedure, patient age, and presence of chronic medical condition(s). Direct surgical complications accounted for 3,432 (29.7%) of all readmissions; and 4,729 (40.9%) of all readmissions occurred following tonsil and adenoid surgery. Conclusion Readmissions after pediatric otolaryngologic surgery are relatively uncommon. These readmission rates vary directly with the type of procedure performed, as well as patient level factors (i.e., patient age, ethnicity, and the presence of other medical comorbidities). These data demonstrate that if readmission rates are to be used as a quality measure in pediatric otolaryngology procedures, complex risk adjustment of patient level variables will be necessary to accurately compare outcomes between different hospitals. Level of Evidence 2c. Laryngoscope, 2015

Purpose – The purchase drivers of merchandise sales rank in professional sport are examined at both a conceptual and an empirical level. The paper aims to discuss these issues. Design/methodology/approach – A database was constructed for all 30 clubs in the National Hockey League based on a conceptual model of relevant variables. Both public and private data sources were accessed, covering an extensive 12-season period (1999-2011), including the 2004-2005 lockout when the season was cancelled. Principal-components analysis was used to reduce the number of variables for regression analysis to distinguish relatedness and to gauge the influence of those variables on merchandise sales rank. Findings – The results reveal that six club-based factors impact merchandise sales rank: Overall Fan Satisfaction, Media Exposure, On-Field Performance, Strength of a Club’s Brand, Local Market Dynamics, and Fan Capacity to Pay. These six categories of purchase drivers form a strong predictive model of merchandise sales rank in the National Hockey League. Research limitations/implications – The resulting model could be extended in future research by adding extra categories to the conceptual framework and by developing alternative or better measures of the variables the authors use. It could also be tested with other sales data as the dependent variable since the study was limited to ranking data on merchandise data for the National Hockey League clubs for each year. Future research could use the actual merchandise dollars for each club in a league to test the model. A further extension would be to model subparts of merchandise (such as jersey sales, impacts of brand changes, etc.). A similar area of future research would be to look at the role of individual athletes as opposed to clubs in driving merchandise sales rank or volume. Practical implications – For managers in professional sport, the results suggest that there are steps that can be taken to improve merchandise sales rank (and, by extension, merchandise sales volume). Practitioners can develop and follow strategies in this regard. Results also suggest that practitioners should put the achievement of high Regional Television Ratings – the strongest influencing variable on merchandise sales rank – as a priority. Social implications – The results confirm that brand is important when attempting to increase merchandise sales rank. Club managers need to be cognizant of their brand and its impact on merchandising in all decisions. Originality/value – The business of professional sport is evolving globally with new sources of revenue, including merchandising increasing in prominence. This research explores the drivers of merchandise sales rank in professional sport and provide direction on key antecedents. The study proposes and tests a conceptual model.

The focus of this short paper has been to use a Raspberry Pi device to perform certain network attacks and exploit vulnerabilities in existing systems. To this end, we developed a new attack tool that can be installed on a Raspberry Pi and allows novice users to perform a Man-in-the-Middle attack and a small-scale Denial-of-Service attack. The first attack has been designed in such a way so that the attacker can gather credentials of legitimate users even when they try to visit websites that are running under SSL/TLS and they have enabled the HSTS protocol. Regarding the second attack, the attacker has the ability to control a set of malicious Raspberry Pi's and intentionally attempt to stop legitimate users from accessing services. The attacker can select a specific target in the network and overload the corresponding device by sending several fake requests. Throughout this work, we discovered that although security protocols have become more effective over the years it is still considerably easy to launch certain attacks with the main aim to breach users' privacy or restrict service to certain users.

This study was conducted to evaluate whether preoperative magnetic resonance imaging (MRI) measurements of the cross-sectional area and length of the semitendinosus tendon correlated with graft diameter. The goal of the study was to identify tendons at risk for requiring graft augmentation. The records of 140 consecutive patients undergoing anterior cruciate ligament (ACL) reconstruction between 2013 and 2016 were examined retrospectively. The study included 39 patients who underwent all-inside ACL reconstruction with a semitendinosus autograft. A single researcher used preoperative MRI scans to measure the cross-sectional area and length of the semitendinosus tendon. Graft cross-sectional area was correlated with semitendinosus tendon cross-sectional area with Pear-son's coefficients of 0.50 (95% confidence interval [CI], 0.21–0.70; P =.0013) and 0.59 (95% CI, 0.34–0.76; P =.0001) when measured under 2× and 4× magnification, respectively. In addition, MRI measurements of semitendinosus tendon length were correlated with both intraoperatively measured tendon length ( r =0.75; 95% CI, 0.40–0.91; P =.0008) and graft diameter ( r =0.43; 95% CI, 0.14–0.66; P =.0058). Average semitendinosus tendon cross-sectional area was 3.10 mm 2 (95% CI, 0.53–5.67; P =.024) greater and semitendinosus tendon length was 14.05 mm (95% CI, 1.25–26.85; P =.035) greater in cases that did not require graft augmentation. Semitendinosus tendons with cross-sectional area of less than 13.2 mm 2 or length of less than 81 mm are most likely to require graft augmentation. In addition, MRI measurements of the length and cross-sectional area of the semitendinosus tendon are significantly correlated with ACL graft diameter and could help to identify patients who may require graft augmentation. [ Orthopedics. 2017; 40(4):e617–e622.]

Objectives/Hypothesis: Recurrent respiratory papillomatosis (RRP) is a benign disease characterized by recurrent lesions in the airway. The prevalence and degree of dysplasia that is present in the natural course of RRP is not well established. Adjuvant therapies, such as cidofovir, have been tried with the goal of decreasing the interval between repeat surgical treatments, the mainstay of therapy. Although, the off-label use of cidofovir to treat RRP has been common, there have been concerns regarding carcinogenic transformation following the use of cidofovir. This study aims to explore the association between increasing degree of papilloma dysplasia and the use of cidofovir in the context of the natural progression of dysplasia in RRP. Study Design: Retrospective case series. Methods: Demographic data and surgical history were obtained through chart reviews for this retrospective case series of 13 patients with RRP who had histopathologic biopsies done before and after exposure to cidofovir. Pathologic data collected over 10 years from serial excisions at the University of Iowa Hospitals were reviewed by a single pathologist, and the highest degree of dysplasia was noted per excision time. Results: Of the 176 specimens collected in these 13 patients with serial papilloma biopsies, 5.7% had no dysplasia, 57.4% had mild dysplasia (grade 1), 28.4% had moderate dysplasia (grade 2), and 8.5% had severe dysplasia (grade 3). A comparison of each patient's multiple biopsies across time suggested that the dysplastic grade was worse in two patients, better in four patients, and virtually unchanged in seven patients. There was no clear-cut pattern between the use of cidofovir and the degree of dysplasia over time. Conclusions: These results strongly suggest that intralesional cidofovir therapy does not correlate with worsening dysplastic progression. Dysplasia is relatively common in the setting of RRP; however, the prognostic significance of this finding is unknown. Additional research is needed to delineate the natural progression of dysplasia and its clinical significance in RRP, as well as the efficacy of cidofovir.

Sepsis is an aggressive inflammatory syndrome and a global health burden estimated to kill 7.3 million people annually. Single-target molecular therapies have not addressed the multiple disease pathways triggered by septic injury. Cell therapies might offer a broader set of mechanisms of action that benefit complex, multifocal disease processes. We describe a population of immune-specialized myofibroblasts derived from lymph node tissue, termed fibroblastic reticular cells (FRCs). Because FRCs have an immunoregulatory function in lymph nodes, we hypothesized that ex vivo-expanded FRCs would control inflammation when administered therapeutically. Indeed, a single injection of ex vivo-expanded allogeneic FRCs reduced mortality in mouse models of sepsis when administered at early or late time points after septic onset. Mice treated with FRCs exhibited lower local and systemic concentrations of proinflammatory cytokines and reduced bacteremia. When administered 4 hours after induction of lipopolysaccharide endotoxemia, or cecal ligation and puncture (CLP) sepsis in mice, FRCs reduced deaths by at least 70%. When administered late in disease (16 hours after CLP), FRCs still conveyed a robust survival advantage (44% survival compared to 0% for controls). FRC therapy was dependent on the metabolic activity of nitric oxide synthase 2 (NOS2) as the primary molecular mechanism of drug action in the mice. Together, these data describe a new anti-inflammatory cell type and provide preclinical evidence for therapeutic efficacy in severe sepsis that warrants further translational study.

An infant with a ventricular septal defect; Vertebral anomalies, Anal atresia, Cardiac anomalies, Tracho Esophageal fistula (TEF), Renal anomalies, Limb anomalies syndrome; and tracheal stenosis with a bridging bronchus underwent repair of the ventricular septal defect and trachea-bronchial reconstruction at age 11 months. Herein we describe our surgical approach to resection of the bridging bronchus and a technique using a modified end-to-end tracheal anastomosis for the correction of this complex anomaly.

IntroductionLactate measurement has been used to identify critical medical illness and initiate early treatment strategies. The prehospital environment offers an opportunity for very early identification of critical illness and commencement of care.HypothesisThe investigators hypothesized that point-of-care lactate measurement in the prehospital aeromedical environment would: (1) identify medical patients with high mortality; (2) influence fluid, transfusion, and intubation; and (3) increase early central venous catheter (CVC) placement.MethodsCritically ill, medical, nontrauma patients who were transported from September 2007 through February 2009 by University of Massachusetts (UMass) Memorial LifeFlight, a university-based emergency medical helicopter service, were eligible for enrollment. Patients were prospectively randomized to receive a fingerstick whole-blood lactate measurement on an alternate-day schedule. Flight crews were not blinded to results. Flight crews were asked to inform the receiving attending physician of the results. The primary endpoint was the ability of a high, prehospital lactate value [> 4 millimoles per liter (mmol/L)] to identify mortality. Secondary endpoints included differences in post-transport fluid, transfusion, and intubation, and decrease in time to central venous catheter (CVC) placement. Categorical variables were compared between groups by Fisher's Exact Test, and continuous variables were compared by t-test.ResultsPatients (N = 59) were well matched for age, gender, and acuity. In the lactate cohort (n = 20), mean lactate was 7 mmol/L [Standard error of the mean, SEM = 1]. Initial analysis revealed that prehospital lactate levels of ≥4 mmol/L did show a trend toward higher mortality with an odds ratio of 2.1 (95% CI, 0.3-13.8). Secondary endpoints did not show a statistically significant change in management between the lactate and non lactate groups. There was a trend toward decreased time to post-transport CVC in the non lactate faction.ConclusionPrehospital aeromedical point-of-care lactate measurement levels ≥4 mmol/L may help stratify mortality. Further investigation is needed, as this is a small, limited study. The initial analysis did not find a significant change in post-transport management.MullenM, CerriG, MurrayR, TalbotA, SanseverinoA, McCahillP, MangoldsV, VolturoJ, DarlingC, RestucciaM. Use of point-of-care lactate in the prehospital aeromedical environment. Prehosp Disaster Med. 2014;29(1):1-4.

We present a case of temporary cochlear nerve dysfunction due to endocochlear inflammation with subsequent recovery. Retrospective case review at a pediatric tertiary care hospital. A nine-year-old male presented seven years post-cochlear implantation with an electrode array extruded into the external auditory canal. Upon exploration in the operating room, turbid perilymph from the scala tympani was discovered. A new electrode array was implanted. The patient had no discernible neural response telemetry (NRT) responses or auditory perception immediately following the procedure. Continuous but varying stimulation was continued postoperatively. Two months after implantation, he began having some auditory awareness; subsequent mapping resulted in the activation of a limited number of channels. Nine months following reimplantation, NRT demonstrated responses in three channels. Additionally, functional gain testing revealed sound awareness levels in the mild-hearing-loss range and the patient was able to detect and repeat all six Ling sounds. Continuous cochlear nerve stimulation at various levels may aid in function recovery after endocochlear inflammation.

Obstructive sleep apnea (OSA) may occur in up to 30% of patients with epilepsy. 1 Excessive sleepiness, such as that seen in OSA, lowers the seizure threshold, and treatment of OSA with continuous positive airway pressure (CPAP) appears to decrease seizure frequency in patients with epilepsy. 1 A growing consensus in the epilepsy literature stresses the importance of effective OSA management in helping to control the symptoms of epilepsy. However, few studies have investigated the converse: epilepsy's effect on sleep apnea.

Results: Nineteen manifested anterior webs during treatment, whereas six were successfully treated with mitomycin c without developing a web. 84% demonstrated resolution of the AGW. Conversely three patients developed new web formation following application of mitomycin C, all of which were subsequently cleared. Only one patient was recalcitrant to therapy and required surgical lysis with keel placement. No patients developed laryngeal cancer during our study period.

We sought to identify which patients with an apparent life-threatening event require infectious evaluation through an analysis of infants aged ≤12 months brought to an emergency department with an apparent life-threatening event. Among the 533 children evaluated, there were no cases of meningitis, 1 case of bacteremia, 17 cases of urinary tract infection, 22 cases of bacterial pneumonia, 22 cases of respiratory syncytial virus, and 2 cases of influenza virus identified in respiratory specimens.