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To test whether a policy approach aimed at decreasing prescription drug misuse, specifically, state monitoring of controlled substance prescriptions-prescription drug monitoring programs (PDMPs)-were associated with changes in Child Protective Services-reported maltreatment prevalence.Using a difference-in-differences design and maltreatment data (2004-2018) from 50 states and the District of Columbia, we compared the prevalence of total maltreatment incidents and total victims, in states with and without PDMPs, before and after implementation. Exploratory analyses further examined models disaggregated by maltreatment type (neglect, physical abuse, sexual abuse, psychological abuse) and among different racial/ethnic groups. Quasi-Poisson models included state-level covariates, state- and year-fixed effects, and cluster-robust standard errors.Difference-in-differences models identified greater relative reductions in PDMP states relative to controls (total prevalence ratio, 0.87; 95% CI, 0.80, 0.940; victimization prevalence ratio, 0.92; 95% CI, 0.85-0.98) over the observation period. Decreases seemed to be driven by changes in neglect (prevalence ratio, 0.87; 95% CI, 0.80-0.93) and physical abuse (prevalence ratio, 0.78; 95% CI, 0.71-0.87) incidents, and may have been especially salient for American Indian/Alaskan Native children (prevalence ratio, 0.78; 95% CI, 0.65-0.94).We found evidence supporting an association between prescription drug monitoring and reduced maltreatment prevalence at the state level. Policies aimed at restricting the prescribing and dispensing of controlled substances may have indirect implications for child welfare.

Shark attack-related injuries (SARIs) are rare but may result in highly complex wounds requiring reconstruction by plastic surgeons. Here, we present an unusual case of SARI of the breast and briefly review literature on reconstructive management of (1) breast injuries from other large animals and (2) SARIs to other parts of the body. Our patient was a 39-year-old woman who experienced massive bilateral breast tissue loss from a shark attack. After primary surgical wound management, including debridement and washout, the patient underwent completion mastectomy with bilateral deep inferior epigastric perforator flap breast reconstruction. Literature review revealed that reports of animal-related injuries to the breast are rare, with ours being the first on SARI to the breast and the only describing major reconstruction of animal-related breast injury. Literature on reconstruction of non-breast SARI wounds is limited to two case reports describing severe tissue damage akin to that seen in our patient, both necessitating extensive debridement followed by reconstruction. Overall, our findings demonstrate the uniquely devastating damage resulting from SARIs and the value of primary wound management and abdominally based free flaps in successfully reconstructing these wounds. Level of evidence: Level V, therapeutic study.

A great technological revolution in surgery occurred with the introduction of laparoscopic and other minimally invasive procedures, with enormous patient benefits. Robotic-assisted surgery (RAS) is a form of minimally invasive surgery that overcomes some of the limitations of laparoscopic techniques. Until recently, there were few standardized curricula for RAS. The Fundamentals of Robotic (FRS) developed a process through expert consensus conferences to develop an effective and validated curriculum for basic robotic surgery. A specialty specific curriculum for thoracic robotic surgery is also needed. The Fundamentals of Thoracic Robotic Surgery (FTRS) Consensus Conference brought together expert thoracic surgeons to build upon the accomplishments of FRS and incorporate the experiences of thoracic societies and academic institutions to establish a standardized FTRS curriculum for the development and maintenance of specialty-specific robotic surgical skills. A task deconstruction was completed for the thoracic ‘signature’ procedure, the lobectomy and training items and potential errors were identified for each step of the procedure. A final outline of the FTRS curriculum was developed during the conference and physical and virtual reality thoracic surgery training models were discussed. Following the conference, the steering committee completed the FTRS curriculum with editorial review from all stakeholders. The FTRS consensus conference followed the validated FRS model but in an accelerated process due to important groundwork set by experts in the FRS consensus conferences. A full online curriculum and supporting psychomotor skills training and team communication has been developed for the lobectomy procedure.

BACKGROUND Sternal wound infection and dehiscence following cardiac surgery remain difficult clinical problems with high morbidity. Older classification systems regarding timing to reconstruction do not take into account recent improvements in critical care, wound vacuum-assisted closure use, or next-generation antibiotic therapies, which may prolong time to reconstruction. METHODS Records of patients undergoing sternal wound reconstruction performed by the senior author (J.A.A.) from 1996 to 2018 at a high-volume cardiac surgery center were reviewed. Indications included sternal wound infection or dehiscence. All patients underwent single-stage removal of hardware, debridement, and flap closure. Patients were divided into two groups based on timing of wound closure after cardiac surgery: less than 30 days or greater than or equal to 30 days. RESULTS Of the 505 patients identified during the study period, 330 had sufficient data for analysis. Mean time to sternal wound surgery was 15.7 days in the early group compared to 64.4 days (p < 0.01) beyond 30 days. Postdebridement cultures were positive in 72 percent versus 62.5 percent of patients (p = 0.11), whereas rates of postoperative infection were significantly higher in the delayed group: 1.9 percent versus 9.5 percent (p < 0.01). Partial wound dehiscence rates were also higher after 30 days (1.9 percent versus 11.3 percent; p < 0.01), whereas total length of stay was decreased. Use of wound vacuum-assisted closure was significantly associated with reconstruction beyond 30 days (p < 0.01). CONCLUSIONS Although performing sternal wound reconstruction more than 30 days after initial cardiac surgery was associated with a shorter overall hospital length of stay and higher extubation rates in the operating room, these patients also had elevated postoperative infection and wound complication rates. The authors thus recommend not delaying definitive surgical reconstruction when possible. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

PURPOSE: The COVID-19 pandemic has significantly affected the well-being of healthcare workers to varying degrees. The aim of the current study was to investigate how the pandemic has affected the burnout, stress, and emotional well-being of pediatric hematology oncology (PHO) providers and staff in the New York and New Jersey epicenter. METHODS: The study was conducted in June 2020 during the pandemic through an electronic survey. The survey contained questions surrounding demographics, pandemic experiences, and validated burnout, stress, and emotional well-being measures. RESULTS: Two hundred fifty-two PHO providers and staff responded to the survey. Overall, half of the participants reported high levels of burnout, average stress scores were in the mild-moderate range, and the majority scored in the none-to-mild symptomatology range for their well-being. Self-reported burnout levels before the pandemic and geographic work location were statistically significant risk factors for all outcomes. Additional predictors for some outcomes included hospital role, lack of trust in leadership, and deployment. The majority of participants (87.0%) reported that their hospitals had made mental health resources related to COVID-19 available to them but only 8.4% reported having used them. CONCLUSION: PHO providers and staff in the NYC/NJ area are experiencing a range of emotional experiences during the COVID-19 pandemic, but the majority are not using current resources. With the continuation of the pandemic, we must continue efforts to improve provider and staff distress to mitigate the degree of potential negative short-term and long-term impact.

Mitochondria are complex organelles that play a critical role within the cell; mitochondrial dysfunction can result in significant cell damage or death. Previous studies have demonstrated the promising therapeutic effects of autologous mitochondria transplantation into ischemic cardiac tissue; however, few studies have examined the in vivo effects of mitochondria infusion into the brain. The aim of this study is to report a procedure for carotid infusion of autologous mitochondria into porcine brains. By using this infusion technique, we propose that a selective and minimally invasive administration is feasible and may provide benefits in the treatment of various central nervous system disorders Las mitocondrias son organelas complejas que desempeñan un papel fundamental en la célula, la disfunción mitocondrial puede ocasionar daños celulares significativos o la muerte. Estudios previos han demostrado los prometedores efectos terapéuticos del trasplante de mitocondrias autólogas a un tejido cardiaco isquémico, sin embargo, pocos estudios han evaluado los efectos in vivo de la infusión de mitocondrias en el cerebro. El presente trabajo tiene como objetivo dar a conocer el procedimiento para la infusión vía carótida de mitocondrias autólogas en cerebros porcinos. Mediante esta técnica de infusión, proponemos que una administración selectiva y mínimamente invasiva es factible y puede proporcionar beneficios en el tratamiento de diversas patologías del sistema nervioso central

Blood flow restriction training (BFRT) provides an alternative approach to traditional strength training. The purpose of this study was to determine differences in quadriceps muscle activation, subject reported pain, and perceived exertion between three exercise conditions: low-load resistance BFRT with (1) regulated and (2) standardized devices, and (3) high-load resistance exercise without BFRT.Randomized cross over study.XX University Biomechanics laboratory.Thirty-four healthy subjects (18 male/16 female) each completed three randomized sessions of knee extensions using Delfi's Personalized Tourniquet System (R) at 30% of 1 repetition maximum (1RM), the B-Strong™ device (S) at 30% 1RM, and high-load resistance exercise (HL) at 80% 1RM.Quadriceps EMG activity, numeric pain rating scale (NPRS), and perceived exertion (OMNI-RES) were recorded.Average and peak EMG were greater in HL sessions than both S and R (p .001). NPRS was greater in the R sessions compared to both S (p .001) and HL (p .001). OMNI-RES was greater in the R sessions compared to S (p .02) and HL (p .001). No differences (p .05) in average or peak EMG activation were found between S and R sessions.Quadriceps EMG amplitude was greater during high-load resistance exercise versus low-load BFR exercise and there were no differences in EMG findings between BFRT devices.

In this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

This study examined perception of the American English (AE) /v/-/w/ consonant contrast by Hindi speakers of English as a second language (L2). A second aim was to determine whether residence in the US modulated perception of this difficult contrast for proficient bilingual Hindi-English listeners. Two groups of Hindi-English bilinguals (the first resided in the US for more than five years, the second lived in India) and a group of AE-speaking listeners participated in the study. Listeners’ identification and discrimination of nonsense words (e.g., “vagag” vs. “wagag”) were examined. Hindi listeners performed significantly less accurately than AE controls. Accuracy by Hindi listeners was near chance for identification and higher-than-chance for discrimination. Exposure to AE in the US did not improve performance. These results are consistent with previous studies of late L2 learners and extend findings to a population that was proficient in an L2 before arriving in the L2 environment.

IQSEC2 is an X-linked gene which is associated with autism spectrum disorder (ASD), intellectual disability and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cortex and hippocampus. Moreover, using a data-driven approach we demonstrate that A350V mice present alterations in structure–function relations of the frontal, auditory, and visual networks. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three–chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.Significance StatementSeveral recent studies have characterized the changes in the organization of brain networks in animal models of autism spectrum disorders (ASD). Here we assessed the effect of an A350V missense mutation in the IQSEC2 gene, which is associated with ASD, on brain-wide functional connectivity and its relation to social behavior deficits in A350V mice relative to controls. We found that the A350V IQSEC2 model results in disrupted functional connectivity of the anterior cingulate cortex and the dorsomedial striatum. Critically, disrupted increased corticostriatal functional connectivity is predictive of individual variability in social interaction only in A350V mice implicating this pathway in the pathophysiology of the A350V IQSEC2 mutation.

Objectives Mutations in the human IQSEC2 gene are associated with drug-resistant epilepsy and severe behavioral dysfunction. We have focused on understanding one human IQSEC2 missense mutation (A350V) for which we have created a corresponding A350V IQSEC2 mouse model by CRISPR which demonstrates seizures when the mice are 15-20 days old and impaired social vocalizations in adulthood. We observed that a child with the A350V mutation stops having seizures when experiencing a fever of greater than 38 °C. In this study, we first sought to determine if we could recapitulate this phenomenon in A350V 15-20 day old mice using a previously established protocol to raise body temperature to 39 °C achieved by housing the mice at 37 °C. We then sought to determine if mice in whom seizure activity had been prevented as pups would develop social vocalization activity in adulthood. Methods 15-20 day old A350V male mice were housed either at 37 °C or 22 °C. Ultrasonic vocalizations of these mice were assessed at 8-10 weeks in response to a female stimulus. Results Housing of 15-20 day old A350V mice at 37 °C resulted in a reduction in lethal seizures to 2% (1/41) compared to 45% (48/108) in mice housed at 22 °C, p = 0.0001. Adult A350V mice who had been housed at 37 °C as pups displayed a significant improvement in the production of social vocalizations. Conclusion Raising the body temperature by raising the ambient temperature might provide a means to reduce seizures associated with the A350V IQSEC2 mutation and thereby allow for an improved neurodevelopmental trajectory.

Objective To define criteria for robotic credentialing using expert consensus. Background A recent review of institutional robotic credentialing policies identified significant variability and determined current policies are largely inadequate to ensure surgeon proficiency and may threaten patient safety. Methods 28 national robotic surgery experts were invited to participate in a consensus conference. After review of available institutional policies and discussion, the group developed a 91 proposed criteria. Using a modified Delphi process the experts were asked to indicate their agreement with the proposed criteria in three electronic survey rounds after the conference. Criteria that achieved 80% or more in agreement (consensus) in all rounds were included in the final list. Results All experts agreed that there is a need for standardized robotic surgery credentialing criteria across institutions that promote surgeon proficiency. 49 items reached consensus in the first round, 19 in the second, and 8 in the third for a total of 76 final items. Experts agreed that privileges should be granted based on video review of surgical performance and attainment of clearly defined objective proficiency benchmarks. Parameters for ongoing outcome monitoring were determined and recommendations for technical skills training, proctoring, and performance assessment were defined. Conclusions Using a systematic approach, detailed credentialing criteria for robotic surgery were defined. Implementation of these criteria uniformly across institutions will promote proficiency of robotic surgeons and has the potential to positively impact patient outcomes.

Excessive fascial tension is a major cause of ventral hernia recurrence. Although hernias are commonly characterized by area, the tension experienced by fascia is directly proportional to the surrounding tissue stiffness. We demonstrate an accurate and simple technique for intra-operative measurement of fascial closing tension and quantify the decrease in tension following Component Separation (CS). A tensiometer was created using a spring with a known recoil constant (k) and a surgical clamp. Using Hooke’s law (Force = kX; X = spring displacement), fascial tension was calculated. This method was first validated on a bench-top model and then applied to the anterior fascia of 4 fresh cadavers (8 hemi-abdomens) over a range of simulated hernia defect sizes. When fascia could no longer reach midline, CS was performed and measures repeated. Tissue stiffness was calculated by plotting defect size versus resulting tension. Fascial defects ranged from 1- to 18-cm wide with average midline closing tension prior to release 36.1 N (range 17–48) and 8.2 N (range 5–11) after CS, a mean 76% decrease (range 70%–85%). Mean R2 values between defect size and tension for the synthetic and cadaver models were 0.99 (p 0.95 (p

Fundamentals of robotic surgery (FRS) is a proficiency-based progression curriculum developed by robotic surgery experts from multiple specialty areas to address gaps in existing robotic surgery training curricula. The RobotiX Mentor is a virtual reality training platform for robotic surgery. Our aims were to determine if robotic surgery novices would demonstrate improved technical skills after completing FRS training on the RobotiX Mentor, and to compare the effectiveness of FRS across training platforms. An observational, pre-post design, multi-institutional rater-blinded trial was conducted at two American College of Surgeons Accredited Education Institutes-certified simulation centers. Robotic surgery novices (n = 20) were enrolled and trained to expert-derived benchmarks using FRS on the RobotiX Mentor. Participants’ baseline skill was assessed before (pre-test) and after (post-test) training on an avian tissue model. Tests were video recorded and graded by blinded raters using the Global Evaluative Assessment of Robotic Skills (GEARS) and a 32-criteria psychomotor checklist. Post hoc comparisons were conducted against previously published comparator groups. On paired-samples T tests, participants demonstrated improved performance across all GEARS domains (p

Poly-4-hydroxybutyric acid (P4HB, Phasix™) is a biosynthetic polymer that degrades by hydrolysis that can be woven into a mesh for use in soft tissue reinforcement. Herein, we describe our initial experience performing complex abdominal wall repair (CAWR) utilizing component separation and P4HB mesh as onlay reinforcement. All patients undergoing CAWR between June 2014 and May 2017 were followed prospectively for postoperative outcomes. Only those patients who underwent components separation with primary repair of the fascial edges followed by onlay of P4HB mesh were included in this study. 105 patients (52 male, 53 female; mean age 59.2 years, range 22–84) met inclusion criteria. Mean BMI was 29.1 (range 16–48); 52% patients had prior attempted hernia repair, most with multiple medical comorbidities (71% of patients with ASA 3 or greater). 30% of cases were not clean at the time of repair (CDC class 2 or greater). Median follow-up was 36 months (range 9–63). Eighteen patients (17%) developed a hernia recurrence ranging from 2 to 36 months postoperatively. Five (5%) patients developed a localized superficial infection treated with antibiotics, three (2.8%) required re-operation for non-healing wounds, and six (6%) patients developed seroma. These data demonstrate a relatively low rate of hernia recurrence, seroma, and other common complications of CAWR in a highly morbid patient population. Importantly, the rate of mesh infection was low and no patients required complete mesh removal, even when placed into a contaminated or infected surgical field.

Robotic surgery has seen unprecedented growth, requiring hospitals to establish or update credentialing policies regarding this technology. Concerns about verification of robotic surgeon proficiency and the adequacy of current credentialing criteria to maintain patient safety have arisen. The aim of this project was to examine existing institutional credentialing requirements for robotic surgery and evaluate their adequacy in ensuring surgeon proficiency. Robotic credentialing policies for community and academic surgery programs were acquired and reviewed. Common criteria across institutions related to credentialing and recredentialing were identified and the average, standard deviation, and range of numeric requirements, if defined, was calculated. Criteria for proctors and assistants were also analyzed. Policies from 42 geographically dispersed US hospitals were reviewed. The majority of policies relied on a defined number of proctored cases as a surrogate for proficiency with an average of 3.24 ± 1.69 and a range of 1–10 cases required for initial credentialing. While 34 policies (81%) addressed maintenance of privileges requirements, there was wide variability in the average number of required robotic cases (7.19 ± 3.28 per year) and range (1–15 cases per year). Only 11 policies (26%) addressed the maximum allowable time gap between robotic cases. Significant variability in credentialing policies exists in a representative sample of US hospitals. Most policies require completion of a robotic surgery training course and a small number of proctored cases; however, ongoing objective performance assessments and patient outcome monitoring was rarely described. Existing credentialing policies are likely inadequate to ensure surgeon proficiency; therefore, development and wide implementation of robust credentialing guidelines is recommended to optimize patient safety and outcomes.

Perinatal hepatic inflammation can have devastating consequences. Monocytes play an important role in the initiation and resolution of inflammation, and their diverse functions can be attributed to specific cellular subsets: pro-inflammatory or classical monocytes (Ly6cHi) and pro-reparative or non-classical monocytes (Ly6cLo). We hypothesized that inherent differences in Ly6cHi classical monocytes and Ly6cLo non-classical monocytes determine susceptibility to perinatal hepatic inflammation in late gestation fetuses and neonates. We found an anti-inflammatory transcriptional profile expressed by Ly6cLo non-classical monocytes, and a physiologic abundance of these cells in the late gestation fetal liver. Unlike neonatal pups, late gestation fetuses proved to be resistant to rhesus rotavirus (RRV) mediated liver inflammation. Furthermore, neonatal pups were rendered resistant to RRV-mediated liver injury when Ly6cLo non-classical monocytes were expanded. Pharmacologic inhibition of Ly6cLo non-classical monocytes in this setting restored susceptibility to RRV-mediated disease. These data demonstrate that Ly6cLo monocytes promote resolution of perinatal liver inflammation in the late gestation fetus, where there is a physiologic expansion of non-classical monocytes, and in the neonatal liver upon experimental expansion of these cells. Therapeutic strategies directed towards enhancing Ly6cLo non-classical monocyte function may mitigate the detrimental effects of perinatal liver inflammation.

Cerebral edema from brain tumors can cause neurological impairment. Steroids treat edema but with possible adverse effects. We surveyed providers regarding steroid use in newly diagnosed patients with brain tumors to determine if practices are standard or markedly variable. An anonymous voluntary online survey was sent to members of neuro-oncology consortiums. Four clinical scenarios were provided and questions regarding initiation of steroids, type, dose, formulation, and duration were asked. Demographic information was collected. 369 providers received the survey, 76 responded (20.6% response rate). The proportion of providers who would start steroids significantly differed among scenarios (scenario 1 vs 2, p

BACKGROUND On the morning of June 12, 2016, an armed assailant entered the Pulse Nightclub in Orlando, Florida, and initiated an assault that killed 49 people and injured 53. The regional Level I trauma center and two community hospitals responded to this mass casualty incident. A detailed analysis was performed to guide hospitals who strive to prepare for future similar events. METHODS A retrospective review of all victim charts and/or autopsy reports was performed to identify victim presentation patterns, injuries sustained, and surgical resources required. Patients were stratified into three groups: survivors who received care at the regional Level I trauma center, survivors who received care at one of two local community hospitals, and decedents. RESULTS Of the 102 victims, 40 died at the scene and 9 died upon arrival to the Level I trauma center. The remaining 53 victims received definitive medical care and survived. Twenty-nine victims were admitted to the trauma center and five victims to a community hospital. The remaining 19 victims were treated and discharged that day. Decedents sustained significantly more bullet impacts than survivors (4 ± 3 vs. 2 ± 1; p = 0.008) and body regions injured (3 ± 1 vs. 2 ± 1; p = 0.0002). Gunshots to the head, chest, and abdominal body regions were significantly more common among decedents than survivors (p < 0.0001). Eighty-two percent of admitted patients required surgery in the first 24 hours. Essential resources in the first 24 hours included trauma surgeons, emergency room physicians, orthopedic/hand surgeons, anesthesiologists, vascular surgeons, interventional radiologists, intensivists, and hospitalists. CONCLUSION Mass shooting events are associated with high mortality. Survivors commonly sustain multiple, life-threatening ballistic injuries requiring emergent surgery and extensive hospital resources. Given the increasing frequency of mass shootings, all hospitals must have a coordinated plan to respond to a mass casualty event. LEVEL OF EVIDENCE Epidemiological Study, level V.

The field of peripheral arterial intervention has exploded over the past 20 years. Current knowledge includes a growing evidence base for treatment as well as a myriad of new interventional approaches to complex disease. This review seeks to outline the current state of the art for interventional approaches to lower extremity peripheral arterial disease.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

A child with a A350V IQSEC2 missense mutation resulting in drug‐resistant epilepsy stops having seizures when he has a fever. We demonstrate that raising the body temperature of the child using a commercial Jacuzzi dramatically reduces his seizures and appears to improve his social behavioral interactions.

The evolution and emergence of drug-resistant tuberculosis (TB) has been studied extensively in some contexts, but the ecological drivers of these two processes remain poorly understood. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant Mycobacterium tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2), where genomic surveillance of drug-resistant M. tuberculosis has been limited thus far. Using whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries. We infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged inpatient treatment of TB patients. We infer exportation of this strain and its isoniazid-resistant ancestral precursor from Moldova to neighbouring countries starting as early as 1985. Our findings suggest temporal and ecological associations between specific public health practices, including inpatient hospitalization of drug-resistant TB cases from the early 2000s until 2013, and the evolution of drug-resistant M. tuberculosis in Moldova. These findings underscore the need for regional coordination in TB control and expanded genomic surveillance efforts across Eastern Europe.

Purpose and Background Clopidogrel is a commonly used antiplatelet for the prevention of thromboembolic complications following several types of neuroendovascular procedures. Its widespread use stems from its relatively low cost, good efficacy, and safety profile. However, concern has emerged for the possibility that clopidogrel may induce severe, intolerable fatigue in a small subset of patients. Thus, the purpose of this study is to systematically investigate this phenomenon and to better characterize the demographic at risk. Methods We performed a dual-institution, 9-year, retrospective study of patients undergoing dual antiplatelet therapy with clopidogrel and aspirin for neuroendovascular procedures. Patients were included only if their response to clopidogrel was assessed by a VerifyNow P2Y12 (VNP) assay, which measures platelet inhibition using P2Y12 reactivity units (PRU). A hyper-response to clopidogrel is defined by a PRU ≤ 60. Patients were considered to have had clopidogrel-induced severe fatigue if 1) the onset of severe, intolerable fatigue followed the initiation of clopidogrel, 2) fatigue resolved or improved following a reduction in the dose of clopidogrel, 3) no hemorrhagic event occurred while on clopidogrel, and 4) fatigue could not be attributed to any other medical explanation. Results Clinical and demographic data were collected on 348 patients across 2 separate institutions. Five patients (1.4%) were identified as having met criteria for clopidogrel-induced severe fatigue. All 5 patients were female, ages 39-68. In addition to severe fatigue, they suffered from headache, nausea, vertigo, and dyspnea. Each patient had been taking clopidogrel for at least one week prior to the onset of symptoms, and VNP assays obtained while the patients were experiencing their symptoms revealed hyper-responses to clopidogrel, with PRU between 0-22. Four of these patients initially had an appropriate response to clopidogrel, with a PRU > 60 immediately prior to the intervention, and they did not report fatigue until later. In response to the severe, intolerable fatigue, clopidogrel was reduced by half, resulting in resolution or improvement of symptoms in all 5 patients. However, VNP assays returned persistently low values (0-16 PRU). One patient developed anemia after her symptoms had already resolved, but no additional complications were reported during the course of their therapy. Notably, 30% of patients (n = 103) demonstrated a hyper-response to clopidogrel on at least one VNP assay, but the vast majority of these patients did not suffer from severe fatigue. The rate of hyper-responses was similar across institutions and across genders. Conclusions Severe, intolerable fatigue is a rare but clinically significant side effect of clopidogrel. It is associated with a hyper-response to therapy as determined by a PRU value ≤ 60 on a VNP assay, but it appears that inhibition of platelet aggregation is merely epiphenomenal. Symptoms develop after an initial loading period and respond well to decreasing the dosage of clopidogrel. Only women were affected in our study, but this gender effect may reflect a sample bias as most of our patients were women. Disclosures D. Bass: None. C. Young: None. M. Park: None. D. Bass: None. K. Carroll: None. K. Vanet: None. C. Lee: None. R. Sen: None. S. Levy: None. C. Kelly: None. L. Kim: None. M. Levitt: None.

Background: The disease and treatment burden of uterine fibroids (UF) in Black women is substantially greater compared with other racial groups, with higher rates of complications and poorer outcom...

BACKGROUND Patients with chiasmatic-hypothalamic low-grade glioma (CHLGG) have frequent MRIs with gadolinium-based contrast agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in the brains of children is a potential concern. The purpose of this study is to evaluate whether MRI with GBCA is necessary for determining radiographic tumor progression in children with CHLGG. METHODS Children who were treated for progressive CHLGG from 2005 to 2019 at Texas Children's Cancer Center were identified. Pre- and post-contrast MRI sequences were separately reviewed by one neuroradiologist who was blinded to the clinical course. Three dimensional measurements and tumor characteristics were evaluated. Radiographic progression was defined as a 25% increase in size (product of two largest dimensions) compared with baseline or best response after initiation of therapy. RESULTS A total of 28 patients with progressive CHLGG were identified with a total of 683 MRIs with GBCA reviewed (mean 24 MRIs/patient; range, 11-43 MRIs). Radiographic progression was observed 92 times, 91 (99%) on noncontrast and 90 (98%) on contrast imaging. Sixty-seven progressions necessitating management changes were identified in all (100%) noncontrast sequences and 66 (99%) contrast sequences. Tumor growth > 2 mm in any dimension was identified in 184/187 (98%) noncontrast and 181/187 (97%) with contrast imaging. Metastatic tumors were better visualized on contrast imaging in 4/7 (57%). CONCLUSION MRI without GBCA effectively identifies patients with progressive disease. When imaging children with CHLGG, eliminating GBCA should be considered unless monitoring patients with metastatic disease.

Description The opioid crisis poses a substantial threat to youth throughout the nation. This crisis has been exacerbated by the COVID-19 pandemic, reversing some of the positive national trends in the fight against the opioid epidemic. Some risk factors for youth opioid use have been identified nationally. The South Florida tri-county region of Miami-Dade, Broward and Palm Beach is a culturally distinct region which may not follow national trends and likely has unique risk and protective factors. To address the concerning spike in youth opioid use in South Florida, a community coalition was formed to identify factors unique to South Florida and create a plan for early awareness and prevention.

Cannabis use and binge drinking are increasingly common in the United States, yet little is known about cannabis use patterns among people who engage in binge drinking. This study explored the relationship between several cannabis use outcomes and past-month binge drinking status. Pooled 2015–2018 National Surveys on Drug Use and Health data (N = 226,632) were used to explore the hypothesis that binge drinking is associated with higher prevalence of cannabis outcomes. Cannabis outcomes included past-month and past-year use, daily/almost daily use, and past-year DSM-IV/DSM-5 cannabis use disorder (CUD). Covariates included age, gender, race, total income, and study year. Separate weighted multivariable logistic regressions assessed associations between binge drinking and each cannabis outcome and provided adjusted prevalences of cannabis outcomes by binge drinking status. Past-month binge drinking was positively associated with past-month (OR: 3.72, 95 %CI: 3.56–3.93) and past-year (OR: 3.90, 95 %CI: 3.74–4.06) cannabis use in adjusted regressions. The adjusted odds of DSM-IV and DSM-5 CUD among people who used cannabis were 15 % and 12 % higher among people who engaged in binge drinking than those who did not, respectively (OR: 1.15, 95 %CI: 1.05, 1.26 and OR: 1.12, 95 %CI: 1.03, 1.21). Conversely, the odds of past-month daily cannabis use among people who used cannabis and reported binge drinking was 18 % lower than those who did not (OR: 0.82, 95 %CI: 0.74, 0.91). Our findings provide evidence of associations between binge drinking and cannabis use. Future studies should explore associations between cannabis and other alcohol use behaviors, including heavy drinking, and simultaneous alcohol and cannabis use.

Learning to perceive non-native speech sounds is difficult for adults. One method to improve perception of non-native contrasts is through a distributional learning paradigm. Three groups of native-English listeners completed a perceptual assimilation task in which they mapped French vowels onto English vowel categories: Two groups (bimodal, unimodal distribution) completed a perceptual learning task for the French /œ/-/o/ contrast and a third completed no training. Both trained groups differed from the untrained group, but participants in the bimodal group showed a different perceptual mapping for the targeted /œ/ vowel, suggesting that the bimodal condition may maximize perception of non-native contrasts.

Flow-diverting stents (FDS) are used to treat cerebral aneurysms. They promote the formation of a stable thrombus within the aneurysmal sac and, if successful, isolate the aneurysmal dome from mechanical stresses to prevent rupture. Platelet activation, a mechanism necessary for thrombus formation, is known to respond to biomechanical stimuli, particularly to the platelets’ residence time and shear stress exposure. Currently, there is no reliable method for predicting FDS treatment outcomes, either a priori or after the procedure. Eulerian computational fluid dynamic (CFD) studies of aneurysmal flow have searched for predictors of endovascular treatment outcome; however, the hemodynamics of thrombus formation cannot be fully understood without considering the platelets’ trajectories and their mechanics-triggered activation. Lagrangian analysis of the fluid mechanics in the aneurysmal vasculature provides novel metrics by tracking the platelets’ residence time (RT) and shear history (SH). Eulerian and Lagrangian parameters are compared for 19 patient-specific cases, both pre- and post-treatment, to assess the degree of change caused by the FDS and subsequent treatment efficacy.

Objective— Coronary endothelial dysfunction (ED) is an early stage of atherosclerosis and is associated with impaired high-density lipoprotein (HDL) function. A functional polymorphism at the haptoglobin (Hp) gene locus (rs72294371) has been associated with marked differences in HDL structure and function. We sought to determine whether Hp phenotype was associated with coronary ED and whether the amount of hemoglobin (Hb) tethered to HDL via Hp was Hp-type dependent and associated with ED. Approach and Results— Microvascular and epicardial coronary endothelial function was assessed in 338 individuals with nonobstructive coronary artery disease. Microvascular ED was defined as P =0.01) and epicardial ED ( P =0.04) among DM individuals. There was a significant and inverse correlation between the amount of HDL-bound Hb and change in coronary blood flow (r=−0.40; P P P =0.03) and the amount of HDL-bound Hb was an independent predictor of both microvascular (odds ratio, 4.6 for each 1-SD increase; P P Conclusions— Hp phenotype is significantly associated with coronary ED in DM individuals. This association is likely related to increased Hb tethering to HDL via Hp 2-2 in DM.

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb h/h ) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220 + B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P P WT (wild type) mice. Additionally, c-myb h/h mice had lower susceptibility to deoxycorticosterone acetate-salt experimental hypertension. Although cardiac (echocardiography) and resistance artery (perfusion myography) functions were normal, metabolic cage studies revealed that c-myb h/h mice had increased 24-hour urine output and sodium excretion versus WT . Reconstitution of WT mice with c-myb h/h bone marrow transplant and chimeric bone marrow transplant using mice lacking B-cells ( J H T ; h/h>WT and h/h:J H T>WT , respectively) decreased blood pressure and increased 24-hour urine output compared with controls ( WT>WT ; WT:J H T>WT ). J H T mice also had decreased systolic (103±2 versus 115±1 mm Hg; P P WT . Real-time quantitative reverse transcription polymerase chain reaction of kidney medulla revealed reduced V 2 R (vasopressin receptor 2) expression in c-myb h/h and J H T mice. These data implicate B-cells in the regulation of V 2 R and its associated effects on salt and water handling and blood pressure homeostasis.

Purpose/objective(s) According to 2020 "NCCN" guidelines, post-treatment positron emission tomography (PET) - computed tomography (CT) imaging of the body is not recommended to predict outcomes of patients undergoing curative intent chemoradiation therapy (CRT) for anal canal cancer. This study used PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) to evaluate CRT response and outcomes for our patient population at a single institution. Materials/methods Our "IRB"-approved anal canal database was queried for patients who have undergone CRT, modified "NIGRO" protocol, for carcinoma of the anal canal. The evaluable patient dataset comprised those with both pre- and post-CRT PET-CT imaging of the body. The primary study endpoint was relapse-free survival (RFS) calculated from date of diagnosis to date of first known appearance of disease or death from any cause. Overall survival (OS) was defined using elapsed time between date of diagnosis and date of death and surviving patients were censored using date of last follow-up. Also, the range and median time to first post-CRT PET-CT imaging was determined. RFS and OS were analyzed using Kaplan-Meier method. Complete response rate (CRR) and objective response rate (ORR) were calculated along with 95% confidence intervals using Fisher's exact method. All tests were two-sided, and statistical significance was considered when P Results Out of an initial 392 patients in our database registry, 62 had pre/post-CRT PET-CT imaging from June 2008 until May 2020. There were 18 males and 44 females. The median age at diagnosis was 57.7 years (range: 38-84 years). "AJCC" (7th edition) staging distribution was as follows: 3 Stage I, 13 Stage II, 41 Stage III, and 5 Stage IV. The median total dose of external beam irradiation was 54 Gy (range: 45-60 Gy). Time to post-CRT PET-CT imaging ranged from 0.2 to 27.8 months (mos) [median: 2.9 mos]. Respective PET-response rates regarding primary tumor (N = 62); largest groin node (N = 33); and largest pelvic node (N = 39) were as follows: 31 CR (Complete Response), 26 PR (Partial Response), 5 SD (Stable Disease), and 0 DP (Disease Progression); 30 CR, 3 PR, 0 SD, 0 DP; and 36 CR, 1 PR, 2 SD, 0 DP. Patient follow-up ranged from 6.8 to 114 mos (median: 38.6 mos). At time of last follow-up, there were 53 alive and 9 dead. Estimated 3-year RFS was 72% (95% "CI": 58.2-81.9%). Estimated 3-year OS was 88.8% (95% CI: 76.6-94.9%). Respective CRRs and ORRs for the primary tumor were 50% (95% CI = 37-63%) and 91.9% (95% CI = 82.2-97.3%); for the groin node 48.4% (95% CI = 35.5-61.4%) and 53.2% (95% CI = 40.1-66%); and for the pelvic node 58.1% (95% CI = 44.8-70.5%) and 59.7% (95% CI = 46.4-71.9%). CRRs and ORRs were not significant prognostic factors for either RFS or OS. Conclusion After applying PERCIST to our institutional study cohort, the use of post-treatment PET-CT imaging to predict outcomes for this patient population remains unproven.

Purpose Children with dysarthria secondary to cerebral palsy may experience reduced speech intelligibility and diminished communicative participation. However, minimal research has been conducted examining the outcomes of behavioral speech treatments in this population. This study examined the effect of Speech Intelligibility Treatment (SIT), a dual-focus speech treatment targeting increased articulatory excursion and vocal intensity, on intelligibility of narrative speech, speech acoustics, and communicative participation in children with dysarthria. Method American English–speaking children with dysarthria ( n = 17) received SIT in a 3-week summer camplike setting at Columbia University. SIT follows motor-learning principles to train the child-friendly, dual-focus strategy, “Speak with your big mouth and strong voice.” Children produced a story narrative at baseline, immediate posttreatment (POST), and at 6-week follow-up (FUP). Outcomes were examined via blinded listener ratings of ease of understanding ( n = 108 adult listeners), acoustic analyses, and questionnaires focused on communicative participation. Results SIT resulted in significant increases in ease of understanding at POST, that were maintained at FUP. There were no significant changes to vocal intensity, speech rate, or vowel spectral characteristics, with the exception of an increase in second formant difference between vowels following SIT. Significantly enhanced communicative participation was evident at POST and FUP. Considerable variability in response to SIT was observed between children . Conclusions Dual-focus treatment shows promise for improving intelligibility and communicative participation in children with dysarthria, although responses to treatment vary considerably across children. Possible mechanisms underlying the intelligibility gains, enhanced communicative participation, and variability in treatment effects are discussed.

Background Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET). Methods Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m2 /day PO on days 1-5) and irinotecan (50 mg/m2 /day IV on days 1-5) with or without bevacizumab (10 mg/kg IV on days 1 and 15). Results One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event-free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative-risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2-16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm. Conclusion The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three-drug regimen demonstrated a sufficient risk reduction to warrant further investigation.

Cancer immunity is mediated by a delicate orchestration between the innate and adaptive immune system both systemically and within the tumor microenvironment. Although several adaptive immunity molecular targets have been proven clinically efficacious, stand-alone innate immunity targeting agents have not been successful in the clinic. Here, we report a nanoparticle optimized for systemic administration that combines immune agonists for TLR9, STING, and RIG-I with a melanoma-specific peptide to induce antitumor immunity. These immune agonistic nanoparticles (iaNPs) significantly enhance the activation of antigen-presenting cells to orchestrate the development and response of melanoma-sensitized T-cells. iaNP treatment not only suppressed tumor growth in an orthotopic solid tumor model, but also significantly reduced tumor burden in a metastatic animal model. This combination biomaterial-based approach to coordinate innate and adaptive anticancer immunity provides further insights into the benefits of stimulating multiple activation pathways to promote tumor regression, while also offering an important platform to effectively and safely deliver combination immunotherapies for cancer.

Over the past decade, increasing attention has been paid to intervening in individuals' health in the "preconception" period as an approach to optimizing pregnancy outcomes. Increasing attention to the structural and social determinants of health and to the need to prioritize reproductive autonomy has underscored the need to evolve the preconception health framework to center race equity and to engage with the historical and social context in which reproduction and reproductive health care occur. In this commentary, we describe the results of a meeting with a multidisciplinary group of maternal and child health experts, reproductive health researchers and practitioners, and Reproductive Justice leaders to define a new approach for clinical and public health systems to engage with the health of nonpregnant people. We describe a novel "Reproductive and Sexual Health Equity" framework, defined as an approach to comprehensively meet people's reproductive and sexual health needs, with explicit attention to structural influences on health and health care and grounded in a desire to achieve the highest level of health for all people and address inequities in health outcomes. Principles of the framework include centering the needs of and redistributing power to communities, having clinical and public health systems acknowledge historical and ongoing harms related to reproductive and sexual health, and addressing root causes of inequities. We conclude with a call to action for a multisectoral effort centered in equity to advance reproductive and sexual health across the reproductive life course.