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Rib fractures are common injuries, especially in the frail and elderly. They can happen in isolation or may be associated with significant concomitant morbidity, including but not limited to pain, pneumonia, or pneumothorax. In the palliative care population, rib fractures can be overlooked or attributed to other entities, which may lead to inappropriate treatment. The commonly accepted standards of care for the treatment of rib fractures are centered around early and adequate pain control, and stabilization of other complications. Accurate diagnosis and management demand a thorough history and physical examination, effective communication, and intentional clinical consideration of all differential diagnoses.
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Paraneoplastic neuropathy, including pruritis, remains a vexing problem as it often does not resolve even with successful treatment of cancer. Scrambler Therapy is a superficial form of neuromodulation that replaces the pain signal with "non-pain information" that is approved for chronic and neuropathic pain, with few side effects. We report here two cases of paraneoplastic neuropathy, one with additional pruritis, that both responded satisfactorily to Scrambler Therapy with no side effects.
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Schwannomatosis patients (SP) suffer from chronic nerve pain that is often inadequately relieved. Scrambler therapy (ST) can relieve neuropathic pain quickly, safely, and inexpensively. We successfully treated a patient who had disabling leg pain with five daily sessions of ST, each for 40 minutes. She had complete relief of pain and hyperalgesia, with return to normal function, by day 5, that has persisted for at least three weeks. This article briefly describes Schwannomatosis, scrambler therapy, and the need for further research to ascertain the best way to use this neuromodulation.
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Structured quality improvement and patient safety (QI/PS) education has increased at every level of medical education; however, great variability exists in the content taught. Here, the authors present a longitudinal model for medical student QI/PS education that is currently implemented at the University of Florida College of Medicine. The curriculum is taught with a variety of teaching methods incorporated into each year with increasing levels of clinical implementation. This curriculum is multimodal and introduces students to QI/PS concepts, presents mock scenarios, and eventually encourages clinical application to situations students experience during their own clinical practice. Additionally, a specialized track for students to have further immersion into this field of medicine is described, which involves specialized training, expanded educational opportunities, and a capstone project. Both the curriculum and specialized track contain explicit clinical integration to ensure students are prepared to enter the medical profession to engage in QI/PS endeavors.
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Faculdades de Medicina , Estudantes de Medicina , Currículo , Humanos , Segurança do Paciente , Melhoria de QualidadeRESUMO
There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.
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Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacologia , Carvedilol/química , Carvedilol/farmacologia , Química Computacional/métodos , Descoberta de Drogas/métodos , Receptor 5-HT2A de Serotonina/química , Antagonistas Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos/metabolismo , Anfetaminas/administração & dosagem , Anfetaminas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Carvedilol/administração & dosagem , Carvedilol/metabolismo , Fluorbenzenos/farmacologia , Células HEK293 , Humanos , Dietilamida do Ácido Lisérgico/química , Masculino , Camundongos , Modelos Animais , Modelos Moleculares , Piperidinas/farmacologia , Ligação Proteica , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia , TransfecçãoRESUMO
Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT2 receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH. In the present study, we examined the effects of 5-HT2 receptor stimulation on hypothermia induced by the injectable anesthetic ketamine in Swiss-Webster mice using rectal thermometry. We report that ketamine dose-dependently induced hypothermia, and mice did not become tolerant to this effect of ketamine over the course of three injections spaced at once per week. Ketamine-induced hypothermia was significantly attenuated by pretreatment with the selective 5-HT2C receptor agonist WAY-163909 but not by pretreatment with the mixed 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Moreover, the blockade of ketamine-induced hypothermia by WAY-163909 was reversed by pretreatment with the selective 5-HT2C receptor antagonist SB-242084. These findings demonstrate that stimulation of 5-HT2C receptors can reduce AIH, at least for ketamine-induced hypothermia. They warrant further study of the pharmacological and neurobiological mechanisms underlying this interaction and its extension to other anesthetics. Furthermore, these findings suggest that the maintenance of body temperature during surgery may be a new clinical use for 5-HT2C receptor agonists.
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Azepinas/farmacologia , Hipotermia/induzido quimicamente , Hipotermia/tratamento farmacológico , Indóis/farmacologia , Ketamina/efeitos adversos , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Azepinas/uso terapêutico , Temperatura Corporal/efeitos dos fármacos , Hipotermia/fisiopatologia , Indóis/uso terapêutico , Masculino , Camundongos , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêuticoRESUMO
Neoantigens, which are expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. Cancer immunotherapies to target neoantigens are of growing interest and are in early human trials, but methods to identify neoantigens either require invasive or difficult-to-obtain clinical specimens, require the screening of hundreds to thousands of synthetic peptides or tandem minigenes, or are only relevant to specific human leukocyte antigen (HLA) alleles. We apply deep learning to a large (N = 74 patients) HLA peptide and genomic dataset from various human tumors to create a computational model of antigen presentation for neoantigen prediction. We show that our model, named EDGE, increases the positive predictive value of HLA antigen prediction by up to ninefold. We apply EDGE to enable identification of neoantigens and neoantigen-reactive T cells using routine clinical specimens and small numbers of synthetic peptides for most common HLA alleles. EDGE could enable an improved ability to develop neoantigen-targeted immunotherapies for cancer patients.
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Sepsis is a common and deadly complication among trauma and surgical patients. Neutrophils must mobilize to the site of infection to initiate an immediate immune response. To quantify the velocity of spontaneous migrating blood neutrophils, we utilized novel microfluidic approaches on whole blood samples from septic and healthy individuals. A prospective study at a level 1 trauma and tertiary care center was performed with peripheral blood samples collected at <12 hours, 4 days, and/or 14 days relative to study initiation. Blood samples were also collected from healthy subjects. Ex vivo spontaneous neutrophil migration was measured on 2 µl of whole blood using microfluidic devices and time-lapse imaging. For each sample, individual neutrophils were tracked to calculate mean instantaneous velocity. Forty blood samples were collected from 33 patients with sepsis, and 15 blood samples were collected from age- and gender-matched healthy, control subjects. Average age was 61 years for septic patients with a male predominance (67%). Overall, average spontaneous neutrophil migration velocity in septic samples was 16.9 µm/min, significantly lower than controls samples at 21.1 µm/min (p = 0.0135). Neutrophil velocity was reduced the greatest at <12 hours after sepsis (14.5 µm/min). Regression analysis demonstrated a significant, positive correlation between neutrophil velocity and days after sepsis (p = 0.0059). There was no significant association between neutrophil velocity and age, gender, APACHE II score, SOFA score, sepsis severity, total white blood cell count, or percentage of neutrophils. Circulating levels of the cytokines IL-6, IL-8, IL-10, MCP-1, IP-10, and TNF were additionally measured using bead-based multiplex assay and found to peak at <12 hours and be significantly increased in patients with sepsis at all three time points (<12 hours, 4 days, and 14 days after sepsis) compared to healthy subjects. In conclusion, these findings may demonstrate an impaired ability of neutrophils to respond to sites of infection during the proinflammatory phase of sepsis.
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Movimento Celular , Citocinas/sangue , Neutrófilos/metabolismo , Sepse/sangue , Feminino , Humanos , Contagem de Leucócitos , Masculino , Microfluídica , Pessoa de Meia-Idade , Neutrófilos/patologia , Estudos Prospectivos , Sepse/epidemiologia , Sepse/patologiaRESUMO
Neonates rely on their innate immune system, and neutrophils in particular, to recognize and combat life-threatening bacterial infections. Pretreatment with lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 agonist, improves survival to polymicrobial sepsis in neonatal mice by enhancing neutrophil recruitment. To understand the response of human neonatal neutrophils to TLR4 stimulation, ex vivo spontaneous neutrophil migration, neutrophil transcriptomics, and cytokine production in the presence and absence of LPS were measured directly from whole blood of adults, term neonates, and preterm neonates. Spontaneous neutrophil migration was measured on novel microfluidic devices with time-lapse imaging for 10 h. Genome-wide neutrophil transcriptomics and plasma cytokine concentrations were also determined. Preterm neonates had significantly fewer spontaneously migrating neutrophils at baseline, and both term and preterm neonates had decreased neutrophil velocity, compared to adults. In the presence of LPS stimulation, the number of spontaneously migrating neutrophils was reduced in preterm neonates compared to term neonates and adults. Neutrophil velocity was not significantly different among groups with LPS stimulation. Preterm neonates upregulated expression of genes associated with the recruitment and response of neutrophils following LPS stimulation, but failed to upregulate the expression of genes associated with antimicrobial and antiviral responses. Plasma levels of IL-1ß, IL-6, IL-8, MIP-1α, and TNF-α increased in response to LPS stimulation in all groups, but IL-10 was increased only in term and preterm neonates. In conclusion, age-specific changes in spontaneous neutrophil migration counts are not affected by LPS despite changes in gene expression and cytokine production. KEY MESSAGES: Preterm neonates have reduced spontaneous neutrophil migration compared to term neonates and adults in the absence and presence of TLR4 stimulation. Preterm and term neonates have reduced neutrophil velocities compared to adults in the absence of TLR4 stimulation but no difference in the presence of TLR4 stimulation. Unique transcriptomic response to TLR4 stimulation is observed in neutrophils from preterm neonates, term neonates, and adults. TLR4 stimulation produces an age-specific cytokine response.
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Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Citocinas/biossíntese , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor 4 Toll-Like/agonistas , Transcriptoma , Adolescente , Adulto , Bioensaio , Células Cultivadas , Biologia Computacional , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Recém-Nascido , Masculino , Adulto JovemRESUMO
BACKGROUND: Many sepsis survivors develop chronic critical illness (CCI) and are assumed to be immunosuppressed, but there is limited clinical evidence to support this. We sought to determine whether the incidence of secondary infections and immunosuppressive biomarker profiles of patients with CCI differ from those with rapid recovery (RAP) after sepsis. METHODS: This prospective observational study evaluated 88 critically ill patients with sepsis and 20 healthy controls. Cohorts were defined based on clinical trajectory (early death, RAP, or CCI), whereas immunosuppression was clinically determined by the presence of a postsepsis secondary infection. Serial blood samples were collected for absolute lymphocyte counts (ALCs), monocytic human leukocyte antigen-DR (mHLA-DR) expression, and plasma-soluble programmed death-ligand 1 (sPD-L1) concentrations. RESULTS: Of the 88 patients with sepsis, 3 (3%) died within 14 days of sepsis onset, 50 (57%) experienced RAP, and 35 (40%) developed CCI. Compared with RAP patients, CCI patients exhibited a higher incidence and overall number of infections adjusted for hospital length of stay. ALC and mHLA-DR levels were dramatically reduced at the time of sepsis diagnosis when compared with healthy controls, whereas sPD-L1 concentrations were significantly elevated. There were no differences between RAP and CCI patients in ALC, sPD-L1, or mHLA-DR at the time of diagnosis or within 24âh after sepsis diagnosis. However, in contrast to the RAP group, CCI patients failed to exhibit any trend toward restoration of normal values of ALC, HLA-DR, and sPD-L1. CONCLUSIONS: Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI.
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Antígeno B7-H1 , Antígenos HLA-DR , Sepse , Adulto , Idoso , Antígeno B7-H1/sangue , Antígeno B7-H1/imunologia , Estado Terminal , Feminino , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Tolerância Imunológica , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/sangue , Sepse/imunologiaRESUMO
Vascular anomalies constitute some of the most difficult diagnostic and therapeutic enigmas in the practice of medicine, ranging from an asymptomatic birthmark to life-threatening congestive heart failure. Hemangiolymphangiomas (HLA) are extremely rare vascular malformations of both lymphatic and blood vessels in which 80-90% are diagnosed during the first 2 years of life. Though rare, these vascular malformations have promising clinical outcomes. We report a case of a 28-year-old male who presented with a neck mass of unknown etiology. A computed axial tomography scan revealed a cystic mass, and subsequent aspiration biopsy showed lymphatic fluid. The mass was surgically excised and identified as a 6 × 6 × 3 cm3 multilocular cystic mass weighing 81 g. Histopathology showed cellular characteristics consistent with HLA. We review the salient clinical and pathophysiologic features of vascular anomalies.
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Neutrophils play a crucial role in combating life-threatening bacterial infections in neonates. Previous studies investigating neonatal cell function have been limited because of restricted volume sampling. Here, using novel microfluidic approaches, we provide the first description of neutrophil chemotaxis and transcriptomics from whole blood of human term and preterm neonates, as well as young adults. Ex vivo percent cell migration, neutrophil velocity, and directionality to N-formylmethionyl-leucyl-phenylalanine were measured from whole blood using time-lapse imaging of microfluidic chemotaxis. Genome-wide expression was also evaluated in CD66b+ cells using microfluidic capture devices. Neutrophils from preterm neonates migrated in fewer numbers compared to term neonates (preterm 12.3%, term 30.5%, P = 0.008) and at a reduced velocity compared to young adults (preterm 10.1 µm/min, adult 12.7 µm/min, P = 0.003). Despite fewer neutrophils migrating at slower velocities, neutrophil directionality from preterm neonates was comparable to adults and term neonates. 3607 genes were differentially expressed among the 3 groups (P < 0.001). Differences in gene expression between neutrophils from preterm and term neonates were consistent with reduced pathogen recognition and antimicrobial activity but not neutrophil migration, by preterm neonates. In summary, preterm neonates have significant disturbances in neutrophil chemotaxis compared to term neonates and adults, and these differences in phenotype appear at the transcriptional level to target inflammatory pathways in general, rather than in neutrophil migration and chemotaxis.
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Quimiotaxia/fisiologia , Recém-Nascido Prematuro/fisiologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Transcriptoma/fisiologia , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Transient intussusception without any underlying lead is a rare clinical entity which can cause abdominal pain in adults. It has been associated with inflammatory bowel disease, cystic fibrosis, and endocrinological disorders. We present a case of transient jejunojejunal intussusception in a 42-year-old Hispanic male patient without any underlying pathological lead point. Surgical intervention yielded a negative laparotomy and resection was not undertaken. We discuss the clinical presentation, surgical procedure, risk factors leading to episodes of transient intussusception, and the use of surgery versus conservative management in such cases.
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Deep brain stimulation (DBS) has been used to treat secondary dystonias caused by inborn errors of metabolism with varying degrees of effectiveness. Here we report for the first time the application of DBS as treatment for secondary dystonia in a 22-year-old male with X-linked adrenoleukodystrophy (X-ALD). The disease manifested at age 6 with ADHD, tics, and dystonic gait, and deteriorated to loss of ambulation by age 11, and speech difficulties, seizures, and characteristic adrenal insufficiency by age 16. DBS in the globus pallidus internus was commenced at age 18. However, after 25 months, no improvement in dystonia was observed (Burke-Fahn-Marsden (BFM) scores of 65.5 and 62 and disability scores of 28 and 26, pre- and post-DBS, respectively) and the DBS device was removed. Treatment with dantrolene reduced skeletal muscle tone and improved movement (Global Dystonia Rating Scores from 5 to 1 and BFM score 42). Therefore, we conclude that DBS was a safe but ineffective intervention in our case with long-standing dystonia, whereas treatment of spasticity with dantrolene did improve the movement disorder in this young man with X-ALD.
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BACKGROUND: Identification of the underlying cause of intellectual disability (ID) is important as it improves genetic counselling, management, adaptation; yet its etiologic heterogeneity is challenging and often leads to an expensive work-up. METHODS: To improve this diagnostic trajectory, the multidisciplinary Complex Diagnostic Clinic (CDC) was established for ID patients with unexplained complex systemic and/or neurologic features that were referred to the CDC and evaluated by three medical specialists followed by multi-disciplinary rounds. Analyses included surveys and interviews, (retrospective) chart review, costs calculations and comparison. RESULTS: 24 children (9 male) were evaluated during seven clinics held over 16 months. The average patient age was 7 years 11 months (range 9 months-18 years). All the children had previously been seen by 2-10 specialist services. The diagnostic yield of the CDC was higher than expected with confirmed and working diagnoses in 11 (46%) and 9 (38%) children respectively. Cost-savings included fewer trips to hospital and fewer tests via more streamlined evaluations. Positive feedback was received from both families and medical professionals. CONCLUSIONS: The CDC represents an innovative model of personalized care. Specialist collaboration in the interpretation of relevant clinical, biochemical and genomic data resulted in diagnoses, where none had previously been possible.