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INTRODUCTION: Surgical stabilization of rib fractures (SSRF) is associated with lower rates of mortality and fewer complications. This study evaluates whether the decision to undergo SSRF is associated with age, race, ethnicity, and insurance status and assesses associated clinical outcomes. METHODS: This retrospective analysis included patients ≥45 y old with rib fractures who underwent SSRF in the Trauma Quality Improvement Program from 2016 to 2020. Race, ethnicity, and insurance statuses were collected. Age in years was dichotomized into two groups: 45-64 and 65+. Outcomes included ventilator-associated pneumonia, unplanned endotracheal intubation, acute respiratory distress syndrome, in-hospital mortality, failure to rescue (FTR) after major complications, and FTR after respiratory complications. Logistic regression models were fit to evaluate outcomes, controlling for gender, body mass index, Injury Severity Score, flail chest, chronic obstructive pulmonary disease, congestive heart failure, and smoking. RESULTS: Two thousand eight hundred thirty-nine patients aged 45-64 and 1828 patients aged 65+ underwent SSRF. No significant difference in clinical outcomes was noted between these groups. Analysis showed that the association of SSRF with ventilator-associated pneumonia, unplanned intubation, acute respiratory distress syndrome, in-hospital mortality, FTR after a major complication, or FTR after a respiratory complication did not vary by age (P > 0.05). Black (odds ratio [OR] 0.67; 95% confidence interval [CI]: 0.59-0.77; P < 0.001), Hispanic (OR 0.80; 95% CI: 0.71-0.91; P < 0.001), and Medicaid (OR = 0.85; 95% CI = 0.76-0.95; P = 0.005) patients were less likely to receive SSRF. CONCLUSIONS: No differences in clinical outcomes were measured between adults aged 45-64 and ≥65 who underwent SSRF. Older age should not preclude patients from receiving SSRF. Further work is needed to improve underutilization in Black, Hispanic and Medicaid patients.
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During pandemics, healthcare providers struggle with balancing obligations to self, family, and patients. While HIV/AIDS seemed to settle this issue, coronavirus disease 2019 (COVID-19) rekindled debates regarding treatment refusal. We searched MEDLINE, Embase, CINAHL Complete, and Web of Science using terms including obligation, refusal, HIV/AIDS, COVID-19, and pandemics. After duplicate removal and dual, independent screening, we analyzed 156 articles for quality, ethical position, reasons, and concepts. Diseases in our sample included HIV/AIDS (72.2%), severe acute respiratory syndrome (SARS) (10.2%), COVID-19 (10.2%), Ebola (7.0%), and influenza (7.0%). Most articles (81.9%, n = 128) indicated an obligation to treat. COVID-19 had the highest number of papers indicating ethical acceptability of refusal (60%, P < .001), while HIV had the least (13.3%, P = .026). Several reason domains were significantly different during COVID-19, including unreasonable risks to self/family (26.7%, P < .001) and labor rights/workers' protection (40%, P < .001). A surge in ethics literature during COVID-19 has advocated for permissibility of treatment refusal. Balancing healthcare provision with workforce protection is crucial in effectively responding to a global pandemic.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Pessoal de Saúde/ética , Infecções por HIV/tratamento farmacológico , Pandemias , Recusa do Paciente ao Tratamento/ética , Obrigações MoraisRESUMO
A 40-year-old woman admitted for hyponatremia and anasarca due to decompensated cirrhosis after a recent steroid taper developed extremely painful cutaneous breast lesions clinically mimicking cellulitis and inflammatory breast cancer and was biopsy-diagnosed instead with diffuse dermal angiomatosis (DDA) of the breasts, a rare and painful disease that can be a diagnostic chameleon. This case highlights the importance of early surgical consultation and tissue biopsy to correctly diagnose the etiology of severely painful mastitis and prevent prolonged symptomology and repeated administrations of ineffective treatments. Diffuse dermal angiomatosis should be considered when suspected breast cellulitis is refractory to treatment or there is concern for inflammatory breast cancer, especially in pendulous-breasted women with comorbidities that increase susceptibility to local tissue hypoxia.
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Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of two concurrent conditions: septic abortion and disseminated intravascular coagulation (DIC). Introduction: Patients with an abortion (spontaneous or induced) of less than twenty weeks gestation may present with concurrent uterine infection, also known as septic abortion. One of the complications of septic abortion is DIC. Early management of both underlying etiology (septic abortion) and subsequent complications (DIC) is crucial to minimize morbidity and mortality. Educational Objectives: At the conclusion of the simulation session, learners will be able to: 1) Obtain a relevant focused history including pregnancy history, medication use, and past medical history. 2) Develop a differential for fever and vaginal bleeding in a pregnant patient. 3) Discuss management of septic abortion, including empiric broad-spectrum antibiotics and obstetric consultation for source control with dilation and curettage (D&C). 4) Discuss expected laboratory findings of disseminated intravascular coagulation (DIC). 5) Discuss management of DIC, including identification of underlying etiology and supportive resuscitation with blood products. 6) Review the components of blood products. 7) Identify appropriate disposition of the patient to the intensive care unit (ICU). Educational Methods: This session was conducted using high-fidelity simulation followed by a debriefing session and discussion about the diagnosis, differential, and management of both septic abortion and DIC. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. In this technique, the facilitator described something they observed in the case, outlined their reasoning as a facilitator why this observation was important or why they had questions, and then asked the learners to share their frame of reference at the time. An example: "I heard the team leader state that the platelets were normal, but then another resident disagreed. No one paused to come to a consensus. I'm wondering why this wasn't explored further in real time. Tell me more." This scenario may also be run as an oral boards case or adapted for other learners such as critical care fellows. Research Methods: Our residents were provided a survey at the completion of the debriefing session so they could rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. The local institution's simulation center's electronic feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form,1 with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. Results: Thirteen learners completed a feedback form out of seventeen participants. This session received all six and seven scores (consistently effective/very good and extremely effective/outstanding, respectively) other than two isolated 4 scores. Discussion: This is a cost-effective method for reviewing septic abortion and DIC. The case may be modified for appropriate audiences, such as simplifying the case to septic abortion without DIC. You can also consider not showing an initial temperature with the initial set of vitals unless it is specifically asked for by the participants. We encourage readers to utilize bleeding moulage techniques as a visual stimulus to increase psychological buy-in. Topics: Medical simulation, septic abortion, pregnancy complications, hematology emergencies, obstetric emergencies, disseminated intravascular coagulation, emergency medicine.
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BACKGROUND: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. OBJECTIVES: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. METHODS: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. RESULTS: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. CONCLUSIONS: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.
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Fadiga , Qualidade de Vida , Ataxias Espinocerebelares , Humanos , Qualidade de Vida/psicologia , Ataxias Espinocerebelares/psicologia , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/epidemiologia , Masculino , Fadiga/psicologia , Fadiga/epidemiologia , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Índice de Gravidade de Doença , Prevalência , Depressão/epidemiologia , Depressão/psicologiaRESUMO
AIMS: While peer support research is growing in the Type 1 diabetes (T1D) community, the peer supporter training (PST) process is rarely documented in detail. This study provides a comprehensive description of PST and evaluation for the REACHOUT mental health support intervention, and examines the feasibility and perceived utility of PST. METHODS: Fifty-three adults with T1D were recruited to participate in a 6-hour, zoom-based PST program for mental health support. The program was structured in three parts: (1) internal motivation, resilience and empathy; (2) mindfulness, emotions and diabetes distress; and (3) active listening and deferring clinical questions to professionals. Candidates were evaluated based on eight pre-established competency criteria during a 5-day support trial with an assigned standardized T1D participant. Perceived usefulness of training skills was also assessed 3 months into the REACHOUT mental health support intervention. RESULTS: Fifty-one of the fifty-three candidates who completed training achieved the criteria to graduate. Mean scores for the eight competency domains were: listens actively (4.55); asks open-ended questions (4.12); expresses empathy (4.42); avoids passing judgment (4.67); sits with strong emotions (4.44); refrains from giving advice (4.38); makes reflections (4.5); and defers medical questions (4.58). Of the skills learned during the PST, 95% rated interpreting and discussing diabetes distress profile and expressing empathy as moderately to extremely useful. CONCLUSIONS: Findings demonstrate that it is feasible to recruit and graduate the number of trainees needed using a rigorous process. Only by making training protocols available can the PST be replicated and translated to other T1D populations (e.g. adolescents, parents of children with T1D).
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Diabetes Mellitus Tipo 1 , Aplicativos Móveis , Adulto , Criança , Adolescente , Humanos , Diabetes Mellitus Tipo 1/terapia , Saúde Mental , Idioma , PaisRESUMO
INTRODUCTION: Firearm injury is a public health crisis. Most victims are minorities in underserved neighborhoods. Measuring firearm injury by mortality underestimates its impact, as most victims survive to discharge. This study was done to determine if race and insurance status are associated with discharge disposition for gunshot wound (GSW)-related trauma. METHODS: Using the 2019 Trauma Quality Improvement Program database, we identified GSW patients with Abbreviated Injury Scale (AIS) = 1-3. Exclusion criteria included patients who died in hospital and routine home discharge. We compared discharge patterns of patients based on demographics (age, gender, race, ethnicity, payor, AIS, hospital designation, and length of stay [LOS]) and injury severity. Multivariable logistic regression models identified factors associated with discharge disposition. RESULTS: Our sample included 2437 patients with GSWs. On univariable analysis, Black patients were more likely to discharge to home with home health (64.1% Black versus 34.7% White; P < 0.001). White patients were more likely to discharge to skilled nursing facility (SNF) (51.4% White versus 44.6% Black; P < 0.001). Controlling for age, race, Latin ethnicity, primary payor, LOS, AIS severity, and injury severity score factors independently associated with discharge to SNF included age (0.0462, P < 0.001), Medicaid (1.136, P < 0.0003), Medicare (1.452, P < 0.001), and LOS (0.03745, P < 0.001). CONCLUSIONS: Postacute care following traumatic injuries is essential to recovery. Black GSW victims are more likely to be discharged to home health than White patients, who are more likely to be discharged to SNF. Targeted programs to reduce barriers to appropriate aftercare are necessary to eliminate this bias and improve the care of underserved populations.
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Armas de Fogo , Ferimentos por Arma de Fogo , Idoso , Humanos , Estados Unidos/epidemiologia , Alta do Paciente , Ferimentos por Arma de Fogo/epidemiologia , Instituições de Cuidados Especializados de Enfermagem , Medicare , Estudos RetrospectivosRESUMO
Cancer of unknown primary (CUP) is a heterogeneous group of metastatic tumors in the absence of a clinically identifiable site. We describe the case of a 66-year-old female with an extensive history of non-specific imaging concerning for malignancy who did not undergo further workup and in whom a diagnosis of CUP was made. The patient initially presented to her specialist with concern of right leg pain. Imaging at that time was concerning for a progressive malignant process. Given this, the patient was referred urgently for surgery. Final surgical pathology and breast prognostic panel were consistent with metastatic breast carcinoma at that time. Follow-up imaging performed 1-week postoperatively did not show suspicious findings in either breast, further supporting a diagnosis of CUP. To this end, we highlight the importance of follow-up imaging but recognize the challenges facing healthcare professionals in navigating the ethical principles of nonmalificience and beneficence in diagnostic workup.
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A 68 year-old woman with no significant medical history discovered a lump incidentally in her left breast. The patient's initial imaging revealed a 4.6-cm irregular mass at 11:00 categorized as a BI-RADS 5 as well as an enlarged axillary lymph node and an area of 2.5 cm of heterogeneous calcifications in the 3 o'clock position. The 4.6-cm lesion was revealed to be infiltrating ductal carcinoma with a squamous component, mixed metaplastic carcinoma, which was strongly ER (100+)/PR (100+) positive, HER-2/Neu negative on FISH. The 2.5-cm calcifications were ductal carcinoma in situ. The patient completed neoadjuvant chemotherapy, and had an excellent response. After further discussion, the patient elected for breast conservation therapy and underwent a left wireless localized partial mastectomy with a left axillary dissection. Surgical pathology revealed a near complete pathologic response with only 8-mm residual tumour as well as a negative conversion of the clipped axillary node.
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In light of rapidly expanding road networks worldwide, there is increasing global awareness of the growing amount of mammalian roadkill. However, the ways in which road mortality affects the population dynamics of different species remains largely unclear. We aimed to categorise the demographic parameters in mammalian populations around the world that are directly or indirectly affected by road mortality, as well as identify the most effective study designs for quantifying population-level consequences of road mortality. We conducted a comprehensive systematic review to synthesise literature published between 2000 and 2021 and out of 11,238 unique studies returned, 83 studies were retained comprising 69 mammalian species and 150 populations. A bias towards research-intensive countries and larger mammals was apparent. Although searches were conducted in five languages, all studies meeting the inclusion criteria were in English. Relatively few studies (13.3%) provided relevant demographic context to roadkill figures, hampering understanding of the impacts on population persistence. We categorised five direct demographic parameters affected by road mortality: sex- and age-biased mortality, the percentage of a population killed on roads per year (values up to 50% were reported), the contribution of roadkill to total mortality rates (up to 80%), and roadkill during inter-patch or long-distance movements. Female-biased mortality may be more prevalent than previously recognised and is likely to be critical to population dynamics. Roadkill was the greatest source of mortality for 28% of studied populations and both additive and compensatory mechanisms to roadkill were found to occur, bringing varied challenges to conservation around roads. In addition, intra-specific population differences in demographic effects of road mortality were common. This highlights that the relative importance of road mortality is likely to be context specific as the road configuration and habitat quality surrounding a population can vary. Road ecology studies that collect data on key life parameters, such as age/stage/sex-specific survival and dispersal success, and that use a combination of methods are critical in understanding long-term impacts. Quantifying the demographic impacts of road mortality is an important yet complex consideration for proactive road management.
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Ecossistema , Mamíferos , Animais , Feminino , Dinâmica Populacional , EcologiaRESUMO
In order to image live cells for prolonged periods of time, an Arduino-based, low-cost imaging incubator was constructed. The imaging incubator keeps cells viable by controlling for temperature and CO 2 in order to maintain physiological conditions for cells during imaging. All devices and parts employed in the build were typical maker-type components in order to minimize the cost of the imaging incubator. The imaging incubator allows for real-time imaging of live cells exposed to any desired perturbation or stimulus. As a proof of the system's functionality, cells are imaged over 24 hours while remaining viable in the imaging incubator.
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Diagnóstico por Imagem , Incubadoras , TemperaturaRESUMO
The most common autosomal dominant ataxia worldwide, spinocerebellar ataxia type 3 (SCA3) is a fatal, progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the ATXN3 gene. Here we report the generation of human embryonic stem cell (hESC) line UM134-1, the first SCA3 disease-specific hESC line to be added to the NIH hESC registry. UM134-1 pluripotency was confirmed by immunocytochemistry and PCR for pluripotency markers and by the ability to form three germ layers in vitro. The established hESC line provides a useful new human cell model to study the pathogenesis of SCA3.
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Células-Tronco Embrionárias Humanas , Doença de Machado-Joseph , Humanos , Doença de Machado-Joseph/patologia , Ataxina-3/genética , Células-Tronco Embrionárias Humanas/metabolismo , Linhagem Celular , Expansão das Repetições de TrinucleotídeosRESUMO
PURPOSE: Xanthogranulomatous pyelonephritis (XGP) is a rare form of pyelonephritis more commonly seen in females and diabetics. Frequently associated with renal tract calculi, it is often difficult to diagnose, as it can clinically and radiologically mimic other disorders. Most cases are treated with antibiotics and nephrectomy. The aim of our review is to summarise and analyse the current evidence focusing on management. METHODS: A literature search was conducted to identify papers relating to xanthogranulomatous pyelonephritis in adults. Studies containing ten or more patients with XGP were included for descriptive analysis, and a meta-analyses of cohort studies conducted comparing open and minimally invasive nephrectomy undertaken. Other papers were included for narrative review. RESULTS: 52 studies were identified, 20 were included for narrative review and 32 retrospective observational studies containing 868 patients were included for descriptive analysis. 99.8% of patients underwent nephrectomy, about one-third laparoscopically. The most commonly cultured organisms were Escherichia coli and Proteus mirabilis. 60% of patients, where reported, underwent preoperative drainage. Seven studies containing 211 patients were included for meta-analysis which found that postoperative complications, length of stay and transfusion requirements were all significantly reduced in those who underwent minimally invasive surgery. CONCLUSION: The mainstay management of XGP is antibiotic therapy and nephrectomy. Some studies highlight a role for preoperative upper urinary tract drainage, but evidence supporting this is limited. We present the first meta-analyses examining operative approach for patients undergoing nephrectomy for XGP. Though limited by the data available, our meta-analysis indicates minimally invasive nephrectomy for XGP provides better postoperative outcomes.
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Pielonefrite Xantogranulomatosa , Adulto , Antibacterianos/uso terapêutico , Estudos de Coortes , Drenagem , Feminino , Humanos , Nefrectomia , Pielonefrite Xantogranulomatosa/complicações , Pielonefrite Xantogranulomatosa/diagnóstico , Pielonefrite Xantogranulomatosa/cirurgia , Estudos RetrospectivosRESUMO
Cardiac hemangiomas are exceedingly rare and can lead to cardiac tamponade. Cardiac tamponade is a true medical emergency that can cause cardiovascular collapse and death if not managed appropriately. There are many causes of cardiac tamponade such as trauma, autoimmune causes, and malignancy. Cardiac tumors are difficult to diagnose and may be present on advanced imaging including cardiac MRI. For patients with cardiac tumors causing tamponade, emergent pericardiocentesis and cardiovascular surgery consultation are necessary in management. We present a unique case of cardiac tamponade caused by a cardiac hemangioma.
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Tamponamento Cardíaco/etiologia , Neoplasias Cardíacas/complicações , Hemangioma/complicações , Idoso , Feminino , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/cirurgia , Hemangioma/diagnóstico , Hemangioma/patologia , Hemangioma/cirurgia , HumanosRESUMO
In the urban environment, wildlife faces novel human disturbances in unique temporal patterns. The weekend effect describes that human activities on weekends trigger changes in the environment and impact wildlife negatively. Reduced occurrence, altered behaviors, and/or reduced fitness have been found in birds, ungulates, and meso-carnivores due to the weekend effect. We aimed to investigate if urban bat activity would differ on weekends from weekdays. We analyzed year-round bat acoustic monitoring data collected from two sites near the city center and two sites in the residential area/park complex in the city periphery. We constructed generalized linear models and found that bat activity was significantly lower on weekends as compared to weekdays during spring and summer at the site in the open space near the city center. In contrast, during the same seasons, the sites in the city periphery showed increased bat activity on weekends. Hourly bat activity overnight suggested that bats might move from the city center to the periphery on weekends. We demonstrated the behavioral adaptability in urban wildlife for co-existing with human. We recommend that urban planning should implement practices such as adding new greenspaces and/or preserving old-growth vegetation to form continuous greenways from the city center to the city periphery as corridors to facilitate bat movements and reduce possible human-wildlife conflict.
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Transport infrastructure is a pervasive element in modern landscapes and continues to expand to meet the demands of a growing human population and its associated resource consumption. Road-induced mortality is often thought to be a major contributor to the marked declines of European hedgehog populations. This review synthesizes available evidence on the population-level impacts of road mortality and the threat to population viability for the five hedgehog species in Europe. Local and national studies suggest that road mortality can cause significant depletions in population sizes, predominantly removing adult males. Traffic collisions are a probable cause of fragmentation effects, subsequently undermining ecological processes such as dispersal, as well as the genetic variance and fitness of isolated populations. Further studies are necessary to improve population estimates and explicitly examine the consequences of sex- and age-specific mortality rates. Hedgehogs have been reported to use crossing structures, such as road tunnels, yet evaluations of mitigation measures for population survival probability are largely absent. This highlights the need for robust studies that consider population dynamics and genetics in response to mitigation. In light of ongoing declines of hedgehog populations, it is paramount that applied research is prioritised and integrated into a holistic spatial planning process.
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OBJECTIVE: We investigated the nature and neural foundations of pathologic tearfulness in a uniquely large cohort of patients who had presented with autoimmune limbic encephalitis (aLE). METHODS: We recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated correlations of questionnaire scores with demographic, clinical, neuropsychological, and brain imaging data across patients. We also compared patients diagnosed with pathologic tearfulness and those without, along with healthy controls, on gray matter volume, resting-state functional connectivity, and activity. RESULTS: Pathologic tearfulness was reported by 50% of the patients, while no patient reported pathologic laughing. It was not associated with depression, impulsiveness, memory impairment, executive dysfunction in the postacute phase, or amygdalar abnormalities in the acute phase. It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons. CONCLUSIONS: Pathologic tearfulness is common following aLE, is not a manifestation of other neuropsychiatric features, and reflects abnormalities in networks of emotion regulation beyond the acute hippocampal focus. The condition, which may also be present in other neurologic disorders, provides novel insights into the neural basis of affective control and its dysfunction in disease.
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Doenças Autoimunes/complicações , Doenças Autoimunes/patologia , Encéfalo/patologia , Choro/fisiologia , Regulação Emocional/fisiologia , Encefalite Límbica/complicações , Encefalite Límbica/patologia , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Programmed death 1 ligand 1 (PD-L1) Immunohistochemistry (IHC) is the key FDA-approved predictive marker to identify responders to anti-PD1 axis drugs. Multiple PD-L1 IHC assays with various antibodies and cut points have been used in clinical trials across tumor types. Comparative performance characteristics of these assays have been extensively studied qualitatively but not quantitatively. Here we evaluate the use of a standardized PD-L1 Index tissue microarray (TMA) to objectively determine agreement between antibody assays for PD-L1 applying quantitative digital image analysis. Using a specially constructed Index TMA containing a panel of ten isogenic cell lines in triplicate, we tested identical but independently grown batches of isogenic cells to prove Index TMAs can be produced in large quantities and hence serve as a standardization tool. Then the Index TMAs were evaluated using quantitative immunofluorescence (QIF) to validate the TMA itself and also to compare antibodies including E1L3N, SP142 and SP263. Next, an inter-laboratory and inter-assay comparison of 5 PD-L1 chromogenic IHC assays (US Food and Drug Administration (FDA) approved and lab developed test (LDT)) were performed at 12 sites around the USA. As previously reported, the SP142 FDA assay failed to detect low levels of PD-L1 in cell lines distinguished by the other four assays. The assays for 22C3 FDA, 28-8-FDA, SP263 FDA, and E1L3N LDT were highly similar across sites and all laboratories showed a high consistency over time for all assays using this Index TMA. In conclusion, we were able to objectively quantify PD-L1 expression on a standardized Index TMA using digital image analysis and we confirmed previous subjective assessments of these assays, but now in a multi-institutional setting. We envision commercial use of this Index TMA or similar smaller version as a useful standardization mechanism to compare results between institutions and to identify abnormalities while running routine clinical samples.
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Antígeno B7-H1/análise , Imunofluorescência , Linhagem Celular , Análise Serial de TecidosRESUMO
Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the respective disease genes. The nine known polyQ disease include Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and six spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17). The underlying disease mechanism in the polyQ diseases is thought principally to reflect dominant toxic properties of the disease proteins which, when harboring a polyQ expansion, differentially interact with protein partners and are prone to aggregate. Among the polyQ diseases, SCA3 is the most common SCA, and second to HD in prevalence worldwide. Here we summarize current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field. We emphasize properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms: 1) altered protein homeostasis; 2) DNA damage and dysfunctional DNA repair; and 3) nonneuronal contributions to disease. We conclude with an overview of the therapeutic implications of recent mechanistic insights.