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PURPOSE: Mastectomy, breast reconstruction (BR) and breast conserving therapy (BCT) are core components of the treatment paradigm for early-stage disease but are differentially associated with significant financial burdens. Given recent price transparency regulations, we sought to characterize rates of disclosure for breast cancer-related surgery, including mastectomy, BCT, and BR (oncoplastic reconstruction, implant, pedicled flap and free flap) and identify associated factors. METHODS: For this cross-sectional analysis, cost reports were obtained from the Turquoise Health price transparency platform for all U.S. hospitals meeting national accreditation standards for breast cancer care. The Healthcare Cost Report Information System was used to collect facility-specific data. Addresses were geocoded to identify hospital referral and census regions while data from CMS was also used to identify the geographic practice cost index. We leveraged a Poisson regression model and relevant Medicare billing codes to analyze factors associated with price disclosure and the availability of an OOP price estimator. RESULTS: Of 447 identified hospitals, 221 (49.4%) disclosed prices for mastectomy and 188 42.1%) disclosed prices for both mastectomy and some form of reconstruction including oncoplastic reduction (n = 184, 97.9%), implants (n = 187, 99.5%), pedicled flaps (n = 89, 47.3%), and free flaps (n = 81, 43.1%). Non-profit status and increased market competition were associated with price nondisclosure. 121 hospitals (27.1%) had an out-of-pocket price estimator that included at least one breast surgery. CONCLUSIONS: Most eligible hospitals did not disclose prices for breast cancer surgery. Distinct hospital characteristics were associated with price disclosure. Breast cancer patients face persistent difficulty in accessing costs.
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Neoplasias de la Mama , Colgajos Tisulares Libres , Mamoplastia , Humanos , Anciano , Estados Unidos/epidemiología , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/cirugía , Mastectomía , Revelación , Estudios Transversales , MedicareRESUMEN
Background: In Somaliland, an estimated one person in every two households suffers from psychiatric disorders. Despite this, access to mental health care is limited because of shortages in facilities, human resources, funding and stigma. Aim: To present the proportion of psychiatric disorders encountered in outpatient psychiatry clinics. Setting: The University if Hargeisa (UoH), Hargesisa, Somaliland. Methods: De-identified data on patients accessing psychiatric care from doctor trainees in the dual psychiatry-neurology residency program at UoH from January 2019 to June 2020 were included in the analysis. The Institutional Review Board from UoH approved data collection and analysis. The most common psychiatric diagnoses were summarised overall and by sex and age. Results: A total of 752 patients were included in the analysis. Most were male (54.7%), with an average age of 34.9 years. The most common psychiatric diagnoses were schizophrenia (28.0%), major depressive disorder (MDD) (14.3%) and bipolar disorder type 1 (BD1) (10.5%). When stratified by sex, patients with schizophrenia and BD1 were more likely to be male (73.5% and 53.3%, respectively), and those with MDD were more likely to be female (58.8%). Trauma- and stressor-related disorders accounted for 0.4% of cases, while 0.8% of patients presented with substance use disorders (alcohol and khat), which is an underestimate of the widespread use in Somaliland. Conclusion: Additional research using structured clinical interviews is needed to determine the epidemiology of psychiatric disorders and promote policies aiming to decrease neuropsychiatric mortality and morbidity. Contribution: This work presents the first data collection related to neuropsychiatric disorders in Somaliland.
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BACKGROUND AND OBJECTIVES: To characterize the disease burden of neurological cases in Hargeisa, Somaliland between January 2019 and June 2020 in order to shape clinical guidelines and develop policy interventions pertaining to brain health in the region. METHODS: In this retrospective, cross-sectional study, data was obtained from a case log of de-identified patients seen over an 18-month period. This case log was pulled from Hargeisa's three major city hospitals. In addition, demographic data including age and gender for each patient was obtained and gender-specific significance for each disease was determined. Patients were seen by one of three neuropsychiatry trainees at the University of Hargeisa. The Institutional Review Board from the University of Hargeisa has approved the data collection and analysis. RESULTS: Of the 1062 patients seen, 86.2% (915) presented with neurologic-specific diagnoses. 426 patients were female and 486 were male. Cerebral vascular accidents (CVAs, n = 272, 29.7%), traumatic brain injuries (TBIs, n = 113, 12.3%), infectious diseases (n = 94, 10.3%), headaches (n = 92, 10%), and epilepsy (n = 92, 10%) were the top five most prevalent diagnoses. The remaining patients (n = 147, 13.8%) presented with other non-neurologic diagnoses which may or may not capture any other co-morbidities the patients might have had. Notable sex-specific differences included headaches, which were more common (p < 0.0001) in female patients (n = 79, 18.5%) than in male patients (n = 13, 2.7%) and TBIs, which were more common (p < 0.0001) in male patients (n = 84, 17.2%) than female patients (n = 18, 4.2%). DISCUSSION: Our data contributes to neurological disease data in Hargeisa, Somaliland, with the top five prevalent diseases at three major city hospitals demonstrating a dire need for clinical guidelines and policy intervention aimed at improving brain health in the region.
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Costo de Enfermedad , Accidente Cerebrovascular , Estudios Transversales , Femenino , Cefalea , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson's Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.
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Transporte Axonal/fisiología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Receptores Presinapticos/metabolismo , alfa-Sinucleína/metabolismo , Animales , Inhibidores Enzimáticos , Femenino , Hipocampo/citología , Hipocampo/efectos de los fármacos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Embarazo , Cultivo Primario de Células , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
The two main pathological hallmarks of Parkinson's disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson's disease (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54-63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.
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Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , alfa-Sinucleína/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Progresión de la Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Agregado de Proteínas/fisiologíaRESUMEN
Nodal-related protein (ndr2) is amember of the transforming growth factor type ß superfamily of factors and is required for ventral midline patterning of the embryonic central nervous system in zebrafish. In humans, mutations in the gene encoding nodal cause holoprosencephaly and heterotaxy. Mutations in the ndr2 gene in the zebrafish (Danio rerio) lead to similar phenotypes, including loss of the medial floor plate, severe deficits in ventral forebrain development and cyclopia. Alleles of the ndr2 gene have been useful in studying patterning of ventral structures of the central nervous system. Fifteen different ndr2 alleles have been reported in zebrafish, of which eight were generated using chemical mutagenesis, four were radiation-induced and the remaining alleles were obtained via random insertion, gene targeting (TALEN) or unknown methods. Therefore, most mutation sites were random and could not be predicted a priori. Using the CRISPR-Cas9 system from Streptococcus pyogenes, we targeted distinct regions in all three exons of zebrafish ndr2 and observed cyclopia in the injected (G0) embryos.We show that the use of sgRNA-Cas9 ribonucleoprotein (RNP) complexes can cause penetrant cyclopic phenotypes in injected (G0) embryos. Targeted polymerase chain reaction amplicon analysis using Sanger sequencing showed that most of the alleles had small indels resulting in frameshifts. The sequence information correlates with the loss of ndr2 activity. In this study, we validate multiple CRISPR targets using an in vitro nuclease assay and in vivo analysis using embryos. We describe one specific mutant allele resulting in the loss of conserved terminal cysteine-coding sequences. This study is another demonstration of the utility of the CRISPR-Cas9 system in generating domain-specific mutations and provides further insights into the structure-function of the ndr2 gene.