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BACKGROUND: Spirituality is an important component of recovery for many individuals with substance use disorder (SUD). However, few studies have compared patient and physician attitudes on spirituality in SUD recovery. OBJECTIVE: This study investigates patient and physician beliefs about the role of spirituality in SUD recovery and about discussing spirituality in relationship to recovery in primary care settings. DESIGN: Semi-structured interviews were conducted with primary care physicians recruited at two academic hospitals, and patients recruited from a faith-based residential therapeutic community. Interview transcripts were independently coded by two researchers and a grounded theory approach was used to generate themes that reflected participants' experiences. KEY RESULTS: Interviews were conducted with 15 patients and 10 physicians. Patients had diverse views about the impact of spirituality on their SUD recovery, including positive, negative, and neutral. Patient and physician opinions on discussing spirituality in a primary care setting differed: most physicians felt positively towards this, believing that understanding their patients' spirituality helped them care for their patients as whole people. Many patients felt neutral, stating that they did not feel like these conversations were necessary for their care, and that they believed physicians preferred not to discuss spirituality in medical settings. Tolerance from both the patient and physician, open-ended questioning, and an individualized approach were identified as facilitators to effective discussions about spirituality and recovery. CONCLUSIONS: Spirituality can have diverse effects on an individual's SUD recovery. Physicians endorsed the benefits of discussing spirituality in the context of their patients' recovery, while patients expressed reservations about engaging in these conversations with their physicians. This variation in perspectives highlights the need for additional research to understand the individual and structural factors that contribute to it, as well as best practices for engaging in effective, non-judgmental conversations about spirituality in recovery.
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OBJECTIVE: Impaired insight and illness denial are common in anorexia nervosa (AN). Missing an AN diagnosis may delay treatment and negatively impact outcomes. METHOD: The current retrospective study examined the prevalence and characteristics of AN symptom non-endorsement (i.e., scoring within the normal range on the Eating Disorder Examination Questionnaire [EDE-Q] or the Eating Disorder Examination [EDE] interview) in three independent samples of hospitalised patients with AN (N1 = 154; N2 = 300; N3 = 194). A qualitative chart review of a subsample of non-endorsers (N4 = 32) extracted reports of disordered eating behaviours observed by the treatment team. RESULTS: The prevalence of non-endorsement ranged from 11% to 34% across sites. Non-endorsers were more likely to be diagnosed with AN restricting type (AN-R) and reported fewer symptoms of co-occurring psychopathology than endorsers. Groups benefitted equally from treatment. The qualitative chart review indicated that objective symptoms of AN were recorded by staff in over 90% of non-endorsers. CONCLUSIONS: Eating disorder symptom assessments using the EDE-Q or EDE may miss symptomatology in up to a third of individuals hospitalised with AN. This study highlights the potential utility of multi-modal assessment including patient interviews, collateral informants, and behavioural observation to circumvent non-endorsement.
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Anorexia Nervosa , Hospitalização , Humanos , Anorexia Nervosa/psicologia , Anorexia Nervosa/epidemiologia , Feminino , Estudos Retrospectivos , Adulto , Adolescente , Masculino , Inquéritos e Questionários , Adulto Jovem , Prevalência , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologiaRESUMO
TOPIC: We provide global estimates of the prevalence of corneal blindness and vision impairment in adults 40 years of age and older and examine the burden by age, sex, and geographic region from 1984 through 2020. CLINICAL RELEVANCE: Corneal opacities (COs) are among the top 5 causes of blindness worldwide, yet the global prevalence, regional differences, and risk factors are unclear. METHODS: Abstracted data from the published literature and surveys were obtained from the Global Burden of Disease Vision Loss Expert Group. We supplemented this by an independent systematic literature search of several databases. Studies that provided CO vision impairment data based on population-based surveys for those 40 years of age or older were included, for a total of 244. For each of the 4 outcomes of blindness and moderate to severe vision impairment (MSVI) caused by trachomatous and nontrachomatous CO (NTCO), time trends and differences in prevalence by region, age, and sex were evaluated using a Poisson log-linear model with a generalized estimating equation method. Age-standardized estimates of global prevalence of blindness and MSVI were calculated using the 2015 United Nations standard populations. RESULTS: The global prevalence of blindness resulting from NTCO in those 40 years and older was 0.081% (95% confidence interval [CI], 0.049%-0.315%); that of MSVI was 0.130% (95% CI, 0.087%-0.372%). A significant increase with age was found (prevalence rate ratio, 2.15; 95% CI, 1.99-2.32). Latin America and Europe showed the lowest rates, with 2- to 8-fold higher rates of blindness or MSVI in other regions. The global prevalence of blindness resulting from trachomatous CO in those 50 years and older was 0.0094% (95% CI, 0%-0.0693%); that from MSVI was 0.012% (95% CI, 0%-0.0761%). Blindness resulting from trachomatous CO and MSVI increased with age and female sex, and rates were significantly higher in the African regions. A decrease in trachomatous blindness rates over time was found (prevalence rate ratio, 0.91; 95% CI, 0.86-0.96). DISCUSSION: An estimated 5.5 million people worldwide are bilaterally blind or have MSVI resulting from CO, with an additional 6.2 million unilaterally blind. Blindness resulting from trachomatous CO is declining over time, likely because of the massive scaleup of the global trachoma elimination program and overall socioeconomic development. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Opacidade da Córnea , Tracoma , Pessoas com Deficiência Visual , Adulto , Humanos , Feminino , Cegueira/epidemiologia , Cegueira/etiologia , Transtornos da Visão/etiologia , Opacidade da Córnea/epidemiologia , PrevalênciaRESUMO
Leg length discrepancies are common orthopedic problems with the potential for poor functional outcomes. These are frequently assessed using bilateral leg length radiographs. The objective was to determine whether an artificial intelligence (AI)-based image analysis system can accurately interpret long leg length radiographic images. We built an end-to-end system to analyze leg length radiographs and generate reports like radiologists, which involves measurement of lengths (femur, tibia, entire leg) and angles (mechanical axis and pelvic tilt), describes presence and location of orthopedic hardware, and reports laterality discrepancies. After IRB approval, a dataset of 1,726 extremities (863 images) from consecutive examinations at a tertiary referral center was retrospectively acquired and partitioned into train/validation and test sets. The training set was annotated and used to train a fasterRCNN-ResNet101 object detection convolutional neural network. A second-stage classifier using a EfficientNet-D0 model was trained to recognize the presence or absence of hardware within extracted joint image patches. The system was deployed in a custom web application that generated a preliminary radiology report. Performance of the system was evaluated using a holdout 220 image test set, annotated by 3 musculoskeletal fellowship trained radiologists. At the object detection level, the system demonstrated a recall of 0.98 and precision of 0.96 in detecting anatomic landmarks. Correlation coefficients between radiologist and AI-generated measurements for femur, tibia, and whole-leg lengths were > 0.99, with mean error of < 1%. Correlation coefficients for mechanical axis angle and pelvic tilt were 0.98 and 0.86, respectively, with mean absolute error of < 1°. AI hardware detection demonstrated an accuracy of 99.8%. Automatic quantitative and qualitative analysis of leg length radiographs using deep learning is feasible and holds potential in improving radiologist workflow.
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Inteligência Artificial , Radiologia , Humanos , Perna (Membro) , Estudos Retrospectivos , Radiografia , Radiologia/métodosRESUMO
Scoliosis is a condition of abnormal lateral spinal curvature affecting an estimated 2 to 3% of the US population, or seven million people. The Cobb angle is the standard measurement of spinal curvature in scoliosis but is known to have high interobserver and intraobserver variability. Thus, the objective of this study was to build and validate a system for automatic quantitative evaluation of the Cobb angle and to compare AI generated and human reports in the clinical setting. After IRB was obtained, we retrospectively collected 2150 frontal view scoliosis radiographs at a tertiary referral center (January 1, 2019, to January 1, 2021, ≥ 16 years old, no hardware). The dataset was partitioned into 1505 train (70%), 215 validation (10%), and 430 test images (20%). All thoracic and lumbar vertebral bodies were segmented with bounding boxes, generating approximately 36,550 object annotations that were used to train a Faster R-CNN Resnet-101 object detection model. A controller algorithm was written to localize vertebral centroid coordinates and derive the Cobb properties (angle and endplate) of dominant and secondary curves. AI-derived Cobb angle measurements were compared to the clinical report measurements, and the Spearman rank-order demonstrated significant correlation (0.89, p < 0.001). Mean difference between AI and clinical report angle measurements was 7.34° (95% CI: 5.90-8.78°), which is similar to published literature (up to 10°). We demonstrate the feasibility of an AI system to automate measurement of level-by-level spinal angulation with performance comparable to radiologists.
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Escoliose , Adolescente , Inteligência Artificial , Humanos , Vértebras Lombares/diagnóstico por imagem , Aprendizado de Máquina , Reprodutibilidade dos Testes , Estudos Retrospectivos , Escoliose/diagnóstico por imagemRESUMO
Maps of the synapses made and neurotransmitters released by all neurons in model systems, such as Caenorhabditis elegans have left still unresolved how neural circuits integrate and respond to neurotransmitter signals. Using the egg-laying circuit of C. elegans as a model, we mapped which cells express each of the 26 neurotransmitter GPCRs of this organism and also genetically analyzed the functions of all 26 GPCRs. We found that individual neurons express many distinct receptors, epithelial cells often express neurotransmitter receptors, and receptors are often positioned to receive extrasynaptic signals. Receptor knockouts reveal few egg-laying defects under standard laboratory conditions, suggesting that the receptors function redundantly or regulate egg-laying only in specific conditions; however, increasing receptor signaling through overexpression more efficiently reveals receptor functions. This map of neurotransmitter GPCR expression and function in the egg-laying circuit provides a model for understanding GPCR signaling in other neural circuits.SIGNIFICANCE STATEMENT Neurotransmitters signal through GPCRs to modulate activity of neurons, and changes in such signaling can underlie conditions such as depression and Parkinson's disease. To determine how neurotransmitter GPCRs together help regulate function of a neural circuit, we analyzed the simple egg-laying circuit in the model organism C. elegans We identified all the cells that express every neurotransmitter GPCR and genetically analyzed how each GPCR affects the behavior the circuit produces. We found that many neurotransmitter GPCRs are expressed in each neuron, that neurons also appear to use these receptors to communicate with other cell types, and that GPCRs appear to often act redundantly or only under specific conditions to regulate circuit function.
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Proteínas de Caenorhabditis elegans/metabolismo , Neurônios/citologia , Neurotransmissores/metabolismo , Oviposição , Receptores Acoplados a Proteínas G/metabolismo , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Vias Neurais/citologia , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Receptores Acoplados a Proteínas G/genéticaRESUMO
Of the approximately 10 million cases of Mycobacterium tuberculosis (Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for the growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor.IMPORTANCEIsoniazid (INH) is a critical frontline antibiotic to treat Mycobacterium tuberculosis (Mtb) infections. INH efficacy is limited by its suboptimal penetration of the Mtb-containing lesion and by the prevalence of clinical INH resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a set of INH-resistant mutants to INH. Resistance is typically mediated by katG mutations that decrease the activation of INH, which is required for INH to inhibit the essential enzyme InhA. Our current work demonstrates that C10 re-sensitizes INH-resistant katG-hypomorphs without enhancing the activation of INH. We furthermore show that C10 causes Mtb to become particularly vulnerable to InhA inhibition without compromising InhA activity on its own. Therefore, C10 represents a novel strategy to curtail the development of INH resistance and to sensitize Mtb to sub-lethal doses of INH, such as those achieved at the infection site.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Isoniazida/farmacologia , Mycobacterium tuberculosis/genética , Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Proteínas de Bactérias/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Mutação , Catalase/genética , Testes de Sensibilidade MicrobianaRESUMO
OBJECTIVE: Avoidant restrictive food intake disorder (ARFID) has similar prevalence to anorexia nervosa (AN) in adults, but research in this population is lacking. Although inpatient or residential treatment involving nutritional rehabilitation is increasingly recommended for malnourished individuals with ARFID, best practices remain poorly defined. Existing studies on self-reported symptomatology and treatment course and outcome are primarily in child and adolescent cohorts and demonstrate inconsistent findings. This study aimed to compare hospital course and self-reported symptomatology of underweight adult inpatients with ARFID and sex- and age-matched patients with AN. METHOD: Underweight adult patients with ARFID or AN admitted to a specialized, hospital-based behavioral treatment program completed measures of body dissatisfaction, drive for thinness, bulimic symptoms, anxiety, depression, and personality traits. Demographic and treatment course data were abstracted from electronic medical records. Patients with ARFID (n = 69) were matched to those with AN (n = 69) based on sex and age. RESULTS: Adults with ARFID were closer to target weight at admission, but gained weight at a slower rate, were discharged at lower BMI, and were less likely to reach target weight by discharge than adults with AN. Patients with ARFID reported less weight and shape-related eating disorder, state anxiety, and depression symptoms and lower neuroticism. DISCUSSION: Adults with ARFID progress through treatment more slowly and achieve less favorable weight outcomes by hospital discharge than patients with AN, but long-term outcomes are unclear. Describing clinical presentations and course of illness of adult ARFID may help inform treatment protocols.
This study examined hospital course and symptomatology in underweight adults with avoidant/restrictive food intake disorder (ARFID) compared to adults with anorexia nervosa (AN). Both groups were admitted at similar BMI, however compared to patients with AN, those with ARFID gained weight slower and were half as likely to reach target weight by discharge. Adults with ARFID were equally likely, however, to be rated as clinically improved at discharge. Patients with ARFID also reported less symptoms of anxiety, depression or neuroticism than did those with AN, and less weight and shape-related eating disorder symptoms at admission. The reason for slower weight restoration in adults with ARFID may reflect the need for more individualized protocols adapted to meet the unique, often heterogeneous needs of these individuals. Longer-term post-discharge outcomes for adults with ARFID remain unclear and require investigation.
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Of the approximately 10 million cases of Mycobacterium tuberculosis (Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor.
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Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (-)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Isoxazóis/farmacologia , Testes de Sensibilidade Microbiana , Proteínas de BactériasRESUMO
Treatment of Mycobacterium tuberculosis (Mtb) infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy in vivo often fails to match drug efficacy in vitro. This is due to multiple reasons, including inadequate drug concentrations reaching Mtb at the site of infection and physiological changes of Mtb in response to host derived stresses that render the bacteria more tolerant to antibiotics. To more effectively and efficiently treat tuberculosis, it is necessary to better understand the physiologic state of Mtb that promotes drug tolerance in the host. Towards this end, multiple studies have converged on bacterial central carbon metabolism as a critical contributor to Mtb drug tolerance. In this review, we present the evidence that changes in central carbon metabolism can promote drug tolerance, depending on the environment surrounding Mtb. We posit that these metabolic pathways could be potential drug targets to stymie the development of drug tolerance and enhance the efficacy of current antimicrobial therapy.
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Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Carbono/metabolismo , Tolerância a Medicamentos , Humanos , Redes e Vias MetabólicasRESUMO
Here, we report our studies of immune-mediated regulation of Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the human cornea. We find that ZIKV can be transmitted via corneal transplantation in mice. However, in human corneal explants, we report that ZIKV does not replicate efficiently and that SARS-CoV-2 does not replicate at all. Additionally, we demonstrate that type III interferon (IFN-λ) and its receptor (IFNλR1) are expressed in the corneal epithelium. Treatment of human corneal explants with IFN-λ, and treatment of mice with IFN-λ eye drops, upregulates antiviral interferon-stimulated genes. In human corneal explants, blockade of IFNλR1 enhances replication of ZIKV and HSV-1 but not SARS-CoV-2. In addition to an antiviral role for IFNλR1 in the cornea, our results suggest that the human cornea does not support SARS-CoV-2 infection despite expression of ACE2, a SARS-CoV-2 receptor, in the human corneal epithelium.
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Betacoronavirus/fisiologia , Córnea/virologia , Infecções por Coronavirus/transmissão , Herpesvirus Humano 1/fisiologia , Interferons/imunologia , Pneumonia Viral/transmissão , Zika virus/fisiologia , Animais , Betacoronavirus/imunologia , COVID-19 , Córnea/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Herpes Simples/imunologia , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Replicação Viral/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia , Interferon lambdaRESUMO
STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4ß7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.