RESUMO
The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding toward one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, which constitute a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence or absence of a presenter protein, using the "presenter ratio", the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity. Through this approach, we identified a range of cooperative, noncooperative, and uncooperative compounds in a single DNA-encoded library screen with bromodomain containing protein (BRD)9 and the VHL-elongin C-elongin B (VCB) complex. Our most cooperative hit compound, 13-7, exhibits micromolar binding affinity to BRD9 but nanomolar affinity for the ternary complex with BRD9 and VCB, with cooperativity comparable to classical molecular glues. This approach may enable the rational discovery of molecular glues for preselected proteins and thus facilitate the transition to a new paradigm of small-molecule therapeutics.
Assuntos
DNA , Proteínas , Sítios de Ligação , Domínios ProteicosRESUMO
BACKGROUND: Delirium is a critically underdiagnosed syndrome of altered mental status affecting more than 50% of older adults admitted to hospital. Few studies have incorporated speech and language disturbance in delirium detection. We sought to describe speech and language disturbances in delirium, and provide a proof of concept for detecting delirium using computational speech and language features. METHODS: Participants underwent delirium assessment and completed language tasks. Speech and language disturbances were rated using standardized clinical scales. Recordings and transcripts were processed using an automated pipeline to extract acoustic and textual features. We used binomial, elastic net, machine learning models to predict delirium status. RESULTS: We included 33 older adults admitted to hospital, of whom 10 met criteria for delirium. The group with delirium scored higher on total language disturbances and incoherence, and lower on category fluency. Both groups scored lower on category fluency than the normative population. Cognitive dysfunction as a continuous measure was correlated with higher total language disturbance, incoherence, loss of goal and lower category fluency. Including computational language features in the model predicting delirium status increased accuracy to 78%. LIMITATIONS: This was a proof-of-concept study with limited sample size, without a set-aside cross-validation sample. Subsequent studies are needed before establishing a generalizable model for detecting delirium. CONCLUSION: Language impairments were elevated among patients with delirium and may also be used to identify subthreshold cognitive disturbances. Computational speech and language features are promising as accurate, noninvasive and efficient biomarkers of delirium.
Assuntos
Disfunção Cognitiva , Delírio , Humanos , Idoso , Fala , Idioma , Disfunção Cognitiva/diagnóstico , Delírio/diagnósticoRESUMO
Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes. Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development.
Assuntos
Antivirais , Proteínas do Capsídeo , Capsídeo , Animais , Camundongos , Antivirais/farmacologia , Modelos Animais de Doenças , Relação Estrutura-Atividade , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/metabolismoRESUMO
We report a short synthetic route for synthesizing 2,3-substituted piperazine acetic acid esters. Optically pure amino acids were efficiently converted into 1,2-diamines that could be utilized to deliver the title 2,3-substituted piperazines in five steps with a high enantiomeric purity. The novel route facilitated, for the first time, the synthesis of 3-phenyl substituted-2-piperazine acetic acid esters that were difficult to achieve using other methods; however, in this case, the products underwent racemization.
Assuntos
Diaminas , Piperazinas , Ácido Acético , Ésteres/química , Piperazina , Piperazinas/química , EstereoisomerismoRESUMO
Recognition of familiar as compared to unfamiliar faces is robust and resistant to marked image distortion or degradation. Here we tested the flexibility of familiar face recognition with a morphing paradigm where the appearance of a personally familiar face was mixed with the appearance of a stranger (Experiment 1) and the appearance of one's own face with the appearance of a familiar face and the appearance of a stranger (Experiment 2). The aim of the two experiments was to assess how categorical boundaries for recognition of identity are affected by familiarity. We found a narrower categorical boundary for the identity of personally familiar faces when they were mixed with unfamiliar identities as compared to the control condition, in which the appearance of two unfamiliar faces was mixed. Our results suggest that familiarity warps the representational geometry of face space, amplifying perceptual distances for small changes in the appearance of familiar faces that are inconsistent with the structural features that define their identities.
Assuntos
Reconhecimento Facial/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Reconhecimento Psicológico/fisiologia , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC50] = 0.08 to 0.27 µM; EC90 = 0.33 to 1.32 µM) with no significant cytotoxicity (50% cytotoxic concentration > 10 µM). Addition of 40% human serum resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.
Assuntos
Antivirais/farmacologia , Capsídeo/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Montagem de Vírus/efeitos dos fármacos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , DNA Circular/metabolismo , DNA Viral/sangue , DNA Viral/metabolismo , Feminino , Guanina/análogos & derivados , Guanina/farmacologia , Vírus da Hepatite B/crescimento & desenvolvimento , Humanos , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , RNA Viral/genéticaRESUMO
The prevalence of psychotic disorders in individuals with 22q11.2 Deletion Syndrome (22q11DS) reaches 25-35% in young adulthood and may provide a neurogenetic model for clinical risk of psychotic disorders in the general population. This review focuses on prospective longitudinal studies in 22q11DS, which capture fluctuations in psychosis symptoms over time and may provide insights into potential demographic, clinical, cognitive, and neuroimaging predictors of psychosis-spectrum outcomes in the general population. Findings are compared and contrasted with those from idiopathic psychosis-spectrum populations. Onset of psychotic disorders in 22q11DS can occur over a wide range of ages, peaking in late adolescence. Symptoms may be gradually progressive or episodic in nature, highlighting the importance and challenge of risk and resilience prediction models. Converging results suggest that psychosis-spectrum outcomes in 22q11DS are predicted by lower baseline functioning, higher baseline psychosis-spectrum symptoms, presence of mood disturbance or anxiety, and lower baseline and subsequent decline in global measures of cognition. Predictors of transition to threshold psychotic disorders and ages of onset are similar in idiopathic clinical risk. They also share similarly global cognitive deficits, but not to the same extent as in 22q11DS. While neuroimaging studies in idiopathic clinical risk suggest loss of prefrontal gray matter, there is no consistent evidence yet emerging in the limited literature in 22q11DS. Interventional efforts in 22q11DS aimed at halting progression to psychosis or mitigating outcomes in early psychosis may be best implemented during the adolescent age range. Collaborative longitudinal efforts may help to address existing gaps in our understanding.
Assuntos
Síndrome de DiGeorge/genética , Transtornos Psicóticos/genética , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos ProspectivosRESUMO
Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with impairment in multiple domains of cognition and risk for several psychiatric disorders. Musical auditory processing is highly heritable, and is impaired in individuals with schizophrenia and other neurodevelopmental disorders, but has never been studied in 22q11DS, notwithstanding anecdotal evidence of its sparing. We aimed to characterize musical auditory processing in 22q11DS and explore potential relationships with other cognitive domains, musical engagement, and psychiatric disorders. The Distorted Tunes Task and Global Musical Sophistication Index were used to assess pitch discrimination and general musical engagement in 58 individuals with 22q11DS aged 8-29 years. Psychopathology was assessed with sections from the modified Schedule for Affective Disorders and Schizophrenia for School-Age Children and the Structured Interview for Prodromal Syndromes. The Penn computerized neurocognitive battery (CNB) examined four domains of cognition (executive functioning, episodic memory, complex cognition, and social cognition). Significant musical auditory processing impairment and reduced musical engagement were found in individuals with 22q11DS. However, deficits in musical auditory processing were not associated with reduced musical engagement. After covarying for age and sex, episodic memory and overall CNB performance accuracy were significantly related to performance in musical auditory processing. There were no relationships between musical auditory processing and presence of any psychiatric diagnoses. Individuals with 22q11DS experience significant deficits in musical auditory processing and reduced musical engagement. Pitch discrimination is associated with overall cognitive ability, but appears to be largely independent of psychiatric illness.
Assuntos
Percepção Auditiva/genética , Cognição/fisiologia , Síndrome de DiGeorge/fisiopatologia , Síndrome da Deleção 22q11/genética , Síndrome da Deleção 22q11/fisiopatologia , Adolescente , Adulto , Transtornos da Percepção Auditiva/genética , Criança , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino , Transtornos do Humor/genética , Música/psicologia , Testes Neuropsicológicos , Sintomas Prodrômicos , Psicopatologia/métodos , Transtornos Psicóticos/genética , Esquizofrenia/genética , Comportamento Social , Adulto JovemRESUMO
The traditional use of the Crawford tube for lacrimal intubation during dacryocystorhinostomy (DCR) carries several drawbacks. We describe the use of the STENTube for DCR intubation and detail its advantages. Retrospective, noncomparative, interventional case series; 313 patients with nasolacrimal duct obstruction (NLDO) underwent 339 DCRs (216 external, 123 endonasal) with the STENTube from January 2007 - June 2013 by 5 surgeons (RS, QN, TS, SB, TN) across 3 institutions (SUNY Downstate Medical Center, Texas Oculoplastics Consultants, and Moorfields Eye Hospital). Study outcome measures included patient demographics, surgical complications, and epiphora improvement/resolution. 206 (66%) females and 107 (34%) males had a mean age of 63 years (range 2-94 years). Distribution of diagnoses included: 314 complete idiopathic acquired NLDO, 20 partial idiopathic acquired NLDO, and 5 congenital complete NLDO. 316 (93%) were primary DCRs and 23 (7%) were revisions. Epiphora improved in 312 (92%) cases with 294 (86%) experiencing resolution with patent lacrimal irrigation at a mean last follow-up of 9.4 months. Twenty-eight (8%) patients experienced surgical complications with 16 (5%) experiencing tube prolapse, and 20 (6%) requiring re-operation. The STENTube represents a simple method for lacrimal intubation during external or endonasal DCR at a comparable cost to the Crawford tube. It allows for low prolapse rates without the need for additional endonasal fixation procedures, resulting in a simple and comfortable post-operative extraction without risk of lacrimal trauma. The STENTube is our preferred intubation technique during DCR, and should be considered by oculofacial surgeons performing DCR with intubation.
Assuntos
Dacriocistorinostomia/métodos , Intubação , Obstrução dos Ductos Lacrimais/terapia , Ducto Nasolacrimal/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Irrigação Terapêutica , Resultado do TratamentoRESUMO
Orbital floor fractures (OFF) with entrapment require prompt clinical and radiographic recognition for timely surgical correction. Correct CT radiographic interpretation of entrapped fractures can be subtle and thus missed. We reviewed the clinical, radiographic and intraoperative findings of 45 cases of entrapped OFF to correlate pre- and intraoperative findings with radiography. Retrospective review and statistical analysis of 45 patients with OFF using the chi squared and Kruskal-Wallis tests. Main outcome measures included patient demographics, clinical features, radiologic interpretation, intraoperative findings, and treatment outcomes. Twenty-one cases (47%) had radiologic evaluations of orbital CT scans that included commentary on possible entrapment. Intraoperatively, 16 (76%) of these patients had the inferior rectus muscle incarcerated in the fracture, while 5 (24%) patients had incarceration of the orbital fat. Possibility of entrapment was not commented on in the radiology reports of the remaining 24 (53%) cases. Intraoperatively, 13 (54%) of these patients had the inferior rectus muscle incarcerated in the fracture, while 11 (46%) patients had incarceration of the orbital fat. It is vital to assess the possibility of entrapment, especially in young patients, in the setting of OFF as a delay in diagnosis may lead to persistent diplopia, disfigurement, or bradycardia. Most radiology reports did not mention the possibility of entrapment in this cohort. A key concept is that entrapment occurs when any orbital tissue (muscle or fat) is trapped in the fracture site.
Assuntos
Músculos Oculomotores/lesões , Órbita/lesões , Fraturas Orbitárias/diagnóstico por imagem , Lesões dos Tecidos Moles/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Traumatismos em Atletas/diagnóstico , Criança , Pré-Escolar , Diplopia/diagnóstico , Dor Ocular/diagnóstico , Feminino , Humanos , Masculino , Transtornos da Motilidade Ocular/diagnóstico , Fraturas Orbitárias/cirurgia , Estudos Retrospectivos , Lesões dos Tecidos Moles/cirurgia , Adulto JovemRESUMO
PURPOSE: Pediatric idiopathic orbital inflammation (IOI) is a rare entity with little known about the clinical presentation and natural history. The authors report the demographics, clinical presentations, radiographic and histopathologic characteristics, and treatment outcome of 30 children with IOI. METHODS: Retrospective chart review of 30 patients 18 years and younger diagnosed with IOI and statistical analysis using analysis of variance and Fisher's exact test. This study was reviewed and approved by the Institutional Review Board of SUNY Downstate Medical Center. RESULTS: There were 9 males (30%) and 21 females (70%) with pediatric IOI who presented at a median age of 11 years (range 2-18 years). Primary IOI was found in 19 patients (63%) and recurrent IOI in 11 patients (37%). Overall, 26 patients (87%) had unilateral IOI while 4 patients (13%) had bilateral disease at presentation. There were 12 patients (40%) with systemic constitutional signs. The most common ophthalmic findings included periorbital edema (n = 20, 67%) and blepharoptosis (n = 17, 57%). All patients had orbital radiography with common findings of dacryoadenitis (n = 12, 40%), orbital mass (n = 12, 40%), or myositis (n=10, 33%). The presence of a radiographic orbital mass was significantly related to the clinical presence of blepharoptosis (p = 0.03). The most common treatment was oral glucocorticoids in 24 patients (80%). Over mean follow up of 19 months (range 6-64 months), females were more likely to display recurrent disease (p = 0.01). CONCLUSIONS: Idiopathic orbital inflammation is an uncommon but important cause of acute orbital syndrome in children, manifesting as a bilateral condition in 13% and with constitutional symptoms in 40%. Posttreatment recurrence is found in 37% of cases.
Assuntos
Glucocorticoides/administração & dosagem , Órbita/diagnóstico por imagem , Pseudotumor Orbitário/diagnóstico , Adolescente , Biópsia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pseudotumor Orbitário/tratamento farmacológico , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: Bilateral lacrimal gland (LG) disease is a unique presentation that can result from varied causes. We reviewed the diagnoses, clinical features, and outcomes of 97 patients with this entity. DESIGN: Case series. PARTICIPANTS: Ninety-seven patients with bilateral LG disease. METHODS: Retrospective review and statistical analysis using analysis of variance and the Fisher exact test. MAIN OUTCOME MEASURES: Patient demographics, clinical features, diagnostic testing, diagnosis, and treatment. RESULTS: Patient age ranging from 8 to 84 years (mean, 46 years). The predominant gender was female (77%), and race included black (49%), white (38%), and Hispanic (12%) patients. Diagnoses fell into 4 categories: inflammatory (n = 51; 53%), structural (n = 20; 21%), lymphoproliferative (n = 19; 20%), and uncommon (n = 7; 7%) entities. The most common diagnoses included idiopathic orbital inflammation (IOI; n = 29; 30%), sarcoidosis (n = 19; 20%), prolapsed LG (n = 15; 15%), lymphoma (n = 11; 11%), lymphoid hyperplasia (n = 8; 8%), and dacryops (n = 5; 5%). Inflammatory conditions were more likely in younger patients (P<0.05) and in those with pain (P<0.001) and mechanical blepharoptosis (P<0.01) at presentation, whereas lymphoma was more common in older patients (P<0.001) without active signs of inflammation at presentation. Black patients were more likely to have sarcoidosis (P<0.01). Laboratory results showed high angiotensin converting enzyme level being significantly more likely in patients with sarcoidosis (P<0.05). However, sensitivity was limited to 45%, with 25% of patients diagnosed with IOI also demonstrating positive results. Corticosteroid therapy was the treatment of choice in 38 cases, corresponding to resolution of symptoms in 29% and improvement in an additional 32%. Overall, chronic underlying disease was found in 71% of patients, among whom 26% achieved a disease-free state, whereas 3% succumbed to their underlying disease. CONCLUSIONS: The cause of bilateral lacrimal gland disease most commonly was inflammatory, followed by structural and lymphoproliferative. Patient characteristics and clinical presentations were key features distinguishing between competing possibilities. Despite local control with corticosteroids or radiotherapy, underlying disease continued in 71% of patients and led to death in 3%.
Assuntos
Doenças do Aparelho Lacrimal , Adolescente , Adulto , Idoso de 80 Anos ou mais , Análise de Variância , Criança , Feminino , Humanos , Doenças do Aparelho Lacrimal/diagnóstico , Doenças do Aparelho Lacrimal/etiologia , Doenças do Aparelho Lacrimal/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Distribuição por Sexo , Esteroides/uso terapêutico , Adulto JovemRESUMO
Children with 22q11.2 deletion syndrome (22q11DS) present with congenital heart disease (CHD) and high prevalence of psychiatric disorders and neurocognitive deficits. Although CHD has been implicated in neurodevelopment, its role in the neuropsychiatric outcome in 22q11DS is poorly understood. We investigated whether CHD contributes to the high prevalence of psychiatric disorders and neurocognitive impairments in 22q11DS. Fifty-four children ages 8-14 years with 22q11DS and 16 age-matched non-deleted children with CHD participated. They were assessed using semi-structured interviews and a Computerized Neurocognitive Battery. CHD status was assessed using available medical records. Prevalence of psychiatric disorders and cognitive profiles were compared among the groups. There were no significant differences between the prevalence of psychiatric disorders in the 22q11DS with and without CHD. In 22q11DS with CHD, the prevalence rates were 41% anxiety disorders, 37% ADHD and 71% psychosis spectrum. In 22q11DS without CHD, the rates were 33% anxiety disorders, 41% ADHD and 64% psychosis spectrum. In comparison, the non-deleted CHD group had lower rates of psychopathology (25% anxiety disorders, 6% ADHD, and 13% psychosis spectrum). Similarly, the 22q11DS groups, regardless of CHD status, had significantly greater neurocognitive deficits across multiple domains, compared to the CHD-only group. We conclude that CHD in this sample of children with 22q11.2DS does not have a major impact on the prevalence of psychiatric disorders and is not associated with increased neurocognitive deficits. These findings suggest that the 22q11.2 deletion status itself may confer significant neuropsychiatric vulnerability in this population.
Assuntos
Transtornos de Ansiedade/genética , Síndrome de DiGeorge/genética , Predisposição Genética para Doença , Transtornos Psicóticos/genética , Adolescente , Criança , Cromossomos Humanos Par 22 , Cognição/fisiologia , Síndrome de DiGeorge/etiologia , Feminino , Testes Genéticos/métodos , Humanos , MasculinoRESUMO
Objective: During the COVID-19 pandemic, the prevalence of depression and anxiety among children and adolescents significantly increased, along with the number of visits to emergency departments due to suicidality and/or suicide attempts. Relatedly, health care workers experienced significant burnout and symptoms of anxiety, depression, and posttraumatic stress disorder during this time. However, the corresponding impact on psychiatric inpatient treatment has not yet been researched. We hypothesized that during the pandemic, adolescents hospitalized in an acute care psychiatric inpatient unit had increased incidents of suicide attempts and nonsuicidal self-injurious behaviors and of aggressive behaviors toward others, resulting in greater use of constant observation and restraints. Method: This study was a retrospective chart review based on electronic medical record data examining use of restraints and constant observation one year before the pandemic (March 2019 to February 2020) and 1 year following the onset of the pandemic (March 2020 to February 2021) in an acute-care adolescent (12 to 17 years old) psychiatric inpatient unit. Results: There were 571 admissions during the year before the pandemic and 500 admissions during the pandemic. The number of patients who were restrained (χ2 = 7.86, p = 0.005), number of patients who were placed on constant observation (χ2 = 13.41, p < 0.001), and number of constant observation orders per patient (χ2 = 91.90, p < 0.001) were all significantly greater during the pandemic. Conclusion: Psychiatrically hospitalized adolescents during the pandemic received more intensive interventions such as restraints and constant observation. Severe patient psychopathology and staff shortages, as well as limitations of and decreases to the dialectical behavior therapy program, may have been the contributing factor.
Assuntos
COVID-19 , Comportamento Autodestrutivo , Tentativa de Suicídio , Humanos , Adolescente , COVID-19/psicologia , COVID-19/epidemiologia , Estudos Retrospectivos , Masculino , Feminino , Tentativa de Suicídio/estatística & dados numéricos , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/terapia , Criança , Pacientes Internados/psicologia , Hospitalização/estatística & dados numéricos , Ansiedade/epidemiologia , Transtornos Mentais/terapia , Transtornos Mentais/epidemiologia , Saúde Mental , Depressão/epidemiologia , Depressão/terapia , Agressão/psicologiaRESUMO
OBJECTIVE: Patients' race and age have each been identified as risk factors for experiencing restraint events during psychiatric hospitalization. Restraint duration is also an important variable in determining disparities in treatment. To the authors' knowledge, no studies to date have examined the effect of the interaction of race and age on restraint use and duration in inpatient psychiatric settings. This retrospective chart review of electronic medical records of patients admitted between 2012 and 2019 sought to examine whether race and age interacted in predicting differences in the use and duration of restraints in a psychiatric inpatient setting. METHODS: Logistic and hierarchical regression analyses were conducted on data from a sample of 29,739 adolescent (ages 12-17 years) and adult (ages ≥18 years) inpatients to determine whether the interaction of race and age group (adolescent or adult) significantly predicted a restraint event or differences in restraint duration. RESULTS: Black (adjusted OR [AOR]=1.85) and multiracial (AOR=1.36) patients were more likely to experience a restraint event than were their White peers. Black race was also significantly (p=0.001) associated with longer restraint duration. No significant interaction was detected between race and age in predicting restraint events or duration. CONCLUSIONS: Although the interaction between race and age did not predict restraint events or duration, the findings indicate racial disparities in the frequency and duration of restraint events among Black and multiracial individuals and may inform efforts to reduce these events.
Assuntos
Hospitalização , Pacientes Internados , Adulto , Adolescente , Humanos , Estudos Retrospectivos , Grupos Raciais , Fatores de Risco , Disparidades em Assistência à SaúdeRESUMO
The morpholine heterocycle is a structural unit found in many bioactive compounds and FDA-approved drugs, but the generation of more complex C-functionalized morpholine derivatives remains considerably underexplored. Using systematic chemical diversity (SCD), a concept that guides the expansion of saturated drug-like scaffolds through regiochemical and stereochemical variation, we describe the synthesis of a collection of methyl-substituted morpholine acetic acid esters starting from enantiomerically pure amino acids and amino alcohols. In total, 24 diverse substituted morpholines were produced that vary systematically in regiochemistry and stereochemistry (relative and absolute). These diverse C-substituted morpholines can be directly applied in fragment screening or incorporated as building blocks in medicinal chemistry and library synthesis.
Assuntos
Morfolinas , Morfolinas/química , Estrutura Molecular , Estereoisomerismo , Ésteres/química , Aminoácidos/química , Aminoácidos/síntese química , Química FarmacêuticaRESUMO
Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments. Here we describe the identification of AB-452, a dihydroquinolizinone (DHQ) analogue. AB-452 is a potent HBV RNA destabilizer by inhibiting PAPD5/7 proteins in vitro with good in vivo efficacy in a chronic HBV mouse model. AB-452 showed acceptable tolerability in 28-day rat and dog toxicity studies, and a high degree of oral exposure in multiple species. Based on its in vitro and in vivo profiles, AB-452 was identified as a clinical development candidate.
Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Camundongos , Ratos , Animais , Cães , Vírus da Hepatite B/genética , Antígenos de Superfície da Hepatite B , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , RNA Viral/genética , Relação Estrutura-Atividade , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , DNA Viral/genética , Replicação ViralRESUMO
Functional impairments contribute to poor quality of life in schizophrenia spectrum disorders (SSD). We sought to (Objective I) define the main functional phenotypes in SSD, then (Objective II) identify key biopsychosocial correlates, emphasizing interpretable data-driven methods. Objective I was tested on independent samples: Dataset I (N = 282) and Dataset II (N = 317), with SSD participants who underwent assessment of multiple functioning areas. Participants were clustered based on functioning. Objective II was evaluated in Dataset I by identifying key features for classifying functional phenotype clusters from among 65 sociodemographic, psychological, clinical, cognitive, and brain volume measures. Findings were replicated across latent discriminant analyses (LDA) and one-vs.-rest binomial regularized regressions to identify key predictors. We identified three clusters of participants in each dataset, demonstrating replicable functional phenotypes: Cluster 1-poor functioning across domains; Cluster 2-impaired Role Functioning, but partially preserved Independent and Social Functioning; Cluster 3-good functioning across domains. Key correlates were Avolition, anhedonia, left hippocampal volume, and measures of emotional intelligence and subjective social experience. Avolition appeared more closely tied to role functioning, and anhedonia to independent and social functioning. Thus, we found three replicable functional phenotypes with evidence that recovery may not be uniform across domains. Avolition and anhedonia were both critical but played different roles for different functional domains. It may be important to identify critical functional areas for individual patients and target interventions accordingly.
RESUMO
Racism is a social determinant of mental health which has a disproportionally negative impact on the experiences of psychiatric inpatients of color. Distinct differences in the physical space and clinical settings of two inpatient buildings at a hospital system in the tristate (New York, New Jersey, Connecticut) area of the United States led to the present investigation of racial inequities in the assignment of patients to specific buildings and units. Archival electronic medical record data were analyzed from over 18,000 unique patients over a period of six years. Hierarchical logistic regression analyses were conducted with assigned building (old vs. new building) as the binary outcome variable. Non-Hispanic White patients were set as the reference group. Black, Hispanic/Latinx, and Asian patients were significantly less likely to be assigned to better resourced units in the new building. When limiting the analysis to only general adult units, Black and Hispanic/Latinx patients were significantly less likely to be assigned to units in the new building. These results suggest ethnoracial inequities in patient assignment to buildings which differed in clinical and physical conditions. The findings serve as a call to action for hospital systems to examine the ways in which structural racism impact clinical care.