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1.
Diabetes Spectr ; 37(2): 130-138, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756429

RESUMO

Objective: The ideal inpatient insulin regimen efficiently attains the target blood glucose range, effectively treats hyperglycemia, and minimizes the risk of hypoglycemia. The objective of this study was to compare glycemic targets achieved by using correctional monotherapy (CM) and basal-bolus therapy (BBT) in insulin-naive patients in the inpatient setting to determine optimal blood glucose management for these patients. Design: This was a retrospective observational cohort study of 792 patients with diabetes not on home insulin therapy who were admitted to an academic hospital over a 5.5-month period. The percentages of hyperglycemic and hypoglycemic values in each group were compared. Results: Among the 3,112 measured blood glucose values obtained from 792 patients within the first 24 hours of insulin administration, 28.5% were hyperglycemic in the BBT group compared with 23.5% in the CM group. When adjusted for covariates, there was a 23% decrease in hyperglycemia in the BBT group (incidence rate ratio = 0.77, 95% CI 0.64-0.95, P = 0.006). Increases in A1C and admission blood glucose, as well as decreases in admission creatinine and inpatient steroid use, were independently associated with higher rates of hyperglycemia, adjusted for all other covariates. There was no significant difference between the groups in the rate of hypoglycemia in the first 24 hours, which was 1.9% in the BBT group and 1.4% in the CM group (P = 0.301). Conclusion: Utilizing BBT in insulin-naive patients admitted to the hospital within the first 24 hours of insulin administration results in lower rates of hyperglycemia without higher rates of hypoglycemia when compared with CM.

2.
Sex Health ; 212024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39038162

RESUMO

Background Over 2million people worldwide receive a new HIV diagnosis annually. Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission, but is underprescribed, including in the US. Lack of clinician comfort and knowledge are the most cited reasons for this discrepancy. We aimed to develop a mobile application (app) to address these barriers and improve patient access to PrEP. Methods We established key criteria to develop a point-of-care app that could be utilised in low-resource settings by various clinicians poised to prescribe PrEP therapy. The app underwent two rounds of beta testing and improvement utilising anonymous survey feedback from US physicians in 2023. Results The PrEP Resource tool was developed. Eleven physicians completed the initial survey addressing prescribing practices and app functionality. A total of 27% (3/11) of participants were uncomfortable prescribing PrEP, with the most common reasons being lack of training, unfamiliarity with guidelines and infrequently prescribing the medication. Our follow-up survey, completed by eight physicians, showed that 100% of participants found the app easy to learn and comprehensive enough to initiate PrEP. Conclusion Clinician discomfort due to lack of knowledge and familiarity is the most common reason for not prescribing PrEP. The PrEP Resource is a free tool that guides healthcare professionals through common clinical scenarios regarding PrEP therapy and may improve clinician comfort levels. It can be used in low-resource and low-bandwidth settings typically encountered in lower-middle-income countries where HIV prevalence is the highest. Further study is required to validate its usefulness across different settings.


Assuntos
Infecções por HIV , Aplicativos Móveis , Profilaxia Pré-Exposição , Humanos , Infecções por HIV/prevenção & controle , Infecções por HIV/diagnóstico , Profilaxia Pré-Exposição/métodos , Padrões de Prática Médica/estatística & dados numéricos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Inquéritos e Questionários , Masculino , Feminino
3.
Infancy ; 29(4): 525-549, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38696120

RESUMO

Turn-taking interactions are foundational to the development of social, communicative, and cognitive skills. In infants, vocal turn-taking experience is predictive of infants' socioemotional and language development. However, different forms of turn-taking interactions may have different effects on infant vocalizing. It is presently unknown how caregiver vocal, non-vocal and multimodal responses to infant vocalizations compare in extending caregiver-infant vocal turn-taking bouts. In bouts that begin with an infant vocalization, responses that maintain versus change the communicative modality may differentially affect the likelihood of further infant vocalizing. No studies have examined how caregiver response modalities that either matched or differed from the infant acoustic (vocal) modality might affect the temporal structure of vocal turn-taking beyond the initial serve-and-return exchanges. We video-recorded free-play sessions of 51 caregivers with their 9-month-old infants. Caregivers responded to babbling most often with vocalizations. In turn, caregiver vocal responses were significantly more likely to elicit subsequent infant babbling. Bouts following an initial caregiver vocal response contained significantly more turns than those following a non-vocal or multimodal response. Thus prelinguistic turn-taking is sensitive to the modality of caregivers' responses. Future research should investigate if such sensitivity is grounded in attentional constraints, which may influence the structure of turn-taking interactions.


Assuntos
Cuidadores , Comportamento do Lactente , Humanos , Feminino , Masculino , Lactente , Comportamento do Lactente/fisiologia , Comportamento Verbal , Adulto , Desenvolvimento da Linguagem
4.
Infancy ; 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39054758

RESUMO

What environmental regularities support infant communicative learning from social interactions? We propose that infants allocate their attention toward and learn from external events that are contingent on their own behaviors. We tested the robustness of the influence of contingency on communicative learning by using a non-biological stimulus, a remote-controlled car, as the social partner. The car approached infants and produced a speech sound either contingently to infants' vocalizations or on a yoked schedule. Two additional groups had an unfamiliar human experimenter as their social partner in contingent and yoked control conditions. We assessed whether infants formed expectations about their partner's responsiveness to their vocalizations. Expectations made based on contingent responsiveness would support the role of contingency in promoting plasticity in early communicative learning. Infants across all conditions increased their vocalization rates when their partner paused in responding, suggesting that they expected their vocalizations to influence their partners' behavior. Infants vocalized significantly more to the social partner than their caregiver if they received contingent rather than yoked responses from the social partner, regardless of if the partner was a human or non-biological agent. Contingent responses to prelinguistic vocalizations facilitated the formation of expectations for interactivity of social partners.

5.
J Psychosoc Oncol ; : 1-14, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831557

RESUMO

OBJECTIVE: Insomnia and repetitive negative thinking (RNT) are both prevalent among cancer survivors, yet little work has investigated their interrelationship. To explore the hypothesis that RNT and insomnia are related, we conducted secondary analyses on data from a pilot clinical trial of cognitive behavioral therapy for insomnia (CBT-I) for cancer survivors. METHODS: This study analyzed survey data from 40 cancer survivors with insomnia who participated in a pilot randomized trial of CBT-I. Correlations and linear regression models were used to determine associations between aspects of RNT and related constructs (fear of cancer recurrence [FCR], cancer-specific rumination, worry, and intolerance of uncertainty) and sleep (insomnia and sleep quality), while accounting for psychiatric symptoms such as anxiety and depression. Treatment-related change in RNT was examined using a series of linear mixed models. RESULTS: Evidence for an association between RNT and insomnia among cancer survivors emerged. Higher levels of FCR and cancer-related rumination were correlated with more severe insomnia symptoms and worse sleep quality. Notably, FCR levels predicted insomnia, even after controlling for anxiety and depression. Results identified potential benefits and limitations of CBT-I in addressing RNT that should be examined more thoroughly in future research. CONCLUSIONS: RNT is a potential target to consider in insomnia treatment for cancer survivors.

6.
Angew Chem Int Ed Engl ; : e202409286, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39018503

RESUMO

Rechargeable Mg batteries are a promising energy storage technology to overcome the limitations inherent to Li ion batteries. A critical challenge in advancing Mg batteries is the lack of suitable cathode materials. In this work, we report a cathode design that incorporates S functionality into two-dimensional metal-organic-frameworks (2D-MOFs). This new cathode material enables good Mg2+ storage capacity and outstanding cyclability. It was found that upon the initial Mg2+ insertion and disinsertion, there is an apparent structural transformation that crumbles the layered 2D framework, leading to amorphization. The resulting material serves as the active material to host Mg2+ through reduction and/or oxidation of S and, to a limited extent, O. The reversible nature of S and O redox chemistry was confirmed by spectroscopic characterizations and validated by density functional calculations. Importantly, during the Mg2+ insertion and disinsertion process, the 2D nature of the framework was maintained, which plays a key role in enabling the high reversibility of the MOF cathode.

7.
J Clin Gastroenterol ; 57(9): 920-927, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37490604

RESUMO

INTRODUCTION: A new bowel preparation for colonoscopy has been developed containing poorly absorbed sulfate salts and polyethylene glycol 3350, which retain water within the intestinal lumen resulting in copious diarrhea, thereby cleansing the bowel. The product was formulated to be safe and effective with a sports drink-like flavor. This study evaluated the new flavored polyethylene glycol and sulfate solution (FPSS) compared with a Food and Drug Administration-approved bowel preparation containing sulfate salts only [oral sulfate solution (OSS)]. METHODS: Five hundred adults were enrolled in this multicenter, noninferiority study. Subjects were assigned FPSS or OSS administered in split-dose regimens (PM/AM). FPSS subjects took 2 L of the flavored osmotic solution (1 L at night and 1 L in the morning). OSS was taken according to its approved labeling. Colonoscopies were graded globally and segmentally by blinded local investigators using a 4-point scale (excellent, good, fair, and poor), with "good" and "excellent" considered successful. Safety was assessed by adverse events (AEs) and laboratory testing. RESULTS: A high rate of cleansing success was seen with FPSS (94%), which was noninferior to OSS (94%). This conclusion was confirmed by blinded central readers. Segmental success rates were >90% for both preparations, including the right colon. Questionnaire ratings indicated the FPSS experience was preferred over OSS with 87% of FPSS subjects noting their preparation was "tolerable" to "very easy" to consume versus 74% for OSS. The majority of FPSS subjects agreed their preparation tasted like a sports drink. Gastrointestinal symptoms were the most common AEs. There was no difference between preparations for any AE and no clinically significant differences in laboratory parameters. CONCLUSIONS: The new sports drink-like flavored preparation achieved a high level of cleansing in the study, demonstrating noninferiority to OSS. FPSS was well-tolerated with low rates of expected gastrointestinal symptoms. The optimized flavor of FPSS resulted in significantly better acceptance ratings.


Assuntos
Catárticos , Sulfatos , Humanos , Adulto , Sulfatos/efeitos adversos , Catárticos/efeitos adversos , Sais , Polietilenoglicóis/efeitos adversos , Colonoscopia/métodos , Compostos de Enxofre
8.
Dev Sci ; 26(2): e13296, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35737680

RESUMO

Infants' prelinguistic vocalizations reliably organize vocal turn-taking with social partners, creating opportunities for learning to produce the sound patterns of the ambient language. This social feedback loop supporting early vocal learning is well-documented, but its developmental origins have yet to be addressed. When do infants learn that their non-cry vocalizations influence others? To test developmental changes in infant vocal learning, we assessed the vocalizations of 2- and 5-month-old infants in a still-face interaction with an unfamiliar adult. During the still-face, infants who have learned the social efficacy of vocalizing increase their babbling rate. In addition, to assess the expectations for social responsiveness that infants build from their everyday experience, we recorded caregiver responsiveness to their infants' vocalizations during unstructured play. During the still-face, only 5-month-old infants showed an increase in vocalizing (a vocal extinction burst) indicating that they had learned to expect adult responses to their vocalizations. Caregiver responsiveness predicted the magnitude of the vocal extinction burst for 5-month-olds. Because 5-month-olds show a vocal extinction burst with unfamiliar adults, they must have generalized the social efficacy of their vocalizations beyond their familiar caregiver. Caregiver responsiveness to infant vocalizations during unstructured play was similar for 2- and 5-month-olds. Infants thus learn the social efficacy of their vocalizations between 2 and 5 months of age. During this time, infants build associations between their own non-cry sounds and the reactions of adults, which allows learning of the instrumental value of vocalizing.


Assuntos
Desenvolvimento da Linguagem , Voz , Adulto , Lactente , Humanos , Retroalimentação , Idioma , Cuidadores
9.
Pediatr Transplant ; 27(5): e14535, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37128132

RESUMO

BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity among immunocompromised patients who have undergone kidney transplantation and is known to rarely induce collapsing focal segmental glomerulosclerosis (FSGS) among adults. METHODS: We present the first reported case of CMV-induced collapsing FSGS in a pediatric patient after kidney transplant. RESULTS: Our patient underwent a deceased donor kidney transplant due to end-stage renal disease secondary to lupus nephritis. Approximately 4 months after transplantation, he developed signs of worsening kidney function in the setting of CMV viremia and was found to have collapsing features of FSGS on kidney transplant biopsy. He was managed with a prompt escalation of antiviral therapy along with a reduction of immunosuppression and recovered without significant complication. At follow-up, he continued to have undetectable CMV titers, creatinine within normal limits, and no significant proteinuria. CONCLUSION: This report demonstrates CMV as a cause of collapsing FSGS and should be considered among pediatric transplant recipients who present with acute kidney injury, as should early assessment of APOL1 genetic status in both donor and recipient.


Assuntos
Infecções por Citomegalovirus , Glomerulosclerose Segmentar e Focal , Falência Renal Crônica , Transplante de Rim , Masculino , Adulto , Humanos , Criança , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/diagnóstico , Transplante de Rim/efeitos adversos , Citomegalovirus , Falência Renal Crônica/complicações , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Apolipoproteína L1
10.
Curr Opin Ophthalmol ; 34(Suppl 1): S1-S13, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36951648

RESUMO

PURPOSE OF REVIEW: To discuss common reasons for nonadherence and review existing and emerging options to reduce nonadherence with ocular medical therapy and optimize therapeutic outcomes. RECENT FINDINGS: Nonadherence can arise from patient-related issues (e.g. physical, cognitive) and healthcare-related issues (e.g. cost, access to care). Multiple strategies have been developed and evaluated to overcome these barriers to adherence. Identifying nonadherence and its cause(s) facilitates the development of strategies to overcome it. SUMMARY: Many common causes of nonadherence can be mitigated through a variety of strategies presented.


Assuntos
Adesão à Medicação , Humanos , Adesão à Medicação/psicologia , Oftalmologia
12.
J Ultrasound Med ; 42(2): 443-451, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36106704

RESUMO

OBJECTIVES: The reported malignancy rate of highly suspicious thyroid nodules based on the ACR TI-RADS criteria (TI-RADS category 5 [TR5]) varies widely. The objective of our study was to determine the rate of malignancy of TR5 nodules at our institution. We also aimed to determine the predictive values of individual sonographic features, as well as the correlation of total points assigned to a nodule and rate of malignancy. METHODS: Our single-institution retrospective study evaluated 450 TR5 nodules that had cytology results available, in 399 patients over a 1-year period. Sonographic features and total TI-RADS points were determined by the interpreting radiologist. Statistical analyses included logistic regression models to find factors associated with increased odds of malignancy, and computing sensitivity, specificity, positive and negative predictive values of various individual sonographic features. RESULTS: Of the 450 nodules, 95 (21.1%, 95% exact confidence interval 17.4-25.2%) were malignant. Each additional TI-RADS point increased the odds of malignancy (adjusted odds ratio 1.35, 95% confidence interval 1.13-1.60, P < .001). "Very hypoechoic" was the sonographic feature with the highest specificity and positive predictive value for malignancy (95.5 and 44.8%, respectively), while "punctate echogenic foci" had the lowest positive predictive value (20.0%). CONCLUSIONS: The rate of malignancy of TR5 nodules at our institution was 21.1%, which is lower than other malignancy rates reported in the literature. The total number of points assigned on the basis of the TI-RADS criteria was positively associated with malignancy, which indicates that TR5 should be viewed as a spectrum of risk.


Assuntos
Nódulo da Glândula Tireoide , Humanos , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/patologia , Estudos Retrospectivos , Ultrassonografia/métodos , Valor Preditivo dos Testes , Radiologistas
13.
Cancer ; 128(7): 1532-1544, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34914845

RESUMO

BACKGROUND: For cancer survivors, insomnia is prevalent, distressing, and persists for years if unmanaged. Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment yet can be difficult to access and may require modification to address survivorship-specific barriers to sleep. In this 2-phase study, the authors adapted and assessed the feasibility, acceptability, and preliminary effects of synchronous, virtual CBT-I adapted for cancer survivors (the Survivorship Sleep Program [SSP]). METHODS: From April to August 2020, cancer survivors with insomnia (N = 10) were interviewed to refine SSP content and delivery. From October 2020 to March 2021, 40 survivors were recruited for a randomized controlled trial comparing 4 weekly SSP sessions with enhanced usual care (EUC) (CBT-I referral plus a sleep hygiene handout). Feasibility and acceptability were assessed by enrollment, retention, attendance, fidelity, survey ratings, and exit interviews. Insomnia severity (secondary outcome), sleep quality, sleep diaries, and fatigue were assessed at baseline, postintervention, and at 1-month follow-up using linear mixed models. RESULTS: The SSP included targeted content and clinician-led, virtual delivery to enhance patient centeredness and access. Benchmarks were met for enrollment (56% enrolled/eligible), retention (SSP, 90%; EUC, 95%), attendance (100%), and fidelity (95%). Compared with EUC, the SSP resulted in large, clinically significant improvements in insomnia severity (Cohen d = 1.19) that were sustained at 1-month follow-up (Cohen d = 1.27). Improvements were observed for all other sleep metrics except sleep diary total sleep time and fatigue. CONCLUSIONS: Synchronous, virtually delivered CBT-I targeted to cancer survivors is feasible, acceptable, and seems to be efficacious for reducing insomnia severity. Further testing in larger and more diverse samples is warranted.


Assuntos
Sobreviventes de Câncer , Terapia Cognitivo-Comportamental , Neoplasias , Distúrbios do Início e da Manutenção do Sono , Sobreviventes de Câncer/psicologia , Terapia Cognitivo-Comportamental/métodos , Humanos , Neoplasias/complicações , Projetos Piloto , Sono , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/terapia , Sobrevivência , Resultado do Tratamento
14.
Immunity ; 38(1): 187-97, 2013 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-23260195

RESUMO

Knowledge of human T cells derives chiefly from studies of peripheral blood, whereas their distribution and function in tissues remains largely unknown. Here, we present a unique analysis of human T cells in lymphoid and mucosal tissues obtained from individual organ donors, revealing tissue-intrinsic compartmentalization of naive, effector, and memory subsets conserved between diverse individuals. Effector memory CD4(+) T cells producing IL-2 predominated in mucosal tissues and accumulated as central memory subsets in lymphoid tissue, whereas CD8(+) T cells were maintained as naive subsets in lymphoid tissues and IFN-γ-producing effector memory CD8(+) T cells in mucosal sites. The T cell activation marker CD69 was constitutively expressed by memory T cells in all tissues, distinguishing them from circulating subsets, with mucosal memory T cells exhibiting additional distinct phenotypic and functional properties. Our results provide an assessment of human T cell compartmentalization as a new baseline for understanding human adaptive immunity.


Assuntos
Memória Imunológica/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Fatores Etários , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Imunofenotipagem , Cadeias alfa de Integrinas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa/imunologia , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/metabolismo , Doadores de Tecidos , Adulto Jovem
15.
Endocr Pract ; 28(9): 853-858, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35793752

RESUMO

OBJECTIVE: Previous studies have reported a low value of ordering inpatient thyroid function tests (TFTs), with few changes in clinical management resulting from these tests. This study was designed to evaluate how often testing the thyroid function during hospitalization leads to medication initiation or adjustment and to determine whether the frequency of medication initiation or adjustment differs based on the indication for testing. METHODS: This is a retrospective observational study of 2278 patients who underwent TFTs tested while admitted to an academic hospital during a 5-month period. The indications for ordering TFTs were determined by reviewing clinical documentation, and those with abnormal test results were reviewed to assess whether thyroid medication was initiated or adjusted. RESULTS: The percentage of abnormal TFTs that led to medication initiation or adjustment was 15.1%, 12.2%, and 6.0%, for those tested based on a history of functional thyroid disease, suspicion of thyroid dysfunction, and reasons not directly related to thyroid dysfunction, respectively. Overall, 63 patients were started on thyroid medication or had their thyroid medication dose adjusted, which represented 10.1% of those with abnormal TFTs and only 2.8% of those tested. CONCLUSION: Abnormal TFTs are common, but a disproportionate number of tests are needed to find a small percentage of clinically significant thyroid dysfunction, of which only a low percentage leads to changes in management. Education on this topic should be provided to inpatient providers to limit thyroid function testing to instances in which they are clinically indicated and abnormal results would lead to changes in management.


Assuntos
Doenças da Glândula Tireoide , Testes de Função Tireóidea , Humanos , Pacientes Internados , Estudos Retrospectivos , Doenças da Glândula Tireoide/diagnóstico
16.
Nephrology (Carlton) ; 27(11): 901-905, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36047901

RESUMO

To describe an experience using a protocol using de novo belatacept (DNB) based maintenance immunosuppression in the setting of lymphocyte depletion. A retrospective, observational study was performed on 37 kidney transplant recipients treated with the DNB protocol, which was defined as belatacept initiated within 7 days after a kidney transplant with steroids and mycophenolate with anti-thymocyte globulin (ATG) induction without concomitant calcineurin inhibitors (CNIs). Patients who received a deceased donor kidney meeting one or more of the following criteria: anticipated cold ischemia time (CIT) greater than 24 h, donation after cardiac death, donor acute kidney injury, and a Kidney Donor Profile Index (KDPI) >85% during the study period were included. Patient survival at 1 year was 97.3% and graft survival was 94.6%. Delayed graft function (DGF) occurred in 40.54% of the patients. Two patients experienced a Banff 1B acute cellular rejection. BK viremia was detected in 32.4% of patients. The mean estimated glomerular filtration rate (eGFR) calculated with the use of modification of diet in renal disease (MDRD) equation at 1 year in the study group was 54.7 ml/min/1.73 m2 . We believe that utilization of the DNB protocol, which allows early CNI avoidance, may decrease organ discard rates.


Assuntos
Soro Antilinfocitário , Inibidores de Calcineurina , Abatacepte/efeitos adversos , Aloenxertos , Soro Antilinfocitário/efeitos adversos , Inibidores de Calcineurina/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão , Imunossupressores/efeitos adversos , Rim , Estudos Retrospectivos , Esteroides
17.
Genes Dev ; 28(24): 2726-38, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25512560

RESUMO

The WD40 domain-containing protein WRAP53ß (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53ß as an essential regulator of DNA double-strand break (DSB) repair. WRAP53ß rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53ß targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53ß facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53ß controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53ß impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. Our findings establish WRAP53ß as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.


Assuntos
Reparo do DNA/fisiologia , Telomerase/metabolismo , Ubiquitina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Células Cultivadas , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Chaperonas Moleculares , Proteínas Nucleares/metabolismo , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Telomerase/genética , Transativadores/metabolismo , Ubiquitina-Proteína Ligases
18.
Curr Opin Ophthalmol ; 32 Suppl 1: S1-S12, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33273209

RESUMO

PURPOSE OF REVIEW: Advances in pharmacology offer freedom from topical medical therapy without compromise of anti-inflammatory and antimicrobial coverage in the perioperative period. In this review, we describe the basis for dropless cataract surgery with the goal of improving outcomes and the patient experience. RECENT FINDINGS: Phacoemulsification outcomes depend largely on surgeon skill but also on adherence to a complex multidrug regimen of perioperative anti-inflammatory and antimicrobial therapy to prevent sight-threatening complications such as cystoid macular edema or endophthalmitis. Successful administration of this regimen can be limited by noncompliance, difficulty administering eye drops, bioavailability, and side effects, among others. The recent development of sustained-release formulations of dexamethasone - one an intracanalicular insert and the other an intraocular suspension - can provide sustained tapering doses of dexamethasone while reducing or eliminating the need for anti-inflammatory eye drop therapy. Similarly, mounting evidence compellingly demonstrates that intracameral antibiotic use intraoperatively is at least as effective as topical antibiotics in preventing endophthalmitis. SUMMARY: Sustained-release dexamethasone coupled with intracameral antibiotics at the time of phacoemulsification can provide antimicrobial and anti-inflammatory prophylaxis without the need for topical eye drop medications. This approach has the potential to improve compliance with therapy, visual acuity outcomes, and the overall patient experience.


Assuntos
Antibacterianos/administração & dosagem , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Satisfação do Paciente/estatística & dados numéricos , Facoemulsificação/métodos , Complicações Pós-Operatórias/prevenção & controle , Preparações de Ação Retardada , Endoftalmite/prevenção & controle , Humanos , Edema Macular/tratamento farmacológico , Edema Macular/prevenção & controle , Corpo Vítreo/efeitos dos fármacos
19.
Endocr Pract ; 27(10): 1046-1051, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34284145

RESUMO

OBJECTIVE: Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19). We conducted this study to determine if there is a correlation between hemoglobin A1C (HbA1C) level and poor outcomes in hospitalized patients with diabetes and COVID-19. METHODS: This is a retrospective, single-center, observational study of patients with diabetes (defined by an HbA1C level of ≥6.5% or known medical history of diabetes) who had a confirmed case of COVID-19 and required hospitalization. All patients were admitted to our institution between March 3, 2020, and May 5, 2020. HbA1C results for each patient were divided into quartiles: 5.1% to 6.7% (32-50 mmol/mol), 6.8% to 7.5% (51-58 mmol/mol), 7.6% to 8.9% (60-74 mmol/mol), and >9% (>75 mmol/mol). The primary outcome was in-hospital mortality. Secondary outcomes included admission to an intensive care unit, invasive mechanical ventilation, acute kidney injury, acute thrombosis, and length of hospital stay. RESULTS: A total of 506 patients were included. The number of deaths within quartiles 1 through 4 were 30 (25%), 37 (27%), 34 (27%), and 24 (19%), respectively. There was no statistical difference in the primary or secondary outcomes among the quartiles, except that acute kidney injury was less frequent in quartile 4. CONCLUSION: There was no significant association between HbA1C level and adverse clinical outcomes in patients with diabetes who are hospitalized with COVID-19. HbA1C levels should not be used for risk stratification in these patients.


Assuntos
COVID-19 , Diabetes Mellitus , Hemoglobinas Glicadas/análise , COVID-19/complicações , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/virologia , Mortalidade Hospitalar , Hospitalização , Humanos , Estudos Retrospectivos
20.
Am J Transplant ; 20(2): 564-572, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31452319

RESUMO

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Função Retardada do Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim , Idoso , Função Retardada do Enxerto/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Doadores de Tecidos , Resultado do Tratamento
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