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1.
Immunity ; 53(4): 733-744.e8, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32946741

RESUMO

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antiprotozoários/imunologia , Antimaláricos/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Esporozoítos/imunologia , Adolescente , Adulto , Animais , Linhagem Celular , Linhagem Celular Tumoral , Epitopos/imunologia , Feminino , Células HEK293 , Hepatócitos/imunologia , Hepatócitos/parasitologia , Humanos , Fígado/imunologia , Fígado/parasitologia , Malária/imunologia , Malária/parasitologia , Vacinas Antimaláricas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto Jovem
2.
Int J Mol Sci ; 24(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36614194

RESUMO

Survival from pancreatic cancer is poor because most cancers are diagnosed in the late stages and there are no therapies to prevent the progression of precancerous pancreatic intraepithelial neoplasms (PanINs). Inhibiting mutant KRASG12D, the primary driver mutation in most human pancreatic cancers, has been challenging. The cholecystokinin-B receptor (CCK-BR) is absent in the normal pancreas but becomes expressed in high grade PanIN lesions and is over-expressed in pancreatic cancer making it a prime target for therapy. We developed a biodegradable nanoparticle polyplex (NP) that binds selectively to the CCK-BR on PanINs and pancreatic cancer to deliver gene therapy. PanIN progression was halted and the pancreas extracellular matrix rendered less carcinogenic in P48-Cre/LSL-KrasG12D/+ mice treated with the CCK-BR targeted NP loaded with siRNA to mutant Kras. The targeted NP also slowed proliferation, decreased metastases and improved survival in mice bearing large orthotopic pancreatic tumors. Safety and toxicity studies were performed in immune competent mice after short or long-term exposure and showed no off-target toxicity by histological or biochemical evaluation. Precision therapy with target-specific NPs provides a novel approach to slow progression of advanced pancreatic cancer and also prevents the development of pancreatic cancer in high-risk subjects without toxicity to other tissues.


Assuntos
Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Camundongos , Humanos , Animais , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Modelos Animais de Doenças , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/prevenção & controle , Pâncreas/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas
3.
Ophthalmology ; 127(2): 186-195, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31474439

RESUMO

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.


Assuntos
Complemento C3/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Atrofia Geográfica/tratamento farmacológico , Degeneração Macular/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Angiofluoresceinografia , Atrofia Geográfica/diagnóstico , Atrofia Geográfica/etiologia , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
4.
Malar J ; 19(1): 113, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183833

RESUMO

BACKGROUND: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. METHODS: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. RESULTS: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. CONCLUSION: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.


Assuntos
Anticorpos Monoclonais/imunologia , Parasitemia/prevenção & controle , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Antiprotozoários/sangue , Modelos Animais de Doenças , Feminino , Concentração Inibidora 50 , Fígado/parasitologia , Malária Falciparum/imunologia , Malária Falciparum/terapia , Camundongos , Camundongos Endogâmicos C57BL , Organismos Geneticamente Modificados , Carga Parasitária , Plasmodium berghei/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética
5.
Health Qual Life Outcomes ; 18(1): 179, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32527270

RESUMO

BACKGROUND: Incorporating family-centered care principles into childhood obesity interventions is integral for improved clinical decision making, better follow-through, and more effective communication that leads to better outcomes and greater satisfaction with services. The purpose of this study is to evaluate the psychometric properties of a modified version of the Family Centered-Care Assessment (mFCCA) tool and to assess the family-centeredness of two clinical-community childhood obesity interventions. METHODS: Connect for Health was a randomized trial testing the comparative effectiveness of two interventions that enrolled 721 children, ages 2-12 years, with a body mass index (BMI) ≥ 85th percentile. The two arms were (1) enhanced primary care; and (2) enhanced primary care plus contextually-tailored, health coaching. At the end of the one-year intervention, the mFCCA was administered. We used Rasch analyses to assess the tool's psychometrics and examined differences between the groups using multiple linear regression. RESULTS: 629 parents completed the mFCCA resulting in an 87% response rate. The mean (SD) age of children was 8.0 (3.0) years. The exploratory factor analysis with 24 items all loaded onto a single factor. The Rasch modeling demonstrated good reliability as evidenced by the person separation reliability coefficient (0.99), and strong validity as evidenced by the range of item difficulty and overall model fit. The mean (SD, range) mFCCA score was 4.14 (0.85, 1-5). Compared to parents of children in the enhanced primary care arm, those whose children were in the enhanced primary care plus health coaching arm had higher mFCCA scores indicating greater perception of family-centeredness (ß = 0.61 units [95% CI: 0.49, 0.73]). CONCLUSIONS: Using the mFCCA which demonstrated good psychometric properties for the assessment of family-centered care among parents of children with obesity, we found that individualized health coaching is a family-centered approach to pediatric weight management. TRIAL REGISTRATION: Clinicaltrials.gov NCT02124460.


Assuntos
Assistência Centrada no Paciente/métodos , Obesidade Infantil/terapia , Atenção Primária à Saúde/métodos , Relações Profissional-Família , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pais/psicologia , Obesidade Infantil/psicologia , Psicometria/métodos , Qualidade de Vida , Reprodutibilidade dos Testes
7.
Prev Chronic Dis ; 16: E39, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925139

RESUMO

INTRODUCTION: Psychosocial stress is associated with obesity in adult and pediatric populations, but few studies have examined the relationship between parent-perceived stress and risk of child obesity and related behaviors. METHODS: We studied 689 pairs of parents and children aged 2 to 12 in Massachusetts with a body mass index (BMI) at or above the 85th percentile. Recruitment occurred from June 2014 to March 2015, and data collection ended in March 2016. We asked parents about their perceived stress and categorized responses as low, moderate, or high. We examined associations of parents' stress with children's BMI, expressed as a percentage of the 95th percentile (%BMIp95), and obesity-related behaviors by using multivariable regression models adjusted for child and parent characteristics. We stratified results by race/ethnicity, annual household income, and the child's age. RESULTS: In fully adjusted models, the association between high versus low parent-reported stress and children's %BMIp95 remained significant only for children in low-income households (ß = 5.12; 95% confidence interval [CI], 0.94-9.30) and for non-Hispanic black children (ß = 7.76; 95% CI, 1.85-13.66). Parents with high or moderate stress versus low stress were less likely to report that their children met recommendations for fast-food consumption (high stress, prevalence ratio [PR] = 0.79; 95% CI, 0.65-0.96; moderate stress, PR = 0.70; 95% CI, 0.59-0.82), but parents with high versus low stress were more likely to report meeting daily physical activity recommendations (PR = 1.21; 95% CI, 1.01-1.45). CONCLUSION: Among children with overweight or obesity, parent-perceived stress was associated with fast-food consumption and physical activity. Parent-perceived stress was associated with child %BMIp95 among children in low-income households and non-Hispanic black children. Obesity interventions should consider parent-perceived stress and potential differences in the nature of stress experienced by parents of different racial/ethnic and socioeconomic backgrounds.


Assuntos
Pais/psicologia , Obesidade Infantil/epidemiologia , Estresse Psicológico/epidemiologia , Negro ou Afro-Americano/estatística & dados numéricos , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Exercício Físico , Fast Foods/estatística & dados numéricos , Feminino , Humanos , Masculino , Massachusetts/epidemiologia , Obesidade Infantil/psicologia , Fatores Socioeconômicos
8.
Prev Chronic Dis ; 14: E53, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28682745

RESUMO

BACKGROUND: Novel approaches to health care delivery that leverage community resources could improve outcomes for children at high risk for obesity. COMMUNITY CONTEXT: We describe the process by which we created an online interactive community resources map for use in the Connect for Health randomized controlled trial. The trial was conducted in the 6 pediatric practices that cared for the highest percentage of children with overweight or obesity within a large multi-specialty group practice in eastern Massachusetts. METHODS: By using semistructured interviews with parents and community partners and geographic information systems (GIS), we created and validated a community resource map for use in a randomized controlled trial for childhood obesity. We conducted semistructured interviews with 11 parents and received stakeholder feedback from 5 community partners, 2 pediatricians, and 3 obesity-built environment experts to identify community resources that could support behavior change. We used GIS databases to identify the location of resources. After the resources were validated, we created an online, interactive searchable map. We evaluated parent resource empowerment at baseline and follow-up, examined if the participant families went to new locations for physical activity and food shopping, and evaluated how satisfied the families were with the information they received. OUTCOME: Parents, community partners, and experts identified several resources to be included in the map, including farmers markets, supermarkets, parks, and fitness centers. Parents expressed the need for affordable activities. Parent resource empowerment increased by 0.25 units (95% confidence interval, 0.21-0.30) over the 1-year intervention period; 76.2% of participants were physically active at new places, 57.1% of participant families shopped at new locations; and 71.8% reported they were very satisfied with the information they received. INTERPRETATION: Parents and community partners identified several community resources that could help support behavior change. Parent resource empowerment and use of community resources increased over the intervention period, suggesting that community resource mapping should inform future interventions.


Assuntos
Obesidade Infantil/epidemiologia , Obesidade Infantil/terapia , Participação da Comunidade , Educação a Distância , Humanos , Entrevistas como Assunto , Massachusetts/epidemiologia , Pais , Saúde Pública
9.
Int J Eat Disord ; 49(7): 641-50, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27206163

RESUMO

OBJECTIVE: Bulimia nervosa (BN) and binge-eating disorder (BED) are associated with significant health impairment. Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) comprise both psychological (disturbances in mood and affect) and physiological (bloating and changes in appetite) symptoms that may trigger binge-eating and/or purging. METHOD: Female participants were drawn from the Collaborative Psychiatric Epidemiological Surveys, conducted from 2001 to 2003. Weighted multivariable logistic regression modeled the association between lifetime PMS and PMDD and lifetime odds of BN or BED. RESULTS: Among 8,694 participants, 133 (1.0%) had BN and 185 (1.8%) BED. Additionally, 366 (4.2%) had PMDD and 3,489 (42.4%) had PMS. Prevalence of PMDD and PMS were 17.4 and 55.4% among those with BN, 10.7 and 48.9% among those with BED and 3.4 and 59.1% among those with subthreshold BED. After adjustment for age, race/ethnicity, income, education, body mass index, age at menarche, birth control use, and comorbid mental health conditions, PMDD was associated with seven times the odds of BN (OR 7.2, 95% CI 2.3, 22.4) and PMS with two times the odds of BN (OR 2.5, 95% CI 1.1, 5.7). Neither PMDD nor PMS were significantly associated with BED. DISCUSSION: Women with PMS and PMDD have a higher odds of BN, independent of comorbid mental health conditions. PMS and PMDD may be important comorbidities to BN to consider in clinical settings, and future research should investigate whether PMS and PMDD affect the onset and duration of bulimic symptoms as well as the potential for shared risk factors across disorders. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016; 49:641-650).


Assuntos
Transtorno da Compulsão Alimentar/complicações , Bulimia Nervosa/complicações , Transtorno Disfórico Pré-Menstrual/complicações , Síndrome Pré-Menstrual/complicações , Adulto , Comorbidade , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Transtorno Disfórico Pré-Menstrual/epidemiologia , Síndrome Pré-Menstrual/epidemiologia , Prevalência , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologia
10.
J Trauma Stress ; 29(3): 259-67, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27163435

RESUMO

Previous studies have demonstrated bidirectional associations between posttraumatric stress disorder (PTSD) and romantic relationship dissatisfaction. Most of these studies were focused at the level of the disorder, examining the association between relationship dissatisfaction and having a diagnosis of PTSD or the total of PTSD symptoms endorsed. This disorder-level approach is problematic for trauma theorists who posit symptom-level mechanisms for these effects. In the present study, we examined the prospective, bidirectional associations between PTSD symptom clusters (e.g., reexperiencing) and relationship satisfaction using the data from 101 previously studied individuals who had had a recent motor vehicle accident. We also conducted exploratory analyses examining the prospective, bidirectional associations between individual PTSD symptoms and relationship satisfaction. Participants had completed the PTSD Checklist-Civilian Version and the Relationship Assessment Scale at 4, 10, and 16 weeks after the MVA. We performed time-lagged mixed-effects regressions to examine the effect of lagged relationship satisfaction on PTSD clusters and symptoms, and vice versa. No cluster effects were significant after controlling for a false discovery rate. Relationship satisfaction predicted prospective decreases in reliving the trauma (d = 0.42), emotional numbness (d = 0.46), and irritability (d = 0.49). These findings were consistent with the position that relationship satisfaction affects PTSD through symptom-level mechanisms.


Assuntos
Acidentes de Trânsito/psicologia , Relações Interpessoais , Satisfação Pessoal , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Autorrelato , Índice de Gravidade de Doença
11.
NPJ Vaccines ; 9(1): 29, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341502

RESUMO

New strategies are needed to reduce the incidence of malaria, and promising approaches include vaccines targeting the circumsporozoite protein (CSP). To improve upon the malaria vaccine, RTS,S/AS01, it is essential to standardize preclinical assays to measure the potency of next-generation vaccines against this benchmark. We focus on RTS,S/AS01-induced antibody responses and functional activity in conjunction with robust statistical analyses. Transgenic Plasmodium berghei sporozoites containing full-length P. falciparum CSP (tgPb-PfCSP) allow two assessments of efficacy: quantitative reduction in liver infection following intravenous challenge, and sterile protection from mosquito bite challenge. Two or three doses of RTS,S/AS01 were given intramuscularly at 3-week intervals, with challenge 2-weeks after the last vaccination. Minimal inter- and intra-assay variability indicates the reproducibility of the methods. Importantly, the range of this model is suitable for screening more potent vaccines. Levels of induced anti-CSP antibody 2A10 equivalency were also associated with activity: 105 µg/mL (95% CI: 68.8, 141) reduced liver infection by 50%, whereas 285 µg/mL (95% CI: 166, 404) is required for 50% sterile protection from mosquito bite challenge. Additionally, the liver burden model was able to differentiate between protected and non-protected human plasma samples from a controlled human malaria infection study, supporting these models' relevance and predictive capability. Comparison in animal models of CSP-based vaccine candidates to RTS,S/AS01 is now possible under well controlled conditions. Assessment of the quality of induced antibodies, likely a determinant of durability of protection in humans, should be possible using these methods.

12.
Curr Opin Psychiatry ; 36(3): 237-242, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36762666

RESUMO

PURPOSE OF REVIEW: Social Contagion is defined as the spread of behaviors, attitudes, and affect through crowds and other types of social aggregates from one member to another. Adolescents are prone to social contagion because they may be especially susceptible to peer influence and social media.In this article, we provide a brief review of the most recent findings on social contagion, violence, and suicide among adolescents. RECENT FINDINGS: Recent evidence support social contagion in gun violence, bullying, cyberbullying, violent offending, and suicide, but is inconclusive on the role of violent video game exposure on aggressive behavior. SUMMARY: The mechanisms underlying the contagion effect of violence and suicide are currently unclear. It has been argued that social learning, identification with significant others, and the normalization of specific norms play a role. All these mechanisms require understanding social contagion as a complex interaction between individual, relational and social factors. This is key if the social contagion perspective is to be used not only to investigate negative outcomes, but also as a framework for promoting prosocial attitudes and behaviors. Additionally, more research is needed on psychosocial interventions and public policies to minimize the potential spillover effect of violence and suicide.


Assuntos
Comportamento do Adolescente , Bullying , Suicídio , Humanos , Adolescente , Violência/psicologia , Suicídio/psicologia , Agressão , Comportamento do Adolescente/psicologia
13.
Front Immunol ; 13: 931273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35860237

RESUMO

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity via regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.


Assuntos
Proteínas do Sistema Complemento , Neoplasias , Ativação do Complemento , Humanos , Linfócitos T , Microambiente Tumoral
14.
Nat Med ; 28(6): 1288-1296, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35551291

RESUMO

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg-1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg-1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml-1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Neutralizantes , Antivirais/uso terapêutico , Anticorpos Amplamente Neutralizantes , Anticorpos Anti-HIV , Humanos , Viremia/tratamento farmacológico
15.
Polit Psychol ; 42(5): 863-880, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34548716

RESUMO

In the context of the COVID-19 pandemic, personal protective measures (e.g., social distancing, handwashing, and mask wearing) have been adopted as a cornerstone to limit the spread of the disease. Yet, the effectiveness of these measures depends on people's levels of adherence. In this article, we apply social-psychological research to the study of compliance with personal protective measures during the COVID-19 pandemic in Chile. We consider three possible models underlying adherence: (1) sociodemographic and socioeconomic factors, (2) instrumental factors, and (3) normative factors. We draw on data from a longitudinal nonrepresentative panel study (Study 1, n = 32,304) and a cross-sectional representative survey (Study 2, n = 1,078) to explore the impact of these different factors on personal protective measures compliance. Findings show the strongest support for the role of instrumental and normative factors, in that people who comply with protective measures report to a greater extent that relatives and friends comply too and tend to perceive high risk of COVID-19. We finish by proposing policy recommendations to promote effective strategies to contain the spread of the virus.

16.
Pediatr Obes ; 16(9): e12784, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33734583

RESUMO

OBJECTIVE: To examine characteristics and lifestyle behaviours associated with achieving clinically important weight loss (CIWL) in two paediatric weight management interventions (PWMIs). METHODS: We examined 1010 children enrolled in the STAR and Connect for Health trials. We defined achieving CIWL as any participant who had decreased their BMI z-score by ≥0.2 units over 1 year. Using log-binomial regression we examined associations of child and household characteristics and lifestyle behaviours with achieving CIWL. RESULTS: In multivariable analyses, children with severe obesity had a lower likelihood of achieving CIWL compared to children without severe obesity (RR: 0.68 [95% CI: 0.49, 0.95]). Children who were ≥10 years were less likely to achieve CIWL (RR: 0.56 [95% CI: 0.42, 0.74]) vs those 2-6 years of age. Children who consumed <1 sugary beverage per day at the end of the intervention were more likely to achieve CIWL vs those who did not meet the goal (RR: 1.36 [95% CI 1.09-1.70]). CONCLUSION: In this analysis of children enrolled in PWMIs, achieving CIWL was associated with younger age, not having severe obesity and consuming fewer sugary beverages at the end of the intervention. Focusing on intervening earlier in life, when a child is at a lower BMI, and reducing sugary beverages could allow for more effective PWMI's.


Assuntos
Bebidas , Obesidade Infantil , Índice de Massa Corporal , Criança , Humanos , Estilo de Vida , Motivação , Obesidade Infantil/epidemiologia , Obesidade Infantil/prevenção & controle , Redução de Peso
17.
Vaccine ; 39(29): 3879-3891, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34099328

RESUMO

A major challenge for HIV vaccine development is to raise anti-envelope antibodies capable of recognizing and neutralizing diverse strains of HIV-1. Accordingly, a full length single chain (FLSC) of gp120-CD4 chimeric vaccine construct was designed to present a highly conserved CD4-induced (CD4i) HIV-1 envelope structure that elicits cross-reactive anti-envelope humoral responses and protective immunity in animal models of HIV infection. IHV01 is the FLSC formulated in aluminum phosphate adjuvant. We enrolled 65 healthy adult volunteers in this first-in-human phase 1a randomized, double-blind, placebo-controlled study with three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. The overall incidence of adverse events (AEs) was not significantly different between vaccinees and controls. The majority (89%) of vaccine-related AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and demonstrated anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was evident in all cohorts as were anti-gp120 T-cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 that mediates antiviral functions.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV , Imunogenicidade da Vacina , Vacinas contra a AIDS/efeitos adversos , Adulto , Animais , Antígenos CD4 , Anticorpos Anti-HIV , Proteína gp120 do Envelope de HIV , Infecções por HIV/prevenção & controle , HIV-1 , Humanos , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia
18.
Clin Pediatr (Phila) ; 58(7): 789-797, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894004

RESUMO

Family-centered childhood obesity interventions have been found to be effective. We describe the use of telehealth for tailored behavior change support in a family-centered randomized trial. Children of 2 to 12 years with body mass index ≥85th percentile were randomized to Enhanced Primary Care (EPC) or Enhanced Primary Care + Coaching (EPC + C). EPC + C received 6 health coach visits (in-person or by video or phone call) over 1 year. Telehealth modalities included interactive text messaging, video calls, and an online community resource map. There were 360 children randomized to the EPC + C arm; 87% of parents completed ≥1 health coaching contacts. Overall, 93% parents were sent text messages of which 99% responded at least once. About 72% parents were very satisfied with the message content and 97% were satisfied with information provided about community health resources. The high level of participant engagement and satisfaction suggests that telehealth is feasible and acceptable in family-centered childhood obesity programs.


Assuntos
Telefone Celular , Obesidade Infantil/prevenção & controle , Atenção Primária à Saúde/organização & administração , Telemedicina/métodos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Massachusetts , Educação de Pacientes como Assunto
19.
Acad Pediatr ; 19(7): 764-772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31128381

RESUMO

OBJECTIVE: To examine parents' interest in continuing and willingness to pay (WTP) for 2 pediatric weight management programs following their participation. METHODS: Participants were parents of 2- to 12-year-old children with body mass index ≥ 85th percentile who participated in the Connect for Health trial. One group received enhanced primary care (EPC) and the other received EPC plus individualized coaching (EPC+C). At 1 year, we assessed parents' self-reported WTP for a similar program and the maximum amount ($/month) they would pay. We used multivariable regression to examine differences in WTP and WTP amount by intervention arm and by individual and family-level factors. RESULTS: Of 638 parents who completed the survey, 85% were interested in continuing and 38% of those parents were willing to pay (31% in the EPC group and 45% in the EPC+C group). The median amount parents were willing to pay was $25/month (interquartile range, $15-$50). In multivariable models, the EPC+C parents were more likely to endorse WTP than the EPC parents (odds ratio, 1.53; 95% confidence interval, 1.05-2.22). Parents of children with Hispanic/Latino versus white ethnicity and those reporting higher satisfaction with the program were also more likely to endorse WTP. CONCLUSIONS: Most parents of children in a weight management program were interested in continuing it after it ended, but fewer were willing to pay out of pocket for it. A greater proportion of parents were willing to pay if the program included individualized health coaching.


Assuntos
Gastos em Saúde , Pais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde , Obesidade Infantil/terapia , Programas de Redução de Peso/economia , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Inquéritos e Questionários , Volição
20.
Acad Pediatr ; 19(5): 515-519, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30415077

RESUMO

BACKGROUND: The presence of small screens in the sleep environment has been associated with shorter sleep duration and later bedtimes in children of normal weight, but the role these devices play in the sleep environment of overweight children is unclear. We sought to examine the association of small screen presence in the sleep environment with sleep behaviors among school-age children with obesity. METHODS: We surveyed 526 parents of children ages 6 to 12 years old with a body mass index ≥95th percentile who were participating in a randomized trial to treat childhood obesity. Twelve months after enrollment, parents were asked how frequently their child slept with or near a small screen (defined as a cellphone, smartphone, or texting/chat-capable device). We used multivariable linear regression to examine associations of the presence of small screens with sleep duration, waketime, and bedtime. RESULTS: Compared with children who rarely/never slept with a small screen in their bedroom, children who did so 1 day or more per week had shorter sleep durations and later bedtimes. After we adjusted for television presence in the bedroom, small screen presence was still associated with shorter sleep duration (-9.9 minutes; P = .02) and later weekday (8.8 minutes; P = .03) and weekend (12.0 minutes; P = .03) bedtimes. CONCLUSIONS: Children with obesity and a small screen present in their sleep environment have shorter sleep durations and later bedtimes than children who rarely/never sleep with a small screen. Pediatricians should consider inquiring about small screens in the bedroom when counseling on healthy sleep and weight management habits.


Assuntos
Telefone Celular , Computadores de Mão , Obesidade Infantil/psicologia , Sono , Televisão , Jogos de Vídeo , Índice de Massa Corporal , Criança , Feminino , Hábitos , Humanos , Masculino , Inquéritos e Questionários , Fatores de Tempo
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