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1.
Artigo em Inglês | MEDLINE | ID: mdl-32918548

RESUMO

BACKGROUND: Although Coronavirus Disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data evaluating agents with potential antiviral activity continue to expand, such that updated guidance is needed regarding use of these agents in children. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion. RESULTS: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for non-invasive or invasive mechanical ventilation or extra-corporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or non-invasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

2.
Clin Infect Dis ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32780095

RESUMO

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based regimens are now recommended as first-line antiretroviral therapy (ART) for adults with human immunodeficiency virus. But evidence on long-term clinical effectiveness of InSTI-based regimens remains limited. We examined whether InSTI-based regimens improved longer-term clinical outcomes. METHODS: We included participants from clinical cohorts in the North American AIDS Cohort Collaboration who initiated their first ART regimen, containing either InSTI (i.e., raltegravir, dolutegravir, and elvitegravir/cobicstat) or efavirenz (EFV) as an active comparator, between 2009 and 2016. We estimated observational analogs of 6-year intention-to-treat and per-protocol risks, risk differences (RD), and hazard ratios (HR) for the composite outcome of AIDS, acute myocardial infarction, stroke, end-stage renal diseases, end-stage liver diseases, or death. RESULTS: Of 15,993 participants, 5,824 (36%) initiated an InSTI-based, and 10,169 (64%) initiated an EFV-based, regimen. During the 6-year follow-up, 440 of the InSTI group and 1,097 of the EFV group incurred the composite outcome. The estimated 6-year intention-to-treat risks were 14.6% for the InSTI group and 14.3% for the EFV group, corresponding with a RD of 0.3 percentage point (95% CI: -2.7, 3.3), and HR was 1.08 (95% CI: 0.97, 1.19); the estimated 6-year per-protocol risks were 12.2% for the InSTI group and 11.9% for the EFV group, corresponding with a RD was 0.3 percentage point (95% CI: -3.0, 3.7), and HR was 1.09 (95% CI: 0.96, 1.25). CONCLUSIONS: InSTI- and EFV-based initial ART regimens had similar 6-year composite clinical outcomes. The risk of adverse clinical outcomes remains substantial even when initiating modern ART.

3.
Clin Infect Dis ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785640

RESUMO

BACKGROUND: Persons living with HIV (PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART). METHODS: We evaluated AIDS-free, ART-naive PLWH during 1996-2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350-500 cells/µl (baseline) until incident cancer, death, lost-to-follow-up or December 2014. Outcomes included six cancer groups and five individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject's age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses. RESULTS: Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.37-0.86), AIDS-defining cancers (HR 0.23; 95% CI 0.11-0.49), any virus-related cancer (HR 0.30; 95% CI 0.16-0.54), Kaposi sarcoma (HR 0.25; 95% CI 0.10-0.61) and non-Hodgkin lymphoma (HR 0.22; 95% CI 0.06-0.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs. 2.3%; adjusted risk difference -1.6; 95% CI -2.8, -0.5). CONCLUSIONS: Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH, but not NADCs without known or suspected viral etiology.

4.
PLoS One ; 15(7): e0236177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687532

RESUMO

BACKGROUND: Transgender women (TW) are disproportionately affected by both HIV and cardiovascular disease (CVD). OBJECTIVES: We aim to quantify prevalence of elevated predicted CVD risk for TW compared to cisgender women (CW) and cisgender men (CM) in HIV care and describe the impact of multiple operationalizations of CVD risk score calculations for TW. DESIGN: We conducted a cross-sectional analysis of patients engaged in HIV care between October 2014 and February 2018. SETTING: The Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of 8 HIV clinical sites in the United States contributed data for this analysis. PATIENTS: 221 TW, 2983 CW, and 13467 CM. MEASUREMENTS: The measure of interest is prevalence of elevated 10-year cardiovascular disease risk based on ACC/AHA Pooled Cohort Risk Assessment equations (PCE) and the Framingham Risk Score (FRS), calculated for TW by: birth-assigned sex (male); history of exogenous sex hormone use (female/male); and current gender (female). RESULTS: Using birth-assigned sex, the adjusted prevalence ratio (aPR) was 2.52 (95% CI: 1.08,5.86) and 2.58 (95% CI: 1.71,3.89) comparing TW to CW, by PCE and FRS, respectively. It was 1.25 (95% CI: 0.54,2.87) and 1.25 (95% CI: 0.84,1.86) comparing TW to CM, by PCE and FRS, respectively. If TW were classified according to current gender versus birth-assigned sex, their predicted CVD risk scores were lower. LIMITATIONS: PCE and FRS have not been validated in TW with HIV. Few adjudicated CVD events in the data set precluded analyses based on clinical outcomes. CONCLUSIONS: After adjustment for demographics and history of HIV care, prevalence of elevated CVD risk in TW was similar to CM and equal to or higher than in CW, depending operationalization of the sex variable. Future studies with CVD outcomes are needed to help clinicians accurately estimate CVD risk among TW with HIV.

6.
Acad Med ; 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379141

RESUMO

PURPOSE: To explore resident and attending physician perceptions of resident behaviors and skills that demonstrate trustworthiness and promote entrustment by supervisors. METHOD: Using grounded theory methodology, the authors conducted 3 focus groups with pediatric residents from the Boston Combined Residency Program and 3 focus groups with attending physicians who were either general pediatric hospitalists or other pediatric subspecialists at Boston Children's Hospital and Boston Medical Center in Boston, Massachusetts from May to December 2018. Data were collected and analyzed iteratively until theoretical saturation was achieved. Three independent reviewers coded each transcript. Codes were grouped into dominant themes to develop a conceptual model. RESULTS: Twelve residents and 18 attending physicians participated in the focus groups. Participants described actions that they felt actively demonstrated residents' trustworthiness within previously described domains of trustworthiness. Four modifiers emerged that affect a resident's progression from trustworthiness to entrustment: (1) self-management, (2) relationships, (3) self-advocacy, and (4) patient-centeredness. Findings were synthesized into a conceptual model depicting how trainees can promote their own entrustment by supervisors. CONCLUSIONS: Trainees must actively demonstrate their trustworthiness to be entrusted. This study proposes that trainees can further gain entrustment through self-management, relationships, self-advocacy, and patient-centeredness. When they understand the actions and behaviors that promote entrustment, trainees may be better able to foster autonomy and progress toward more independent clinical practice. These findings add to existing evidence regarding entrustment and provide a novel, actionable framework for trainees to increase their own entrustment.

8.
Artigo em Inglês | MEDLINE | ID: covidwho-102020

RESUMO

BACKGROUND: Although Coronavirus Disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develops severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion. RESULTS: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare children who develop severe or critical disease, this guidance offer an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32318706

RESUMO

BACKGROUND: Although Coronavirus Disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develops severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion. RESULTS: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare children who develop severe or critical disease, this guidance offer an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

10.
BMJ Open ; 10(3): e031487, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32198297

RESUMO

OBJECTIVE: Anaemia is common among people living with HIV (PLWH) and has been associated with certain, often older, antiretroviral medications. Information on current antiretroviral therapy (ART) and anaemia is limited. The objective was to compare the associations between anaemia incidence or haemoglobin change with core ART classes in the current ART era. DESIGN: Retrospective cohort study. SETTING: USA-based prospective clinical cohort of PLWH aged 18 and above receiving care at eight sites between January 2010 and March 2018. PARTICIPANTS: 16 505 PLWH were included in this study. MAIN OUTCOME MEASURES: Anaemia risk and haemoglobin change were estimated among PLWH for person-time on a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI)-based regimen, relative to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based reference. We also examined PLWH on regimens containing multiple core classes. Cox proportional hazards regression analyses were conducted to measure the associations between time-updated ART classes and incident anaemia or severe anaemia. Linear mixed effects models were used to examine the relationships between ART classes and haemoglobin change. RESULTS: During a median of 4.9 years of follow-up, 1040 developed anaemia and 488 developed severe anaemia. Compared with NNRTI use, INSTI-based regimens were associated with an increased risk of anaemia (adjusted HR (aHR) 1.26, 95% CI 1.00 to 1.58) and severe anaemia (aHR 1.51, 95% CI 1.07 to 2.11) and a decrease in haemoglobin level. Time on multiple core classes was also associated with increased anaemia risk (aHR 1.39, 95% CI 1.13 to 1.70), while no associations were found for PI use. CONCLUSION: These findings suggest INSTI use may increase the risk of anaemia. If confirmed, screening for anaemia development in users of INSTIs may be beneficial. Further research into the underlying mechanisms is warranted.

11.
Clin Infect Dis ; 70(5): 867-874, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30994900

RESUMO

BACKGROUND: Substance use is common among people living with human immunodeficiency virus (PLWH) and a barrier to achieving viral suppression. Among PLWH who report illicit drug use, we evaluated associations between HIV viral load (VL) and reduced use of illicit opioids, methamphetamine/crystal, cocaine/crack, and marijuana, regardless of whether or not abstinence was achieved. METHODS: This was a longitudinal cohort study of PLWH from 7 HIV clinics or 4 clinical studies. We used joint longitudinal and survival models to examine the impact of decreasing drug use and of abstinence for each drug on viral suppression. We repeated analyses using linear mixed models to examine associations between change in frequency of drug use and VL. RESULTS: The number of PLWH who were using each drug at baseline ranged from n = 568 (illicit opioids) to n = 4272 (marijuana). Abstinence was associated with higher odds of viral suppression (odds ratio [OR], 1.4-2.2) and lower relative VL (ranging from 21% to 42% by drug) for all 4 drug categories. Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with VL suppression (OR, 2.2, 1.6, respectively). Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with lower relative VL (47%, 38%, respectively). CONCLUSIONS: Abstinence was associated with viral suppression. In addition, reducing use of illicit opioids or methamphetamine/crystal, even without abstinence, was also associated with viral suppression. Our findings highlight the impact of reducing substance use, even when abstinence is not achieved, and the potential benefits of medications, behavioral interventions, and harm-reduction interventions.

12.
Clin Infect Dis ; 70(6): 1131-1138, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-31573601

RESUMO

BACKGROUND: Prior studies suggest that transgender women (TW) with human immunodeficiency virus (HIV) are less likely to be virally suppressed than cisgender women (CW) and cisgender men (CM). However, prior data are limited by small sample sizes and cross-sectional designs. We sought to characterize the HIV care continuum comparing TW to CW and CM in the United States and Canada. METHODS: We analyzed annual HIV care continuum outcomes by gender status from January 2001 through December 2015 among adults (aged ≥18 years) in 15 clinical cohorts. Outcomes were retention in care and viral suppression. RESULTS: The study population included TW (n = 396), CW (n = 14 094), and CM (n = 101 667). TW had lower proportions retained in care than CW and CM (P < .01). Estimates of retention in care were consistently lower in TW, with little change over time within each group. TW and CW had similar proportions virally suppressed over time (TW, 36% in 2001 and 80% in 2015; CW, 35% in 2001 and 83% in 2015) and were lower than CM (41% in 2001 and 87% in 2015). These differences did not reach statistical significance after adjusting for age, race, HIV risk group, and cohort. CONCLUSIONS: TW experience challenges with retention in HIV care. However, TW who are engaged in care achieve viral suppression that is comparable to that of CW and CM of similar age, race, and HIV risk group. Further research is needed to understand care engagement disparities.

13.
Aerosp Med Hum Perform ; 91(1): 51-55, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31852575

RESUMO

BACKGROUND: The risks associated with high positive Gz (+Gz) aerobatic flight, especially with respect to +Gz-induced loss of consciousness (G-LOC), are well known. Less appreciated is the effect of negative Gz (-Gz) flight on subsequent +Gz maneuvers, known as the "push-pull effect." This is an example involving the loss of an F-16 and pilot that was caused by the push-pull effect.CASE REPORT: The mishap pilot (MP) was killed during a training flight when his F-16 crashed without an ejection attempt. The MP, while transitioning from prolonged -Gz flight to sustained +Gz flight, maneuvered the mishap aircraft (MA) from -2.06 Gz to +8.56 Gz in less than 5 s. At this point, there were only minimal control inputs for 5 s, indicating the MP experienced transient incapacitation, most likely due to G-LOC or almost loss of consciousness (A-LOC). The MP's subsequent recovery attempt was interrupted by ground impact. The Accident Investigation Board (AIB) concluded the MP experienced G-LOC due to the push-pull effect.DISCUSSION: Since this is not the first time the push-pull effect has resulted in G-LOC mishaps, the adverse effects of such maneuvers should continue to be emphasized during military physiological training, as well as during general aviation (GA) aerobatics training. Furthermore, A-LOC, instead of being considered a discrete phenomenon, may need to be included in a broader G-LOC definition that encompasses the entire continuum of G-LOC and A-LOC.Metzler MM. G-LOC due to the push-pull effect in a fatal F-16 mishap. Aerosp Med Hum Perform. 2020; 91(1):51-55.


Assuntos
Medicina Aeroespacial , Aeronaves , Militares , Inconsciência/etiologia , Aceleração , Adulto , Evolução Fatal , Gravitação , Humanos , Masculino , Fatores de Tempo
14.
Am J Epidemiol ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712804

RESUMO

Hepatitis C virus (HCV) is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic Type 1 MI (T1MI) and supply-demand mismatch Type 2 MI (T2MI). We examined the association between HCV and MI in the Centers for Acquired Immunodeficiency Syndrome Research Network of Integrated Clinical Systems, a multi-center clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Universal MI definition. We estimated the association between chronic HCV (RNA+) and time to MI adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics and history of injecting drug use. Among 23,407 PLWH aged ≥18, there were 336 T1MI and 330 T2MI during a median of 4.7 years of follow-up during 1998 through 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) 1.46, 95% CI: 1.09, 1.97) but not T1MI (aHR 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

15.
Clin Infect Dis ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712815

RESUMO

BACKGROUND: Rates of early syphilis in US women are steadily increasing but predictors of infection in this group are not clearly defined. METHODS: This retrospective analysis focused on women enrolled in the US CFAR Network of Integrated Clinical Systems cohort between January 2005 and December 2016 with syphilis testing performed. The primary outcome of incident syphilis infection was defined serologically as a newly positive test with positive confirmatory testing after a negative test or a 2-dilution increase in RPR titer. Infection rates were calculated for each woman-year in care with testing. Predictors of syphilis were sought among socio-demographics, clinical information, and self-reported behaviors. Multivariable logistic regression models were created and a subgroup analysis assessed predictors in women of reproductive age. RESULTS: The annual rate of incident syphilis among 4416 women engaged in HIV care and tested during the 12-year study period was 760 per 100,000 person-years. Independent predictors of infection were injection drug use (IDU) as a risk factor for HIV acquisition (aOR 2.2, CI 1.3-3.9), hepatitis C infection (aOR 1.9, CI 1.1-3.4), black race (aOR 2.2, CI 1.3-3.7 compared to white race) and more recent entry to care (since 2005 compared to 1994-2004). Predictors were similar in women age 18-49. CONCLUSIONS: Syphilis infection is common among US women in HIV care. Syphilis screening and prevention efforts should focus on women reporting drug use and with hepatitis C co-infection. Future studies should identify specific behaviors that mediate syphilis acquisition risk in women who use drugs.

16.
Clin Infect Dis ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31758196

RESUMO

BACKGROUND: Retention in care (RIC) leads to reduced HIV transmission and mortality. Few studies have investigated the availability of clinic services and RIC among people living with HIV (PLWH) in the United States (US). We conducted a multi-site retrospective cohort study to identify clinic services associated with RIC from 2010-2016 in the US. METHODS: PLWH with ≥1 attended HIV primary care visit from 2010-2016 at seven sites in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) were included. Clinic-level factors evaluated via site survey included patients per provider/trainee, peer navigation, RIC posters/brochures, laboratory test timing, flexible scheduling, appointment reminder methods, and stigma support services. RIC was defined as ≥2 encounters per year, ≥90 days apart, observed until death, administrative censoring (December 31, 2016), or loss to follow-up (censoring at first 12-month interval without a visit if there were no future visits). Poisson regression with robust error variance, clustered by site and adjusted for calendar year, age, sex, race/ethnicity, and HIV transmission risk factor, estimated risk ratios (RR) and 95% confidence intervals (CI) for RIC. RESULTS: Among 21,046 PLWH contributing 103,348 person-years, 67% of person-years were retained. Availability of text appointment reminders (RR:1.13; 95% CI:1.03-1.24) and stigma support services (RR:1.11; 95% CI:1.04-1.19) were associated with better RIC. Disparities persisted with respect to age, sex, and race after accounting for clinic-level factors. CONCLUSION: Availability of text appointment reminders and stigma support services was associated with higher rates of RIC indicating that these may be feasible and effective approaches for improving RIC.

17.
BMC Med ; 17(1): 149, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31362721

RESUMO

BACKGROUND: Persons with human immunodeficiency virus (HIV) have higher risks for myocardial infarction (MI) than the general population. This is driven in part by higher type 2 MI (T2MI, due to coronary supply-demand mismatch) rates among persons with HIV (PWH). In the general population, T2MI has higher mortality than type 1 MI (T1MI, spontaneous and generally due to plaque rupture and thrombosis). PWH have a greater burden of comorbidities and may therefore have an even greater excess risk for complication and death in the setting of T2MI. However, mortality patterns after T1MI and T2MI in HIV are unknown. METHODS: We analyzed mortality after MI among PWH enrolled in the multicenter, US-based Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort (N = 28,186). Incident MIs occurring between January 1, 1996, and December 31, 2014, were centrally adjudicated and classified as T1MI or T2MI. We first compared mortality following T1MI vs. T2MI among PWH. Cox survival analyses and Bayesian model averaging were then used to evaluate pre-MI covariates associated with mortality following T1MI and T2MI. RESULTS: Among the 596 out of 28,186 PWH who experienced MI (2.1%; 293 T1MI and 303 T2MI), mortality rates were significantly greater after T2MI (22.2/100 person-years; 1-, 3-, and 5-year mortality 39%, 52%, and 62%) than T1MI (8.2/100 person-years; 1-, 3-, and 5-year mortality 15%, 22%, and 30%). Significant mortality predictors after T1MI were higher HIV viral load, renal dysfunction, and older age. Significant predictors of mortality after T2MI were low body-mass index (BMI) and detectable HIV viral load. CONCLUSIONS: Mortality is high following MI for PWH and substantially greater after T2MI than T1MI. Predictors of death after MI differed by type of MI, reinforcing the different clinical scenarios associated with each MI type and the importance of considering MI types separately.


Assuntos
Infecções por HIV/mortalidade , Infarto do Miocárdio/mortalidade , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/epidemiologia , Síndrome de Imunodeficiência Adquirida/mortalidade , Adulto , Idoso , Estudos de Coortes , Redes Comunitárias , Comorbidade , Feminino , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia , Placa Aterosclerótica/complicações , Placa Aterosclerótica/epidemiologia , Placa Aterosclerótica/mortalidade , Estados Unidos/epidemiologia
18.
J Oral Biosci ; 61(3): 163-172, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31252053

RESUMO

OBJECTIVE: To provide in vivo biochemical evidence for the isolation, identification, and characterization of porcine keratin 75 (K75) in developing enamel. METHODS: Immunolocalization of K75 was observed in mandibles from mice at postnatal days 5 and 11. K75 gene expression was analyzed by quantitative reverse transcription-polymerase chain reaction using enamel organ epithelium (EOE) of incisors from pigs at 5 months of age. Enamel protein was extracted and isolated from both immature and mature enamel of second molars from 5-month-old pigs, and the K75 antibody-positive fraction was analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). In vitro protease digestion of K75-antibody-positive fraction was carried out using porcine kallikrein 4 (pKLK4) or recombinant human enamelysin (rhMMP20) and their degradation patterns were characterized by both SDS-PAGE and western blotting. RESULTS: Specific immunostaining for K75 was restricted to the layers of stratum intermedium and the enamel side of ameloblasts in mice at postnatal day 5, and to the papillary layer at postnatal day 11. Porcine K75 was expressed throughout enamel formation, but its transcript levels were significantly higher in the transition EOE than in the secretory- and maturation-stage EOE. Porcine K75 was extracted from the neutral soluble fraction from both immature and mature enamel. It was identified by LC-MS/MS analysis, and was found not to be degraded by either pKLK4 or rhMMP20. CONCLUSION: We propose that K75 is present in the developing enamel and undergoes different processing/degradation compared to other enamel proteins.


Assuntos
Amelogênese , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Esmalte Dentário , Humanos , Queratinas , Camundongos , Suínos
19.
J Acquir Immune Defic Syndr ; 81(5): e141-e147, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31135582

RESUMO

OBJECTIVE: Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is associated with decreased cardiovascular events in HIV-uninfected populations. We examined these associations in people living with HIV (PLWH). METHODS: Potential myocardial infarctions (MIs) and strokes were centrally adjudicated. We examined MI types: type 1 MI (T1MI) from atherosclerotic plaque instability and type 2 MI (T2MI) in the setting of oxygen demand/supply mismatch such as sepsis. We used multivariable Cox regression analyses to determine associations between total bilirubin levels and outcomes adjusting for traditional and HIV-specific risk factors. To minimize confounding by hepatobiliary disease, we conducted analyses limited to bilirubin values <2.1 mg/dL; among those with fibrosis-4 values <3.25; and among everyone. We repeated analyses stratified by hepatitis C status and time-updated atazanavir use. RESULTS: Among 25,816 PLWH, there were 392 T1MI and 356 T2MI during follow-up. Adjusted hazard ratios for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. By contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (hazard ratio 0.56:0.33-1.00). Higher bilirubin levels among those on atazanavir were associated with fewer T1MI combined with ischemic stroke. LIMITATIONS: Analyses were conducted with total rather than unconjugated bilirubin. CONCLUSIONS: Among PLWH, higher bilirubin levels were associated with T2MI among some subgroups. However, among those on atazanavir, there was a protective association between bilirubin and T2MI. These findings demonstrate different associations between outcomes and elevated bilirubin due to diverse causes and the importance of distinguishing MI types.


Assuntos
Sulfato de Atazanavir/uso terapêutico , Bilirrubina/sangue , Infecções por HIV/complicações , Inibidores da Protease de HIV/uso terapêutico , Infarto do Miocárdio/etiologia , Adulto , Sulfato de Atazanavir/efeitos adversos , Feminino , Infecções por HIV/epidemiologia , Inibidores da Protease de HIV/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estados Unidos/epidemiologia
20.
Sci Adv ; 5(5): eaau8857, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31123703

RESUMO

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Ubiquitina-Proteína Ligases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Transdiferenciação Celular , Humanos , Lisina/metabolismo , Camundongos , Camundongos Knockout , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Mioblastos/citologia , Mioblastos/metabolismo , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
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