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Ubiquitination is an essential regulator of cell division. The kinase Polo-like kinase 1 (PLK1) promotes protein degradation at G2/M phase through the E3 ubiquitin ligase Skp1-Cul1-F box (SCF)ßTrCP. However, the magnitude to which PLK1 shapes the mitotic proteome is uncharacterized. Combining quantitative proteomics with pharmacologic PLK1 inhibition revealed a widespread, PLK1-dependent program of protein breakdown at G2/M. We validated many PLK1-regulated proteins, including substrates of the cell-cycle E3 SCFCyclin F, demonstrating that PLK1 promotes proteolysis through at least two distinct E3 ligases. We show that the protein-kinase-A-anchoring protein A-kinase anchor protein 2 (AKAP2) is cell-cycle regulated and that its mitotic degradation is dependent on the PLK1/ßTrCP signaling axis. Expression of a non-degradable AKAP2 mutant resulted in actin defects and aberrant mitotic spindles, suggesting that AKAP2 degradation coordinates cytoskeletal organization during mitosis. These findings uncover PLK1's far-reaching role in shaping the mitotic proteome post-translationally and have potential implications in malignancies where PLK1 is upregulated.
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BACKGROUND: Persons assigned female or intersex at birth and identify as transgender and/or gender-diverse (TGD) may undergo gender-affirming chest masculinization surgery (GACMS); however, GACMS is not considered equivalent to risk-reducing mastectomies (RRM). This study aimed to estimate the prevalence of elevated breast cancer (BC) risk in TGD persons, compare self-perceived versus calculated risk, and determine how risk impacts the decision for GACMS versus RRM. METHODS: A prospective single-arm pilot educational intervention trial was conducted in individuals assigned female or intersex at birth, age ≥ 18 years, considering GACMS, without a BC history or a known pathogenic variant. BC risk was calculated using the Tyrer-Cuzik (all) and Gail models (age ≥ 35 years). Elevated risk was defined as ≥ 17%. RESULTS: Twenty-five (N = 25) participants were enrolled with a median age of 24.0 years (interquartile range, IQR 20.0-30.0 years). All were assigned female sex at birth, most (84%) were Non-Hispanic (NH)-White, 48% identified as transgender and 40% as nonbinary, and 52% had a first- and/or second-degree family member with BC. Thirteen (52%) had elevated risk (prevalence 95% confidence interval (CI) 31.3-72.2%). Median self-perceived risk was 12% versus 17.5% calculated risk (p = 0.60). Of the 13 with elevated risk, 5 (38.5%) underwent/are scheduled to undergo GACMS, 3 (23%) of whom underwent/are undergoing RRM. CONCLUSIONS: Over half of the cohort had elevated risk, and most of those who moved forward with surgery chose to undergo RRM. A BC risk assessment should be performed for TGD persons considering GACMS. Future work is needed to examine BC incidence and collect patient-reported outcomes. Trial Registration Number ClinicalTrials.gov (No. NCT06239766).
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This paper describes the successful implementation of an assessment literacy strategy within a Biomedical Sciences degree. Teaching was aligned with an assessment literacy framework and aimed to prepare undergraduates for a literature comprehension assessment. Students were introduced to the assessment purpose and an adapted Miller's pyramid model illustrated how the assessment contributed to competency development during their degree. Students read primary research papers and answered questions relating to the publications. They were then introduced to the processes of assessment and collaboratively graded answers of different standards. Finally, student and faculty grades were compared, differences considered, and key characteristics of answers discussed. Most students reported that they understood more about assessment standards than prior to the intervention [139/159 (87.4%)] and felt it had helped prepare them for their exam [138/159 (86.8%)]. The majority also reported they had increased confidence in evaluating data [118/159 (74%)], communicating their reasoning [113/159 (71%)] and considering what a reader needs to know [127/159 (79.9%)]. Students were asked to state the most important thing they had learned from the assessment literacy teaching. Notably, no responses referred to domain-specific knowledge. 129 free text responses were mapped to the University of Edinburgh graduate attribute framework. 93 (72%) statements mapped to the graduate attribute category "Research and Enquiry," 66 (51.16%) mapped to "Communication" and 21 (16.27%) mapped to "Personal and Intellectual Autonomy." To explore any longer-term impact of the assessment literacy teaching, a focus group was held with students from the same cohort, 2 years after the original intervention. Themes from this part of the study included that teaching had provided insights into standards and expectations for the assessment and the benefits of domain specific knowledge. A variety of aspects related to graduate attributes were also identified. Here, assessment literacy as a vehicle for graduate attribute development was an unexpected outcome. We propose that by explicitly engaging students with purpose, process, standards, and expectations, assessment literacy strategies may be used to successfully raise awareness of developmental progression, and enhance skills, aptitudes, and dispositions beneficial to Biomedical Sciences academic achievement and life after university.
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Curriculum , Evaluación Educacional , Humanos , Evaluación Educacional/métodos , Alfabetización , Masculino , Femenino , Estudiantes/psicología , ComprensiónRESUMEN
Soil organic carbon (SOC) is a dynamic soil property (DSP) that represents the largest portion of terrestrial carbon. Its relevance to carbon sequestration and the potential effects of land use on SOC storage, make it imperative to map across both space and time. Most regional-scale studies mapping SOC give static estimates and train different models for different periods with varying accuracies. We developed a flexible modeling approach called DSP-Scale to map SOC in both space and time. DSP-Scale uses ecological concepts and empirical data to predict DSP dynamics using inherent soil properties (static factors) and land cover changes (dynamic factors). We compiled SOC data for the 0-20 cm depth (SOC20) from 1441 points spanning a 25 million ha study area in the southeastern U.S. Coastal Plain, incorporating data from the Rapid Carbon Assessment, National Cooperative Soil Survey Soil Characterization database, and other regional studies. We developed a random forest model using climate, topography, soil survey, and land cover changes to predict SOC20 dynamics for five-year periods between 2001 and 2019. Our model explained 66 % and 59 % of the variation for the training and test data, respectively. Top predictors included mean annual precipitation, slope, and soil erosion class. Land cover 10 years before measurements of SOC20 was more important than current land cover for estimating SOC20. We estimated total SOC stocks of 207.1 and 208.3 Tg for 2001 and 2019, respectively. Highest gains of total SOC stock (0.9 Tg from 2001 to 2019) were associated with land cover change from mixed to evergreen forest. The greatest loss of total SOC stock (0.2 Tg) in the same period was associated with land cover change from pasture/hay to evergreen forest. We concluded that the DSP-Scale approach provides a flexible way to use dynamic and static factors affecting SOC stocks to predict changes in space and time at regional scales.
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BACKGROUND: Barrett's oesophagus surveillance places significant burden on endoscopy services yet is vital to detect early cancerous change. Oesophageal cell collection device (OCCD) testing was introduced across Scotland for Barrett's surveillance in response to the COVID-19 pandemic. This national pragmatic retrospective study presents the CytoSCOT programme results and evaluates whether OCCD testing is successfully identifying high-risk Barrett's patients requiring urgent endoscopy. METHODS: All patients undergoing OCCD testing for Barrett's surveillance across 11 Scottish health boards over a 32-month period were identified. Patients who underwent endoscopy within 12 months of OCCD test were included. Individual patient records were interrogated to record clinical information and OCCD test result to categorize patients into risk groups. Endoscopic histopathology results were analysed according to risk group and segment length. Patients were deemed high risk if the OCCD test demonstrated atypia and/or p53 positivity. RESULTS: 4204 OCCD tests were performed in 3745 patients: 608 patients underwent endoscopy within 12 months and were included in this analysis. Patients with longer Barrett's segments were significantly more likely to have an abnormal OCCD test. 50/608 patients (8.2%) had high-grade dysplasia or cancer on endoscopic biopsies: this equates to 1.3% of the total group (50/3745). 46/50 patients (92.0%) were deemed high risk, triggering urgent endoscopy: this rose to 100% with insufficient tests removed. There were no cancers diagnosed within 12 months post-OCCD in the low-risk group. CONCLUSION: OCCD testing is an effective triage tool to identify high-risk patients with Barrett's oesophagus requiring further investigation with endoscopy within the real-world setting.
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Esófago de Barrett , Neoplasias Esofágicas , Esofagoscopía , Humanos , Esófago de Barrett/patología , Esófago de Barrett/diagnóstico , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Esofagoscopía/métodos , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , COVID-19/diagnóstico , Escocia/epidemiología , Biomarcadores/metabolismo , Medición de Riesgo , Esófago/patología , Detección Precoz del Cáncer/métodos , AdultoRESUMEN
High quality Barrett's esophagus surveillance is crucial to detect early neoplastic changes. An esophageal cell collection device (OCCD) was introduced as a triage tool for Barrett's surveillance. This study aims to evaluate whether the Scottish OCCD program (CytoSCOT) has reduced delays to Barrett's surveillance, and whether delayed surveillance negatively impacts endoscopic pathology. All patients undergoing OCCD testing for Barrett's surveillance across 11 Scottish health boards between 14/9/2020 and 13/9/2022 were identified. Patients were dichotomised into two groups (Year 1 vs. Year 2), with individual records interrogated to record demographics, recommended surveillance interval, time from last endoscopy to OCCD test, and OCCD result. Patients were deemed high-risk if the OCCD demonstrated atypia and/or p53 positivity. Further analysis was performed on patients who underwent endoscopy within 12 months of OCCD testing. A total of 3223 OCCD tests were included in the analysis (1478 in Year 1; 1745 in Year 2). In Year 1 versus Year 2, there was a longer median delay to surveillance (9 vs. 5 months; P < 0.001), increased proportion of patients with delayed surveillance (72.6% vs. 57.0%; P < 0.001), and more high-risk patients (12.0% vs. 5.3%; P < 0.001). 425/3223 patients (13.2%) were further investigated with upper gastrointestinal endoscopy, 57.9% of which were high-risk. As surveillance delay increased beyond 24 months, high-risk patients were significantly more likely to develop dysplasia or malignancy (P = 0.004). Delayed Barrett's esophagus surveillance beyond 24 months is associated with increased risk of pre-cancerous pathology. The CytoSCOT program has reduced delays in surveillance, promoting earlier detection of dysplasia and reducing burden on endoscopy services.
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Esófago de Barrett , Neoplasias Esofágicas , Esofagoscopía , Esófago de Barrett/patología , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Esofágicas/patología , Esofagoscopía/métodos , Esofagoscopía/estadística & datos numéricos , Escocia/epidemiología , Factores de Tiempo , Detección Precoz del Cáncer/métodos , Esófago/patología , Diagnóstico Tardío/estadística & datos numéricos , Lesiones Precancerosas/patología , Adenocarcinoma/patologíaRESUMEN
Targeted protein degradation by the ubiquitin-proteasome system is an essential mechanism regulating cellular division. The kinase PLK1 coordinates protein degradation at the G2/M phase of the cell cycle by promoting the binding of substrates to the E3 ubiquitin ligase SCFßTrCP. However, the magnitude to which PLK1 shapes the mitotic proteome has not been characterized. Combining deep, quantitative proteomics with pharmacologic PLK1 inhibition (PLK1i), we identified more than 200 proteins whose abundances were increased by PLK1i at G2/M. We validate many new PLK1-regulated proteins, including several substrates of the cell cycle E3 SCFCyclin F, demonstrating that PLK1 promotes proteolysis through at least two distinct SCF-family E3 ligases. Further, we found that the protein kinase A anchoring protein AKAP2 is cell cycle regulated and that its mitotic degradation is dependent on the PLK1/ßTrCP-signaling axis. Interactome analysis revealed that the strongest interactors of AKAP2 function in signaling networks regulating proliferation, including MAPK, AKT, and Hippo. Altogether, our data demonstrate that PLK1 coordinates a widespread program of protein breakdown at G2/M. We propose that dynamic proteolytic changes mediated by PLK1 integrate proliferative signals with the core cell cycle machinery during cell division. This has potential implications in malignancies where PLK1 is aberrantly regulated.
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Trimethoprim-sulfamethoxazole (TMP-SMX) and phenazopyridine are individually associated with methemoglobinemia through a series of altered reduction-oxidation reactions. We report a case of methemoglobinemia associated with concurrent use of TMP/SMX and phenazopyridine in a 70-year-old woman with recurrent urinary tract infections. She presented to the emergency department for worsening back pain in the setting of recurrent urinary tract infections, concerning for pyelonephritis. During her workup, she became acutely hypoxic. The emergency department provider suspected the presence of abnormal hemoglobin. An arterial blood gas showing elevated levels of methemoglobinemia confirmed the suspicion. The combined use of TMP/SMX and phenazopyridine was thought to be the likely etiology of hypoxia. This case highlights the importance of medication management in the geriatric population, as well as the judicious use of antibiotics for urinary tract infections-a common chief complaint in the primary care setting.
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Metahemoglobinemia , Infecciones Urinarias , Anciano , Femenino , Humanos , Combinación Trimetoprim y Sulfametoxazol/efectos adversos , Fenazopiridina/efectos adversos , Metahemoglobinemia/inducido químicamente , Metahemoglobinemia/tratamiento farmacológico , Infecciones Urinarias/tratamiento farmacológico , Ingestión de AlimentosRESUMEN
Whereas the Coastal Plain of the southeastern United States historically experienced fire primarily during the mid-summer lightning season, managers today typically apply prescribed fire during the late winter or early spring months. The ecological implications of this discrepancy remain poorly understood, especially with regard to pollinators and their interactions with flowers. In a replicated field experiment, we compared the abundance and richness of bees and bee-flower interactions among pine savanna plots in Florida that were burned either during the winter, spring, summer, or fall. We netted 92 bee species from 77 species of flowers, representing 435 unique bee-flower interactions in total. When analyzing the results from each month separately, we detected significant short-term reductions in the number of bees and bee-flower interactions following fires regardless of season. Although bee abundance and richness did not differ over the entire season, bee-flower interaction richness was significantly higher overall in spring and summer plots than in fall plots and the composition of both bees and bee-flower interactions differed significantly among treatments. Several bee-flower interactions were significantly associated with one or more of the treatments. Some of these associations could be attributed to differences in flowering phenology among treatments. Taken together, our findings suggest that season of fire has modest but potentially important implications for interactions between bees and flowers in southeastern pine ecosystems. Because most flowering plants within our study region are pollinated by a variety of bees and other insects, and most bees endemic to the region are polylectic, season of fire may not be very important to either group overall. However, the timing of fire may be more important to particular species including certain flower specialists and fire-sensitive taxa such as butterflies. Future research targeting such species would be of interest.
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BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Femenino , Terapia Antirretroviral Altamente Activa/métodos , VIH-1/genética , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos , Carga ViralRESUMEN
Accurate interpretation of the martian sedimentary rock record-and by extension that planet's paleoenvironmental history and potential habitability-relies heavily on rover-based acquisition of textural and compositional data and researchers to properly interpret those data. However, the degree to which this type of remotely sensed information can be unambiguously resolved and accurately linked to geological processes in ancient sedimentary systems warrants further study. In this study, we characterize Mars-relevant siliciclastic-evaporite samples by traditional laboratory-based geological methods (thin section petrography, X-ray diffraction [XRD], backscattered electron imaging, microprobe chemical analyses) and remote sensing methods relevant to martian rover payloads (visible-near-mid infrared reflectance spectroscopy, X-ray fluorescence mapping, XRD). We assess each method's ability to resolve primary and secondary sedimentologic features necessary for the accurate interpretation of paleoenvironmental processes. While the most dominant textures and associated compositions (i.e., bedded gypsum evaporite) of the sample suite are readily identified by a combination of remote sensing techniques, equally important, although more subtle, components (i.e., interbedded windblown silt, meniscus cements) are not resolved unambiguously in bulk samples. However, rover-based techniques capable of coordinating spatially resolved compositional measurements with textural imaging reveal important features not readily detected using traditional assessments (i.e., subtle clay-organic associations, microscale diagenetic nodules). Our findings demonstrate the improved generational capacity of rovers to explore ancient sedimentary environments on Mars while also highlighting the complexities in extracting comprehensive paleoenvironmental information when limited to currently available rover-based techniques. Complete and accurate interpretation of ancient martian sedimentary environments, and by extension the habitability of those environments, likely requires sample return or in situ human exploration. Plain Language Summary Only when correctly translated can the ancient martian sedimentary rock record reveal the environmental evolution of the planet's surface through time. In this case study, we characterize Mars-relevant sedimentary rocks and evaluate the degree to which a comprehensive geological picture can be resolved unambiguously when limited to microscale remote sensing methods relevant to rovers on Mars. While the most dominant textural features and associated compositions of the sample suite are readily identified by a combination of remote sensing techniques, equally important but more subtle components are not resolved unambiguously in bulk samples. However, rover-based techniques capable of coordinating spatially resolved compositional measurements with textural imaging, such as Perseverance Rover's Planetary Instrument for X-Ray Lithochemistry instrument, reveal important features not readily detected by more traditional methods. We demonstrate that rovers have, generationally, improved in their capacity to resolve a true geological picture in ancient sedimentary environments, likely owing to an improved ability to coordinate spatially resolved compositional measurements with textural imaging at the microscale. However, our work also highlights the complexities involved in extracting subtle environmental information when limited to currently available rover-based techniques and suggests that comprehensive interpretation of ancient martian sedimentary systems likely requires sample return or in situ human exploration. Key Points Mars-relevant samples are characterized using both traditional laboratory and microscale rover-based remote sensing techniques to assess each method's ability to recognize features necessary for accurate paleoenvironmental process interpretation. While some key paleoenvironmental processes can reasonably be inferred via remote sensing methods, others cannot be resolved unambiguously. Perseverance Rover's Planetary Instrument for X-Ray Lithochemistry instrument reveals diagenetic features that would otherwise remain unseen by traditional thin section petrography.
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Medio Ambiente Extraterrestre , Marte , Humanos , Medio Ambiente Extraterrestre/química , Exobiología/métodos , Tecnología de Sensores Remotos , Sedimentos Geológicos/químicaRESUMEN
Blood flow autoregulation in cerebral white matter was measured before and after acute nicardipine-induced changes in mean arterial pressure of 10-21% in 21 treatment naïve HIV-positive adults and 32 controls. The autoregulatory index (-% cerebral blood flow change/% mean arterial pressure change) was not different at baseline ( P â=â0.71) or after 1 year of treatment ( n â=â11, P â=â0.17). We found no autoregulatory defect to explain the increased stroke risk or the development of cerebral white damage in people with HIV.
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Infecciones por VIH , Accidente Cerebrovascular , Sustancia Blanca , Adulto , Humanos , Sustancia Blanca/diagnóstico por imagen , Infecciones por VIH/complicaciones , Circulación Cerebrovascular/fisiología , Homeostasis/fisiología , Presión SanguíneaRESUMEN
ABSTRACT: With advances in HIV treatment, people with HIV (PWH) are living longer but experience aging-related comorbidities, including cognitive deficits, at higher rates than the general population. Previous studies have shown alterations in lysosomal proteins in blood from PWH with severe dementia. However, these markers have not been evaluated in PWH with milder neurocognitive impairment. We sought to determine whether levels of the lysosomal cysteine protease cathepsin B (CatB) and its endogenous inhibitor cystatin B (CysB) were altered in PWH with neurocognitive impairment and whether antiretroviral therapy (ART) further influenced these levels. Peripheral blood mononuclear cells were obtained from the tenofovir arm of a multicenter clinical trial in which ART-naive, HIV+ participants received treatment for 48 weeks (ACTG A5303, NCT01400412). PWH were divided by neurocognitive status (eg, with or without neurocognitive impairment) before ART initiation. Intracellular levels of CatB and CysB were measured in T cells and monocytes by means of flow cytometry. Levels of CysB were significantly decreased in both CD4 + T cells and CD8 + T cells after 48 weeks of ART in HIV+ participants without neurocognitive impairment but not in participants with neurocognitive impairment. Levels of CysB were increased in CD14 + monocytes from the participants with neurocognitive impairment after ART. Levels of CysB and CatB positively correlated regardless of HIV, neurocognitive status, or exposure to ART. These findings suggest that CysB has the potential to provide mechanistic insight into HIV-associated neurocognitive disorders or provide a molecular target for systemic monitoring or treatment of neurocognitive impairment in the context of ART and should be investigated further.
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Infecciones por VIH , Humanos , Cistatina B , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Leucocitos Mononucleares , Trastornos Neurocognitivos/complicaciones , Carga Viral , Estudios Multicéntricos como Asunto , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND AND PURPOSE: Regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2 ) in whole brain, white matter, gray matter and lenticular nuclei were studied in people living with human immunodeficiency virus (PLHIV) as well as HIV-associated neurocognitive disorder (HAND). METHODS: Treatment-naïve PLHIV underwent neurocognitive assessment and magnetic resonance (MR) measurement of rCBF and rCMRO2 with repeat after 12 months of antiretroviral therapy (ART). Age- and sex-matched controls underwent single MR measurements. Regional CBF and rCMRO2 were compared amongst symptomatic, asymptomatic, normal HAND and controls using analysis of variance. Longitudinal analysis of HAND worsening (≥1 category) was assessed after 12 months of ART and correlated with rCBF and rCMRO2 measured by MR imaging using the paired-sample t test. RESULTS: Thirty PLHIV completed baseline and 12-month assessments (29 with rCMRO2 measurement). At baseline HAND assessment, 13% had no cognitive impairment, 27% had asymptomatic neurocognitive impairment, 60% had mild neurocognitive disorder and none had HIV-associated dementia. At 12 months, 13% had no cognitive impairment, 20% had asymptomatic neurocognitive impairment, 50% had mild neurocognitive disorder and 17% had HIV-associated dementia. In those without HAND worsening (N = 21) rCMRO2 remained stable and in those with HAND worsening (N = 8) rCMRO2 measurement declined from baseline to 12 months in white matter (2.05 ± 0.40 to 1.73 ± 0.51, p = 0.03) and lenticular nuclei (4.32 ± 0.39 to 4.00 ± 0.51, p = 0.05). CONCLUSIONS: In recently diagnosed PLHIV, no association was found between rCBF or rCMRO2 and cognitive impairment at baseline. There was a reduction in rCMRO2 in those with worsening of cognitive function at 12 months on ART. Reduction in rCMRO2 may be a biomarker of cognitive decline in PLHIV.
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Disfunción Cognitiva , Infecciones por VIH , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Circulación Cerebrovascular/fisiología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , VIH/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Humanos , Oxígeno/metabolismoRESUMEN
OBJECTIVES: HIV-associated neurocognitive disorders (HAND) remain prevalent in people living with HIV (PLWH) despite widespread use of combined antiretroviral therapy (ART). Vascular disease contributes to the pathogenesis of HAND, but traditional vascular risk factors do not fully explain the relation between vascular disease and HAND. A more direct measure of vascular dysfunction is needed. This cross-sectional study tested whether the cardio-ankle vascular index (CAVI), a novel method to assess arterial stiffness, is associated with HAND among PLWH. METHODS: Participants included 75 non-diabetic adults with well-controlled HIV from an outpatient HIV clinic. We assessed the relation between CAVI and neurocognitive impairment (NCI). The latter was primarily characterized by the Frascati criteria and secondarily (post hoc) using the Global Deficit Score (GDS). Logistic regression models tested whether high CAVI (≥ 8) was independently associated with NCI when controlling for potential confounders. RESULTS: Participants (Mage = 45.6 ± 8.3 years; 30.1% male) had few traditional cardiovascular disease (CVD) risk factors (hypertension, n = 7; dyslipidaemia, n = 34; body mass index ≥ 25 kg/m2 , n = 12; smoking history, n = 13; 2.2% mean 10-year risk of CVD or stroke). Twelve (16%) participants had high CAVI, which was independently associated with meeting Frascati criteria for NCI [n = 39, odds ratio (OR) = 7.6, p = 0.04], accounting for age, education, gender, income, CD4 nadir, recent CD4 and traditional CVD risk factors. High CAVI was also associated with NCI as reflected by higher GDS (OR = 17.4, p = 0.02). CONCLUSIONS: Cardio-ankle vascular index is a promising measure of vascular dysfunction that may be independently associated with NCI in relatively healthy PLWH. Larger studies should test the utility of CAVI in predicting NCI/decline in PLWH.
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Enfermedades Cardiovasculares , Infecciones por VIH , Enfermedades Vasculares , Rigidez Vascular , Adulto , Tobillo/irrigación sanguínea , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Restoration of savanna ecosystems within their historic range is expected to increase provision of ecosystem services to resident human populations. However, the benefits of restoration depend on the degree to which ecosystems and their services can be restored, the rate of restoration of particular services, and tradeoffs in services between restored ecosystems and other common land uses. We use a chronosequence approach to infer multi-decadal changes in ecosystem services under management aimed at restoring fire-dependent pine savannas, including the use of frequent prescribed fire, following abandonment of row-crop agriculture in the southeastern U.S. We compare ecosystem services between restored pine savannas of different ages and reference pine savannas as well as other common land uses (row-crop agriculture, improved pasture, pine plantation, unmanaged forest). Our results suggest that restoring pine savannas results in many improvements to ecosystem services, including increases in plant species richness, perennial grass cover, tree biomass, total ecosystem carbon, soil carbon and C:N, reductions in soil bulk density and predicted erosion and sedimentation, shifts from soil fungal pathogens to fungal symbionts, and changes in soil chemistry toward reference pine savanna conditions. However, the rate of improvement varies widely among services from a few years to decades. Compared to row-crop agriculture and improved pasture, restored savannas have lower erosion, soil bulk density, and soil pathogens and a higher percentage of mycorrhizal fungi and ecosystem carbon storage. Compared to pine plantations and unmanaged forests, restored pine savannas have lower fire-prone fuel loads and higher water yield and bee pollinator abundance. Our results indicate that restoration of pine savanna using frequent fire provides a broad suite of ecosystem services that increase the landscape's overall resilience to climate change. These results are likely relevant to other savannas dominated by perennial vegetation and maintained with frequent fire.
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Incendios , Micorrizas , Pinus , Agricultura , Animales , Abejas , Ecosistema , Pradera , ÁrbolesRESUMEN
INTRODUCTION: Early systemic and central nervous system viral replication and inflammation may affect brain integrity in people with HIV, leading to chronic cognitive symptoms not fully reversed by antiretroviral therapy (ART). This study examined associations between cognitive performance and markers of CNS injury associated with acute HIV infection and ART. METHODS: HIV-infected MSM and transgender women (average age: 27 years and education: 13 years) enrolled within 100 days from the estimated date of detectable infection (EDDI). A cognitive performance (NP) protocol was administered at enrollment (before ART initiation) and every 24 weeks until week 192. An overall index of cognitive performance (NPZ) was created using local normative data. Blood (n = 87) and cerebrospinal fluid (CSF; n = 29) biomarkers of inflammation and neuronal injury were examined before ART initiation. Regression analyses assessed relationships between time since EDDI, pre-ART biomarkers, and NPZ. RESULTS: Adjusting for multiple comparisons, shorter time since EDDI was associated with higher pre-ART VL and multiple biomarkers in plasma and CSF. NPZ scores were within the normative range at baseline (NPZ = 0.52) and at each follow-up visit, with a modest increase through week 192. Plasma or CSF biomarkers were not correlated with NP scores at baseline or after ART. CONCLUSIONS: Biomarkers of CNS inflammation, immune activation, and neuronal injury peak early and then decline during acute HIV infection, confirming and extending results of other studies. Neither plasma nor CSF biomarkers during acute infection corresponded to NP scores before or after sustained ART in this cohort with few psychosocial risk factors for cognitive impairment.
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Infecciones por VIH , Adulto , Biomarcadores , Cognición , Estudios de Cohortes , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Inflamación/complicacionesRESUMEN
BACKGROUND: Individuals with previous syphilis may experience cognitive impairment. The goal of this study was to determine if those at high risk for laboratory-defined neurosyphilis are cognitively impaired, and whether treatment based on cerebrospinal fluid (CSF) findings results in better outcomes. METHODS: Participants had a new syphilis diagnosis, serum RPR titer ≥ 1:32 or peripheral blood CD4+ T cells ≤ 350/ul (in persons living with HIV) and did not endorse neurological symptoms. They underwent computerized cognitive assessment with the CogState. Thirty-two were randomized to either undergo lumbar puncture (LP) or to not undergo LP and 14 underwent LP; 64 were not randomized and 48 opted to undergo LP. RESULTS: Demographics, cognitive complaints and cognitive impairment did not differ between randomized and nonrandomized participants. Two-thirds were cognitively impaired, and impairment was not more common in those with cognitive complaints. The adjusted odds of increased severity of impairment were 3.8 times greater in those with CSF pleocytosis compared to those without. Time to cognitive normalization, improvement or decline did not differ between those who did not undergo LP and those who underwent LP and whose treatment was based on CSF analysis. Taking into account pre-treatment cognitive impairment, the risk of cognitive decline was lower in those with CSF pleocytosis treated for neurosyphilis compared to those without CSF pleocytosis not treated for neurosyphilis, (HR 0.24 (95% CI 0.07-0.88], p = 0.03). CONCLUSION: In individuals at high risk for laboratory-defined neurosyphilis, cognitive complaints are not a good indicator of cognitive impairment. Severity of cognitive impairment was greater in those with CSF pleocytosis. Identification and treatment of those with neurosyphilis may mitigate subsequent cognitive decline.
Asunto(s)
Disfunción Cognitiva/fisiopatología , Neurosífilis/fisiopatología , Sífilis/fisiopatología , Disfunción Cognitiva/terapia , Humanos , Concentración de Iones de Hidrógeno , Neurosífilis/terapia , Factores de Riesgo , Punción Espinal , Sífilis/terapiaRESUMEN
OBJECTIVE: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance. DESIGN: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected. METHODS: Participants (Nâ=â93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography-tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning. RESULTS: Strong correlation (râ=â0.66, Pâ<â0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85âng/mg (4.56-10.93). CYP2B6 516G>T, (Pâ<â0.001) and CYP2B6 983T>C (Pâ=â0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (Pâ<â0.001) and 983T>C (Pâ=â0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (râ=â0.23, Pâ=â0.043) and 983T>C genotype (râ=â0.38, Pâ<â0.0005). CONCLUSION: This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Alquinos , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/efectos adversos , Estudios Transversales , Ciclopropanos/uso terapéutico , Citocromo P-450 CYP2B6/genética , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Nigeria , Farmacogenética , Polimorfismo de Nucleótido SimpleRESUMEN
There is a growing need for brief screening measures for HIV Associated Neurocognitive Disorders (HAND). We compared two commonly used measures (the Montreal Cognitive Assessment [MoCA] and the International HIV Dementia Scale [IHDS]) in their ability to identify asymptomatic HAND (i.e., asymptomatic neurocognitive impairment [ANI]). Participants included 74 Thai PLWH: 38 met Frascati criteria for ANI and 36 were cognitively normal (CN). Participants completed Thai language versions of the MoCA (MoCA-T) and IHDS, and a validated neurocognitive battery. We examined between-group differences for MoCA-T and IHDS total scores, and scale subcomponents. We also conducted receiver operating characteristic (ROC) analyses to determine the ability of the MoCA-T and IHDS to discriminate between CN and ANI groups, and compared their area under the curve (AUC) values. Results revealed lower MoCA-T total score, as well as the Visuospatial/Executive and Delayed Recall subtask scores, in the ANI relative to CN group. Groups did not differ on the IHDS. For ROC analyses, the MoCA-T, but not the IHDS, significantly differentiated the ANI from CN group, and there was a significant difference in AUC values between the MoCA-T (AUC = .71) and IHDS (AUC = .56). Sensitivity and specificity statistics were poor for both screening measures. These data indicate while the MoCA-T functions better than the IHDS in detecting Thai PLWH with ANI, the mildest form of HAND, neither cognitive screener, showed strong utility. Our findings reflect the limited efficacy of common screening measures in detecting subtler cognitive deficits among Thai PLWH, and highlight the need for better screening tools.