Abstract
Background
We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial.
Methods
Children aged 3–15 ...years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)–recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8–9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration–time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults.
Results
Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation CV%) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors.
Conclusions
In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children.
Clinical Trials Registration
ISRCTN22964075.
In a pharmacokinetic substudy of the CHAPAS-4 second-line antiretroviral therapy trial, pharmacokinetic profiles of 104 children showed adequate exposure to tenofovir alafenamide fumarate (TAF) and tenofovir when TAF is dosed according to WHO-recommended weight bands and combined with dolutegravir or ritonavir-boosted protease inhibitors.
The buzz about honey-based biosurveys Vuong, Paton; Griffiths, Anna Poppy; Barbour, Elizabeth ...
Npj Biodiversity,
04/2024, Volume:
3, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
Approximately 1.8 million metric tonnes of honey are produced globally every year. The key source behind this output, the honey bee (
Apis mellifera)
, works tirelessly to create the ...delicious condiment that is consumed worldwide. The honey that finds its way into jars on store shelves contains a myriad of information about its biogeographical origins, such as the bees that produced it, the botanical constituents, and traces of other organisms or pathogens that have come in contact with the product or its producer. With the ongoing threat of honey bee decline and overall global biodiversity loss, access to ecological information has become an key factor in preventing the loss of species. This review delves into the various molecular techniques developed to characterize the collective DNA harnessed within honey samples, and how it can be used to elucidate the ecological interactions between honey bees and the environment. We also explore how these DNA-based methods can be used for large-scale biogeographical studies through the environmental DNA collected by foraging honey bees. Further development of these techniques can assist in the conservation of biodiversity by detecting ecosystem perturbations, with the potential to be expanded towards other critical flying pollinators.
In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the ...initiation of antiretroviral therapy (ART) is approximately 10%.
In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality.
A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients 8.9% vs. 108 12.2%; hazard ratio, 0.73; 95% confidence interval CI, 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups.
Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374 .).
Troponin T (cTnT) elevation is common in patients in the Intensive Care Unit (ICU) and associated with morbidity and mortality. Our aim was to determine the epidemiology of raised cTnT levels and ...contemporaneous electrocardiogram (ECG) changes suggesting myocardial infarction (MI) in ICU patients admitted for non-cardiac reasons.
cTnT and ECGs were recorded daily during week 1 and on alternate days during week 2 until discharge from ICU or death. ECGs were interpreted independently for the presence of ischaemic changes. Patients were classified into four groups: (i) definite MI (cTnT ≥15 ng/L and contemporaneous changes of MI on ECG), (ii) possible MI (cTnT ≥15 ng/L and contemporaneous ischaemic changes on ECG), (iii) troponin rise alone (cTnT ≥15 ng/L), or (iv) normal. Medical notes were screened independently by two ICU clinicians for evidence that the clinical teams had considered a cardiac event.
Data from 144 patients were analysed (42% female; mean age 61.9 (SD 16.9)). A total of 121 patients (84%) had at least one cTnT level ≥15 ng/L. A total of 20 patients (14%) had a definite MI, 27% had a possible MI, 43% had a cTNT rise without contemporaneous ECG changes, and 16% had no cTNT rise. ICU, hospital and 180-day mortality was significantly higher in patients with a definite or possible MI.
The majority of critically ill patients (84%) had a cTnT rise and 41% met criteria for a possible or definite MI of whom only 20% were recognised clinically. Mortality up to 180 days was higher in patients with a cTnT rise.
In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the ...greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events.
In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio aHR = 1.10 95% CI 0.82-1.46, p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 41.0% versus 113/841 13.4% with standard ART, p < 0.001) and 12 weeks (567/789 71.9% versus 415/803 51.7% with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 95% CI 0.76-1.28, p = 0.91); in serious (aHR = 0.99 0.81-1.21, p = 0.88), grade-4 (aHR = 0.88 0.71-1.09, p = 0.29), or ART-modifying (aHR = 0.90 0.63-1.27, p = 0.54) adverse events (the latter occurring in 59 6.5% participants with raltegravir-intensified ART versus 66 7.3% with standard ART); in events judged compatible with IRIS (occurring in 89 9.9% participants with raltegravir-intensified ART versus 86 9.5% with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 95% CI 0.76-1.17, p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes.
Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals.
ClinicalTrials.gov NCT01825031.
International Standard Randomised Controlled Trials Number ISRCTN 43622374.
Dengue continues to cause significant global morbidity and mortality. Severe disease is characterized by cardiovascular compromise from capillary leakage. Cardiac involvement in dengue has also been ...reported but has not been adequately studied.
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Seventy-nine patients aged 8-6 yrs with different dengue severity grades were studied using echocardiography including tissue Doppler imaging. The patients were split into severity grades: dengue, dengue with warning signs, and severe dengue. Changes in cardiac functional parameters and hemodynamic indices were monitored over the hospital stay.
None.
Patients with severe dengue had worse cardiac function compared with dengue in the form of left ventricular systolic dysfunction with increased left myocardial performance index (0.58 0.26-0.80 vs. 0.38 0.22-0.70, p = .006). Septal myocardial systolic velocities were reduced (6.4 4.8-10 vs. 8.1 6-13 cm/s, p = .01) as well as right ventricular systolic (11.4 7.5-17 vs. 13.5 10-17 cm/s, p = .016) and diastolic velocities (13 8-23 vs. 17 12-25 cm/s, p = .0026). In the severe group, these parameters improved from hospital admission to discharge; septal myocardial systolic velocities to 8.8 (7-11) cm/s (p = .002), right ventricular myocardial systolic velocities to 15.0 (11.8-23) cm/s, (p = .003), and diastolic velocity to 21 (11-25) cm/s (p = .002). Patients with cardiac impairment were more likely to have significant pleural effusions.
Patients with severe dengue have evidence of systolic and diastolic cardiac impairment with septal and right ventricular wall being predominantly affected.
Severely immunocompromised human immunodeficiency virus (HIV)-infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early ...mortality and "late presenter" phenotypes.
The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children ≥5 years of age with CD4 counts <100 cells/µL initiating ART in Uganda, Zimbabwe, Malawi, and Kenya. Baseline predictors of mortality through 48 weeks were identified using Cox regression with backwards elimination (exit P > .1).
Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/µL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/µL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/µL), but low symptom burden and maintained fat mass. The remaining groups had 4%-6% mortality.
Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.
ISRCTN43622374.
The UK has been criticised for its inequitable education system, as student outcomes are strongly linked to parental socio-economic status. Children and young people experiencing poverty are less ...likely than their better off peers to leave school with good grades, which can perpetuate disadvantage in later life. The attainment gap between children and young people experiencing poverty and their better off peers in the UK is widening, despite an increasing media and policy focus in this area. Poverty-related educational inequality is a complex area and there is no conclusive evidence in what works to reduce its effects. While there is a plethora of research on the impact of poverty on education, very little of it includes the voice of children and young people and/or the psychological impact of poverty on learning. The importance of hearing the views of children and young people is central to educational psychology, as is social justice and facilitating access to the curriculum for all students. The barriers presented by the experience of poverty to learning are thus vital for educational psychologists to address. This study used qualitative methods to explore the learning journey of Key Stage 3 (age 12-13) young people experiencing poverty in an English coastal borough. Questions from the Little Box of Big Questions 2 were used as a tool in semi-structured interviews, in addition to questions devised by the researcher. Young people discussed aspects of their lives that enabled them to learn at school, and aspects that presented barriers to learning. The research used Positive Psychology, taking a strengths based approach to explore the skills young people thought they brought to education, skills they would like to develop, and how they could be supported in this. The study has highlighted themes that, if addressed, could potentially raise the attainment of children and young people experiencing poverty.
The UK has been criticised for its inequitable education system, as student outcomes are strongly linked to parental socio-economic status. Children and young people experiencing poverty are less ...likely than their better off peers to leave school with good grades, which can perpetuate disadvantage in later life. The attainment gap between children and young people experiencing poverty and their better off peers in the UK is widening, despite an increasing media and policy focus in this area. Poverty-related educational inequality is a complex area and there is no conclusive evidence in what works to reduce its effects. While there is a plethora of research on the impact of poverty on education, very little of it includes the voice of children and young people and/or the psychological impact of poverty on learning. The importance of hearing the views of children and young people is central to educational psychology, as is social justice and facilitating access to the curriculum for all students. The barriers presented by the experience of poverty to learning are thus vital for educational psychologists to address. This study used qualitative methods to explore the learning journey of Key Stage 3 (age 12-13) young people experiencing poverty in an English coastal borough. Questions from the Little Box of Big Questions 2 were used as a tool in semi-structured interviews, in addition to questions devised by the researcher. Young people discussed aspects of their lives that enabled them to learn at school, and aspects that presented barriers to learning. The research used Positive Psychology, taking a strengths based approach to explore the skills young people thought they brought to education, skills they would like to develop, and how they could be supported in this. The study has highlighted themes that, if addressed, could potentially raise the attainment of children and young people experiencing poverty.
This thesis aims to advance academic understanding of same-sex intimate partner violence (SSIPV). This is achieved via three pieces of research. First, a systematic review of the literature ...investigating risk factors of male SSIPV is presented. This highlighted the lack of research in this field, together with methodological and definitional problems. However, findings indicated that risk factors for male SSIPV are similar to those established for heterosexual male IPV, with some specific exceptions. Second, an empirical investigation into a sample of women’s beliefs and approval of heterosexual and same-sex intimate partner violence (IPV) and their involvement as a risk factor to perpetration is presented. Results showed that certain types of IPV are deemed to be more acceptable than others and that approval of IPV is tentatively linked as a risk factor for perpetration. Finally, a critique of a psychometric measure used in the research project is presented, namely the Revised Conflict Tactics Scales (CTS2). This highlighted many strengths of the CTS2 for use in the field, particularly its ability to quickly obtain large amounts of data, and the inclusion of many acts of IPV. However, it has some limitations, namely the lack of ability to ascertain the context of IPV. The implications of the thesis findings for the early identification, support, treatment, and education for perpetrators, victims, services, and the general public are discussed.
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