Revealing the maternal demographic history of Panthera leo using ancient DNA and a spatially explicit genealogical analysis

Background: Understanding the demographic history of a population is critical to conservation and to our broader understanding of evolutionary processes. For many tropical large mammals, however, this aim is confounded by the absence of fossil material and by the misleading signal obtained from genetic data of recently fragmented and isolated populations. This is particularly true for the lion which as a consequence of millennia of human persecution, has large gaps in its natural distribution and several recently extinct populations. Results: We sequenced mitochondrial DNA from museum-preserved individuals, including the extinct Barbary lion (Panthera leo leo) and Iranian lion (P. l. persica), as well as lions from West and Central Africa. We added these to a broader sample of lion sequences, resulting in a data set spanning the historical range of lions. Our Bayesian phylogeographical analyses provide evidence for highly supported, reciprocally monophyletic lion clades. Using a molecular clock, we estimated that recent lion lineages began to diverge in the Late Pleistocene. Expanding equatorial rainforest probably separated lions in South and East Africa from other populations. West African lions then expanded into Central Africa during periods of rainforest contraction. Lastly, we found evidence of two separate incursions into Asia from North Africa, first into India and later into the Middle East. Conclusions: We have identified deep, well-supported splits within the mitochondrial phylogeny of African lions, arguing for recognition of some regional populations as worthy of independent conservation. More morphological and nuclear DNA data are now needed to test these subdivisions.European Union�s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. FP7-PEOPLE-2011-IEF-298820.Scopu

Measurement of retinal vessels as a biomarker of cerebrovascular ageing in older HIV positive men compared to controls

Background: To compare retinal vascular measurements, biomarkers of cerebral small vessel disease (SVD), in HIV positive men aged 50 years and above with similarly-aged HIV negative men and younger HIV positive men. Methods: We recruited white, non-diabetic men to a cross-sectional substudy of a larger cohort including three demographically-matched groups. Optic disc centred 45° colour fundus photographs were used to calculate central retinal arterial and venous calibre and the arterial- venous ratio (AVR). We used univariate and multivariable linear regression to compare retinal vessel measurements in the three groups and to identify factors associated with AVR. Results: All HIV positive men were virologically suppressed. In a multivariable model, study group was not associated with AVR (adjusted β 0.010 for HIV positive men 50 years [n=120], 95% CI -0.018 to 0.038, p=0.47; adjusted β 0.00002 for HIV negative men >50 years [n=52], 95% CI -0.022 to 0.022, p=0.99). Factors associated with lower AVR were systolic BP (adjusted β -0.009 per +10 mmHg, 95% CI - 0.015 to -0.003, p=0.002), history of stroke or transient ischemic attack (adjusted β -0.070, 95% CI -0.12 to -0.015, p=0.01), and recent recreational drug use (adjusted β -0.037, 95% CI -0.057 to -0.018, p=0.0002). Conclusion: There were no differences in retinal vascular indices between HIV positive men aged >50 years and HIV negative men aged >50 years or HIV positive men aged <50 years, suggesting that HIV is not associated with an increased burden of cerebral SVD

Thoracic arachnoiditis, arachnoid cyst and syrinx formation secondary to myelography with Myodil, 30 years previously

Spinal arachnoiditis can rarely occur following irritation from foreign body substances, including certain oil based contrast agents used for myelography. We describe a patient with thoracic arachnoiditis, arachnoid cyst and syringomyelia, 30 years following a myelogram with Myodil. A 62-year-old female presented with chronic thoraco-lumbar back pain, a spastic paraparesis and sphincter disturbance. She had undergone a myelogram with Myodil, 30 years previously for investigation of back pain. A MRI scan revealed evidence of arachnoiditis, thoracic syringomyelia (T6–T8) and an anteriorly placed, extramedullary, arachnoid cyst at T10–T12, compressing the cord. At surgery, T7–T10 thoracic laminectomies were carried out and syringo- and cysto-subarachnoid shunts were inserted. At 12 months follow-up, the sphincter disturbance, lower limb weakness and mobility problems had almost resolved. Although, the use of oil based contrast agents such as Myodil has been discontinued, the present case illustrates some of the rare sequelae of its use, manifesting decades later. Aggressive surgical intervention produced symptomatic benefit

Pain in people living with HIV and its association with healthcare resource use, well-being and functional status

Objective: We describe the prevalence of pain and its associations with healthcare resource utilisation and quality-of-life. Design: The POPPY Study recruited three cohorts: older PLWH (≥50 years, n = 699), younger demographically/lifestyle similar PLWH (<50 years, n = 374) and older demographically/lifestyle similar HIV-negative (≥50 years, n = 304) people from April 2013-February 2016. Methods: Current pain and pain-related healthcare use was collected via a self-reported questionnaire. Logistic regression assessed between-group differences in the prevalence of pain in the past month and current pain after controlling for potential confounders. Associations between current pain and healthcare resource use, reported joint problems, depressive symptoms, quality-of-life and functional status were assessed in PLWH using Mann-Whitney U and Chi-squared tests. Results: Pain in the past month was reported by 473/676 (70.0%) older PLWH, 224/357 (62.7%) younger PLWH and 188/295 (63.7%) older HIV-negative controls (p = 0.03), with current pain reported in 330 (48.8%), 134 (37.5%) and 116 (39.3%), respectively (p = 0.0007). Older PLWH were more likely to experience current pain, even after adjustment for confounders. Of those with pain in the past month, 56/412 (13.6%) had missed days of work or study due to pain, and 520 (59%) had seen a doctor about their pain. PLWH experiencing current painhad more depressive symptoms, poorer quality-of-life on all domains, and greater functional impairment, regardless of age group. Conclusions: Even in the effective ART era, pain remains common in PLWH and has a major impact on quality-of-life and associated healthcare and societal costs. Interventions are required to assist clinicians and PLWH to proactively manage pain

Risk of Myocardial Infarction in Patients with HIV Infection Exposed to Specific Individual Antiretroviral Drugs from the 3 Major Drug Classes: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study

Background. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Methods. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with 130,000 person-years of exposure. Results. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. Conclusions. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provid

Defining cognitive impairment in people-living-with-HIV: the POPPY study

Background The reported prevalence of cognitive impairment (CI) varies widely in cohorts of people living with HIV (PLWH); this may partly be due to the use of different diagnostic criteria. Agreement between diagnostic criteria of CI, the optimal definition to use, and associations with patient-reported cognitive symptoms have not been fully investigated. Methods Two hundred ninety PLWH aged >50 years and 97 matched negative controls completed a detailed assessment of cognitive function and three questions regarding cognitive symptoms. Age- and education-adjusted test scores (T-scores) determined if subjects met the following definitions of CI: Frascati, global deficit score (GDS) and the multivariate normative comparison (MNC) method. Results PLWH were more likely than controls to meet each definition of CI (ORs were 2.17, 3.12 and 3.64 for Frascati, GDS and MNC, respectively). Agreement of MNC with Frascati and GDS was moderate (Cohen’s k = 0.42 and 0.48, respectively), whereas that between Frascati and GDS was good (k = 0.74). A significant association was found between all the three criteria and reporting of memory loss but not with attention and reasoning problems. The 41 (14 %) PLWH meeting all the three criteria had the lowest median global T-score (36.9) and highest rate of symptom reporting (42 %). Conclusions Different CI criteria show fair diagnostic agreement, likely reflecting their ability to exclude CI in the same group of individuals. Given the lower overall cognitive performance and higher rates of symptom reporting in those meeting all three criteria of CI, further work assessing this as a definition of CI in PLWH is justified

Cohort profile: the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study

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Changes in multimorbidity burden over a 3–5 year period among people with HIV

Introduction: As people living with HIV age, the increasing burden of multimorbidity poses a significant health challenge. The aims of this study were to identify common patterns of multimorbidity and examine changes in their burden, as well as their associations with risk factors, over a 3–5 year period in people with HIV, enrolled in the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study.Methods: Common multimorbidity patterns were identified in POPPY participants with HIV using principal component analysis, based on Somers’ D statistic. Multimorbidity burden scores were calculated for each participant/pattern at study entry/follow-up and were standardised relative to the mean in the sample at baseline (scores &gt;0 thus reflect a greater number of comorbidities relative to the mean). Two multivariable linear regression models were fitted to examine the associations between risk factors and burden z-scores at baseline and change in z-scores over a 3–5 year period.Results: Five patterns were identified among the 1073 POPPY participants with HIV {median age [interquartile range (IQR)], 52 (47–59) years; 85% male and 84% white}: Cardiovascular diseases (CVDs), Sexually transmitted diseases (STDs), Neurometabolic, Cancer and Mental-gastro-joint. The multivariable linear regression showed that older age, behavioural factors (i.e., body mass index (BMI), history of injection drug use, current recreational drug use and sex between men), and HIV-specific factors (i.e., duration since HIV diagnosis and a prior AIDS diagnosis) were associated with higher multimorbidity burden at baseline. However, only three of the factors (age, BMI and duration since HIV diagnosis) were significantly associated with an increase in burden across specific patterns over time.Discussion: Key modifiable and non-modifiable factors contributing to an increase in burden of multimorbidity were identified. Our findings may inform the development of more targeted interventions and guidelines to effectively prevent and manage the rising burden of multimorbidity in people with HIV

Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined. Methods and Findings: A5164 was a randomized strategy trial of ‘‘early ART’’ - given within 14 days of starting acute OI treatment versus ‘‘deferred ART’’ - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) [greater than or equal to] 50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Conclusions: Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications