Developmental effects of estrogen and PCBs in the reproductive tract of BALB/C mice

Many of the tumorigenic effects that result from neonatal exposure to both natural and synthetic estrogens resemble those found in humans exposed to diethylstilbestrol (DES) in utero. Using this established DES neonatal mouse model, my goal was to investigate long-term molecular and morphological effects of certain polychlorinated biphenyls (PCBs) that are weakly estrogenic in adult mice. Focusing on the cervicovaginal (CV) tract, since this is where tumors develop in the BALB/c mouse, I first assessed the 17β-estradiol (E2) dose-response for expression of lactoferrin (LTF). LTF is a highly inducible estrogen biomarker that is permanently altered in uteri from neonatally treated mice. Treatments were administered via 5 subcutaneous injections beginning within 16 hrs after birth, days 1–5. ^ The ontogeny of LTF expression from mouse CV tracts was determined by examining three different stages of life: pups, immature, and mature mice. Northern RNA analysis and immunohistochemistry showed that neonatal E 2 treatment both increases and decreases LTF expression. Early expression of LTF in the CV tract at all doses occurred in pups. In both immature and adult mice, increased LTF expression was dependent on whether E2 induced ovary-dependent or ovary-independent persistent vaginal cornification. ^ Next, I studied biological responses from neonatally PCB exposed adult mice. As expected, using a neonatal uterine bioassay I showed that 2 ′4′6′-trichloro-4-biphenylol (OH-PCB-30), 2′3′4′ 5-tetrachloro-4-biphenyloI (OH-PCB-61), and OH-PCB-30/61 (50/50 mixture), were estrogenic causing a dose-dependent increase in uterine weight. ^ Long-term effects of OH-PCB 30 [200 μg/pup/day] were most similar to E2 as seen by an increased uterine wet weight in day 50 mice similar to E2 [5 μg/pup/day] (141% and 140% of control, respectively). Another similarity between OH-PCB 30 and E2 neonatally treated mice was found in those sacrificed at 20 months of age. At these same doses CV tract squamous cell carcinoma induction was 43% of E2 treated mice and 47% of OH-PCB 30 treated mice. Differences were noted in adenoaquamous; cell carcinoma development, where 16% of OH-PCB-30 neonatally treated mice developed tumors versus 8% for E2. Based on these results using the neonatal mouse model, I conclude that the OH-PCBs tested are strongly estrogenic and tumorigenic showing dose-response relationships when exposure occurs during development of the reproductive tract in mice. These results may have important implications for risk assessment in determining the effects of xenoestrogens exposure early versus later in life. ^

CISPLATIN NEPHROTOXICITY AND ITS EFFECTS ON GENTAMICIN PHARMACOKINETICS

Myelosuppression is a common side effect of anticancer agents such as cisplatin. This makes patients more susceptible to infections. Gentamicin is an aminoglycoside antibiotic that is very effective in the treatment of gram negative infections. Both these drugs are excreted by the kidney, and are also nephrotoxic. Thus, each may affect the disposition of the other. This project deals with the nature and duration of the effects of cisplatin on gentamicin pharmacokinetics in F-344 rats.^ The appropriate cisplatin dose was determined by comparing the nephrotoxicity of four intravenous doses--3, 4, 5, and 6 mg/kg. The 6 mg/kg dose gave the most consistent nephrotoxic effect, with peak plasma urea nitrogen and creatinine levels on the 7th day. Plasma and tissue gentamicin levels were compared between rats given gentamicin alone (30 mg/kg, intraperitoneally, twice a day for four days), and those given cisplatin (6 mg/kg, intraperitoneally) with the first gentamicin dose. Cisplatin caused a significant elevation of gentamicin levels in plasma, liver, and spleen. However, cisplatin given in three weekly doses of 2 mg/kg each, had no effect on plasma or tissue gentamicin levels.^ In order to determine the duration of cisplatin effects, a single dose of gentamicin (30 mg/kg, intravenously) was given to different groups of rats either alone, or on day 1, 4, 7, 15, or 29 following cisplatin (6 mg/kg, intravenously on day 1). Plasma samples were collected through a cannula placed on the external jugular vein at 0.5, 1, 2, 3, 4, 5, and 6 hours after gentamicin; the rats were sacrificed at 24 hours. Cisplatin caused a significant decrease in gentamicin excretion and an elevation of gentamicin levels in plasma, kidneys, liver, and spleen at all the time points that were tested, except with concomitant administration. Plasma urea nitrogen was elevated, and creatinine clearance decreased by the 4th day after cisplatin and these continued to be significantly different even on the 29th day after cisplatin.^ These results demonstrate that cisplatin nephrotoxicity reduced gentamicin excretion for at least a month in F-344 rats. This could increase the risk of toxicity from the second drug by elevating its levels in plasma and tissue. Thus, caution should be exercised when renally excreted drugs are given after cisplatin. ^

EMPLOYMENT AND EXPOSURES IN THE PETROLEUM REFINING AND PETROCHEMICAL INDUSTRIES AND THE RISK OF LUNG CANCER (EPIDEMIOLOGY, ASSESSMENT)

This dissertation addresses the risk of lung cancer associated with occupational exposures in the petroleum refining and petrochemical industries. Earlier epidemiologic studies of this association did not adjust for cigarette smoking or have specific exposure classifications. The Texas EXposure Assessment System (TEXAS) was developed with data from a population-based, case-comparison study conducted in five southeast Texas counties between 1976 and 1980. The Texas Exposure Assessment System uses job and process categories developed by the American Petroleum Institute, as well as time-oriented variables to identify high risk groups.^ An industry-wide, increased risk for lung cancer was associated with jobs having low-level hydrocarbon exposure that also include other occupational inhalation exposures (OR = 2.0--adjusted for smoking and latency effects). The prohibition of cigarette smoking for jobs with high-level hydrocarbon exposure might explain part of the increased risk for jobs with low-level hydrocarbon exposures. Asbestos exposure comprises a large part of the risk associated with jobs having other inhalation exposures besides hydrocarbons. Workers in petroleum refineries were not shown to have an increased, occupational risk for lung cancer. The increased risk for lung cancer among petrochemical workers (OR = 3.1--smoking and latency adjusted) is associated with all jobs that involve other inhalation exposure characteristics (not only low-level hydrocarbon exposures). Findings for contract workers and workers exposed to specific chemicals were inconclusive although some hypotheses for future research were identified.^ The study results demonstrate that the predominant risk for lung cancer is due to cigarette smoking (OR = 9.8). Cigarette smoking accounts for 86.5% of the incident lung cancer cases within the study area. Workers in the petroleum industry smoke significantly less than persons employed in other industries (p << 0.001). Only 2.2% of the incident lung cancer cases may be attributed to petroleum industry jobs; lifestyle factors (e.g., nutrition) may be associated with the balance of the cases. The results from this study also suggest possible high risk time periods (OR = 3.9--smoking and occupation adjusted). Artifacts in time-oriented findings may result because of the latency interval for lung cancer, secular peaks in age-, sex-specific incidence rates, or periods of hazardous exposures in the petroleum industry. ^

High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis.

OBJECTIVES This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD). BACKGROUND Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. METHODS The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. RESULTS In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD. CONCLUSIONS High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.

Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.

Background:Erythropoiesis-stimulating agents (ESAs) reduce the need for red blood cell transfusions; however, they increase the risk of thromboembolic events and mortality. The impact of ESAs on quality of life (QoL) is controversial and led to different recommendations of medical societies and authorities in the USA and Europe. We aimed to critically evaluate and quantify the effects of ESAs on QoL in cancer patients.Methods:We included data from randomised controlled trials (RCTs) on the effects of ESAs on QoL in cancer patients. Randomised controlled trials were identified by searching electronic data bases and other sources up to January 2011. To reduce publication and outcome reporting biases, we included unreported results from clinical study reports. We conducted meta-analyses on fatigue- and anaemia-related symptoms measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and FACT-Anaemia (FACT-An) subscales (primary outcomes) or other validated instruments.Results:We identified 58 eligible RCTs. Clinical study reports were available for 27% (4 out of 15) of the investigator-initiated trials and 95% (41 out of 43) of the industry-initiated trials. We excluded 21 RTCs as we could not use their QoL data for meta-analyses, either because of incomplete reporting (17 RCTs) or because of premature closure of the trial (4 RCTs). We included 37 RCTs with 10 581 patients; 21 RCTs were placebo controlled. Chemotherapy was given in 27 of the 37 RCTs. The median baseline haemoglobin (Hb) level was 10.1 g dl(-1); in 8 studies ESAs were stopped at Hb levels below 13 g dl(-1) and in 27 above 13 g dl(-1). For FACT-F, the mean difference (MD) was 2.41 (95% confidence interval (95% CI) 1.39-3.43; P<0.0001; 23 studies, n=6108) in all cancer patients and 2.81 (95% CI 1.73-3.90; P<0.0001; 19 RCTs, n=4697) in patients receiving chemotherapy, which was below the threshold (⩾3) for a clinically important difference (CID). Erythropoiesis-stimulating agents had a positive effect on anaemia-related symptoms (MD 4.09; 95% CI 2.37-5.80; P=0.001; 14 studies, n=2765) in all cancer patients and 4.50 (95% CI 2.55-6.45; P<0.0001; 11 RCTs, n=2436) in patients receiving chemotherapy, which was above the threshold (⩾4) for a CID. Of note, this effect persisted when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. There was some evidence that the MDs for FACT-F were above the threshold for a CID in RCTs including cancer patients receiving chemotherapy with Hb levels below 12 g dl(-1) at baseline and in RCTs stopping ESAs at Hb levels above 13 g dl(-1). However, these findings for FACT-F were not confirmed when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy.Conclusions:In cancer patients, particularly those receiving chemotherapy, we found that ESAs provide a small but clinically important improvement in anaemia-related symptoms (FACT-An). For fatigue-related symptoms (FACT-F), the overall effect did not reach the threshold for a CID.British Journal of Cancer advance online publication, 17 April 2014; doi:10.1038/bjc.2014.171 www.bjcancer.com.

Parasite- and predator-induced maternal effects in the great tit (Parus major)

Both predators and parasites can elicit behavioral and physiological responses in prey and hosts, respectively. These responses may involve the reallocation of resources and may thus limit each other. We investigated the effects of concurrent pre-laying exposure of great tit females (Parus major) to both a simulated predation risk and a nest-based ectoparasite, the hen flea (Ceratophyllus gallinae), on nestling growth and development. We manipulated perceived predation risk using models and vocalizations of sparrowhawks (Accipiter nisus). At the start of incubation, we swapped whole clutches between treated and untreated nests to separate pre-laying maternal effects from posthatching effects. Since costs and benefits of maternal responses to parasites need to be assessed under parasite pressure, we infested half of the rearing nests with hen fleas. Parasites had negative effects on mass gain and wing growth, both via maternal effects and via direct exposure of nestlings, whereas maternal predation risk had no significant effect. The interaction between predator and parasite treatments was not significant and, thus, suggests the absence of a trade-off between the 2 stressors operating at the level of maternal effects. Alternatively, the complexity of the design, despite a relatively large sample size, may have limited the power for detection of this expected trade-off.

Effects of Thoratec pulsatile ventricular assist device (PVAD) timing on the abdominal aortic wave intensity pattern

Arterial waves are seen as possible independent mediators of cardiovascular risks, and the wave intensity analysis (WIA) has therefore been proposed as a method for patient selection for ventricular assist device (VAD) implantation. Interpreting measured wave intensity (WI) is challenging and complexity is increased by the implantation of a VAD. The waves generated by the VAD interact with the waves generated by the native heart, and this interaction varies with changing VAD settings. Eight sheep were implanted with a pulsatile VAD (PVAD) through ventriculo-aortic cannulation. The start of PVAD ejection was synchronized to the native R-wave and delayed between 0 % - 90 % of the cardiac cycle in 10 % steps or phase shifts (PS). Pressure and velocity signals were registered, using a combined Doppler and pressure wire positioned in the abdominal aorta, and used to calculate the WI. Depending on the PS, different wave interference phenomena occurred. Maximum unloading of the left ventricle (LV) coincided with constructive interference and maximum blood flow pulsatility, and maximum loading of the LV coincided with destructive interference and minimum blood flow pulsatility. We believe, that non-invasive WIA could potentially be used clinically to assess the mechanical load of the LV, and to monitor the peripheral hemodynamics such as blood flow pulsatility and risk of intestinal bleeding.

Cognitive and emotional effects of carotid stenosis

PRINCIPLES Patients with carotid artery stenosis (CAS) are at risk of ipsilateral stroke and chronic compromise of cerebral blood flow. It is under debate whether the hypo-perfusion or embolism in CAS is directly related to cognitive impairment. Alternatively, CAS may be a marker for underlying risk factors, which themselves influence cognition. We aimed to determine cognitive performance level and the emotional state of patients with CAS. We hypothesised that patients with high grade stenosis, bilateral stenosis, symptomatic patients and/or those with relevant risk factors would suffer impairment of their cognitive performance and emotional state. METHODS A total of 68 patients with CAS of ≥70% were included in a prospective exploratory study design. All patients underwent structured assessment of executive functions, language, verbal and visual memory, motor speed, anxiety and depression. RESULTS Significantly more patients with CAS showed cognitive impairments (executive functions, word production, verbal and visual memory, motor speed) and anxiety than expected in a normative sample. Bilateral and symptomatic stenosis was associated with slower processing speed. Cognitive performance and anxiety level were not influenced by the side and the degree of stenosis or the presence of collaterals. Factors associated with less cognitive impairment included higher education level, female gender, ambidexterity and treated hypercholesterolemia. CONCLUSIONS Cognitive impairment and increased level of anxiety are frequent in patients with carotid stenosis. The lack of a correlation between cognitive functioning and degree of stenosis or the presence of collaterals, challenges the view that CAS per se leads to cognitive impairment.

Comparative Behavioral and Neural Effects of Tryptophan and Catecholamine Depletion in Remitted Depression

Background: Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catechominergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber’s selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Methods: Using identical neuroimaging procedures with [18F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared to healthy controls in a double-blind, randomized, crossover design. Results: While TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex (PCC). While we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. Conclusions: In conclusion, this study showed that serotonin and catecholamines play common and differential roles in the pathophysiology of depression.

What constitutes vulnerable self-esteem? Comparing the prospective effects of low, unstable, and contingent self-esteem on depressive symptoms

A growing body of longitudinal studies suggests that low self-esteem is a risk factor for depression. However, it is unclear whether other characteristics of self-esteem, besides its level, explain incremental or even greater variance in subsequent depression. We examined the prospective effects of self-esteem level, instability (i.e., the degree of variability in self-esteem across short periods), and contingency (i.e., the degree to which self-esteem fluctuates in response to self-relevant events) on depressive symptoms in 1 overarching model, using data from 2 longitudinal studies. In Study 1, 372 adults were assessed at 2 waves over 6 months, including 40 daily diary assessments at Wave 1. In Study 2, 235 young adults were assessed at 2 waves over 6 weeks, including about 6 daily diary assessments at each wave. Self-esteem contingency was measured by self-report and by a statistical index based on the diary data (capturing event-related fluctuations in self-esteem). In both studies self-esteem level, but not self-esteem contingency, predicted subsequent depressive symptoms. Self-esteem instability predicted subsequent depressive symptoms in Study 2 only, with a smaller effect size than self-esteem level. Also, level, instability, and contingency of self-esteem did not interact in the prediction of depressive symptoms. Moreover, the effect of self-esteem level held when controlling for neuroticism and for all other Big Five personality traits. Thus, the findings provide converging evidence for a vulnerability effect of self-esteem level, tentative evidence for a smaller vulnerability effect of self-esteem instability, and no evidence for a vulnerability effect of self-esteem contingency.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

The effects of anti-infective preventive measures on the occurrence of biologic implant complications and implant loss: a systematic review.

PURPOSE To systematically appraise whether anti-infective protocols are effective in preventing biologic implant complications and implant loss after a mean observation period ≥ 10 years after loading. MATERIALS AND METHODS An electronic search of Medline via PubMed and Embase via Ovid databases complemented by manual search was conducted up to October 31, 2012. Studies were included provided that they were published in English, German, French, or Italian, and conducted on ≥ 20 partially and fully edentulous patients with dental implants and regular (≥ 1×/year) supportive periodontal therapy (SPT) over a mean observation period ≥ 10 years. Assessment of the identified studies and data extraction were performed independently by two reviewers. Authors were contacted if required. Collected data were reported by descriptive methods. RESULTS The initial electronic search resulted in the identification of 994 titles from Medline via PubMed and 531 titles from Embase via Ovid databases, respectively. After elimination of duplicate titles and exclusion of 60 full-text articles, 143 articles were analyzed, resulting in 15 studies eligible for qualitative analysis. The implant survival rate ranged from 85.7% to 99.2% after a mean observation period ≥ 10 years. One comparative study assessed the effects of regular SPT on the occurrence of biologic complications and implant loss. Overall, regular diagnosis and implementation of anti-infective therapeutic protocols were effective in the management of biological complications and prevention of implant loss. Residual probing depths at the end of active periodontal therapy and development of reinfection during supportive periodontal therapy (SPT) represented a significant risk for the onset of peri-implantitis and implant loss. Comparative studies indicated that implant survival and success rates were lower in periodontally compromised vs noncompromised patients. CONCLUSIONS In order to achieve high long-term survival and success rates of dental implants and their restorations, enrollment in regular SPT including anti-infective preventive measures should be implemented. Therapy of peri-implant mucositis should be considered as a preventive measure for the onset of peri-implantitis. Completion of active periodontal therapy should precede implant placement in periodontally compromised patients.

Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis.

BACKGROUND Data on the association between subclinical thyroid dysfunction and fractures conflict. PURPOSE To assess the risk for hip and nonspine fractures associated with subclinical thyroid dysfunction among prospective cohorts. DATA SOURCES Search of MEDLINE and EMBASE (1946 to 16 March 2014) and reference lists of retrieved articles without language restriction. STUDY SELECTION Two physicians screened and identified prospective cohorts that measured thyroid function and followed participants to assess fracture outcomes. DATA EXTRACTION One reviewer extracted data using a standardized protocol, and another verified data. Both reviewers independently assessed methodological quality of the studies. DATA SYNTHESIS The 7 population-based cohorts of heterogeneous quality included 50,245 participants with 1966 hip and 3281 nonspine fractures. In random-effects models that included the 5 higher-quality studies, the pooled adjusted hazard ratios (HRs) of participants with subclinical hyperthyroidism versus euthyrodism were 1.38 (95% CI, 0.92 to 2.07) for hip fractures and 1.20 (CI, 0.83 to 1.72) for nonspine fractures without statistical heterogeneity (P = 0.82 and 0.52, respectively; I2= 0%). Pooled estimates for the 7 cohorts were 1.26 (CI, 0.96 to 1.65) for hip fractures and 1.16 (CI, 0.95 to 1.42) for nonspine fractures. When thyroxine recipients were excluded, the HRs for participants with subclinical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures and 1.43 (CI, 0.73 to 2.78) for nonspine fractures. For participants with subclinical hypothyroidism, HRs from higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures and 1.04 (CI, 0.76 to 1.42) for nonspine fractures (P for heterogeneity = 0.69 and 0.88, respectively; I2 = 0%). LIMITATIONS Selective reporting cannot be excluded. Adjustment for potential common confounders varied and was not adequately done across all studies. CONCLUSION Subclinical hyperthyroidism might be associated with an increased risk for hip and nonspine fractures, but additional large, high-quality studies are needed. PRIMARY FUNDING SOURCE Swiss National Science Foundation.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis.

BACKGROUND Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Delay effects in the response of low-grade gliomas to radiotherapy: a mathematical model and its therapeutical implications

Low-grade gliomas (LGGs) are a group of primary brain tumours usually encountered in young patient populations. These tumours represent a difficult challenge because many patients survive a decade or more and may be at a higher risk for treatment-related complications. Specifically, radiation therapy is known to have a relevant effect on survival but in many cases it can be deferred to avoid side effects while maintaining its beneficial effect. However, a subset of LGGs manifests more aggressive clinical behaviour and requires earlier intervention. Moreover, the effectiveness of radiotherapy depends on the tumour characteristics. Recently Pallud et al. (2012. Neuro-Oncology, 14: , 1-10) studied patients with LGGs treated with radiation therapy as a first-line therapy and obtained the counterintuitive result that tumours with a fast response to the therapy had a worse prognosis than those responding late. In this paper, we construct a mathematical model describing the basic facts of glioma progression and response to radiotherapy. The model provides also an explanation to the observations of Pallud et al. Using the model, we propose radiation fractionation schemes that might be therapeutically useful by helping to evaluate tumour malignancy while at the same time reducing the toxicity associated to the treatment.