Fifteen years of env C2V3C3 evolution in six individuals infected clonally with human immunodeficiency virus type 1

The study of the evolution of human immunodeficiency virus type 1 (HIV-1) requires blood samples collected longitudinally and data on the approximate time point of infection. Although these requirements were fulfilled in several previous studies, the infectious sources were either unknown or heterogeneous genetically. In the present study, HIV-1 env C2V3C3 (nt 7029-7315) evolution was examined retrospectively in a cohort of hemophiliacs. Compared to other cohorts, the area of interest here was the infection of six hemophiliacs by the same virus strain, that is, the infecting viruses shared an identical genome. As expected, divergence from the founder sequence as well as interpatient divergence of the predominant virus strains increased significantly over time. Based on the V3 nucleotide sequences, CCR5 usage was predicted exclusively throughout the whole period of infection in all patients. Interestingly, common patterns of viral evolution were detected in the patients of the cohort. Four amino acid substitutions within the V3 loop emerged and persisted subsequently in five (positions 305 and 308 of the HXB2 gp120 reference sequence) and six patients (positions 325 and 328 in HXB2 gp120), respectively. These common changes within the V3 loop are likely to be enforced by HIV-1 specific immune response.     

Impact of Early Initiation of Enteral Nutrition on Survival During Pediatric Extracorporeal Membrane Oxygenation

Introduction: Pediatric data related to safety, tolerance, and outcomes of enteral nutrition (EN) for patients requiring extracorporeal membrane oxygenation (ECMO) are lacking. The objectives of this study were to evaluate early nutrition status and timing of EN initiation on survival during pediatric ECMO. Methods: A single center institutional review board–approved retrospective chart review was performed on all pediatric patients requiring ECMO from October 2008 through December 2013. Demographics, ECMO variables, laboratory values, vasoactive inotropic score (VIS), and nutrition data on day 5 (d5) were collected. Patients receiving parenteral nutrition (PN) were compared with those receiving any EN on d5. Analyses were conducted to identify factors influencing survival to completion of ECMO and to discharge. Results: Forty‐nine patients aged 53 ± 76 months met inclusion criteria. Kaplan‐Meier curves demonstrated greater survival to discharge in patients receiving any EN, compared with only receiving PN (P = .031). EN on d5 of ECMO support (P = .040) and a higher percentage of daily energy intake achieved (P = .013) were protective, whereas a higher VIS was associated with increased mortality (P = .010). Multivariable analysis demonstrated EN was no longer associated with survival to discharge (P = .139), whereas energy intake (P = .021) and VIS (P = .013) remained significant. Conclusions: Pediatric patients who received nutrition that was closer to goal energy intake, as well as those who received any EN early during ECMO, had improved survival to hospital discharge.     

Low cost of ventilation in the vagotomised alligator (Alligator mississippiensis)

Pulmonary ventilation requires energy, but the estimated costs of breathing in reptiles vary from 1 to 30% of resting metabolic rate. The low values have been estimated from changes in oxygen uptake during hypoxia or hypercapnia, but it remains possible that these treatments affected metabolism. We equipped alligators with masks for simultaneous measurements of ventilation and oxygen uptake during hypercapnia, hypoxia and bilateral vagotomy. Hypercapnia and hypoxia caused a marked increase in total ventilation, but oxygen uptake remained unchanged indicating a very low energetic cost of breathing. Upon vagotomy, breathing pattern changed to occasional and exceedingly deep breaths (76.1+/-11.1 ml kg(-1)) followed by buccal oscillations and shallower breaths (22.2+/-2.3 ml kg(-1)) interspersed between long non-ventilatory periods. This change in breathing pattern did not affect oxygen uptake. The duration of inspiration increased substantially upon vagotomy, so that inspiratory flow rate did not increase proportionally to tidal volume. These prolonged inspiratory times leads to less flow resistance and may explain that tidal volume could be increased substantially without a measurable energetic cost.     

Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation

Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as the chondrodysplasias. One such disorder, multiple epiphyseal dysplasia (MED), is characterized by mild dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the disease mechanisms that underpin the pathophysiology of MED we generated a murine model of epiphyseal dysplasia by knocking-in a matn3 mutation. Mice that are homozygous for the mutation develop a progressive dysplasia and have short-limbed dwarfism that is consistent in severity with the relevant human phenotype. Mutant matrilin-3 is retained within the rough endoplasmic reticulum of chondrocytes and is associated with an unfolded protein response. Eventually, there is reduced proliferation and spatially dysregulated apoptosis of chondrocytes in the cartilage growth plate, which is likely to be the cause of disrupted linear bone growth and the resulting short-limbed dwarfism in the mutant mice.     

Stroke surveillance: population-based estimates and projections for New Zealand

OBJECTIVE: To estimate the incidence, prevalence and mortality of stroke in New Zealand (NZ) in 2001, projected to 2011. METHODS: Multistate lifetable models were constructed using smoothed rates of first-ever stroke incidence and relative risks of mortality estimated from the most recent Auckland Regional Community Stroke (ARCOS) Study. Estimates of the burden of stroke in NZ were calculated by applying rates output by the model to the 2001 population. Stroke incidence, prevalence and mortality were then projected to 2011, assuming similar trends in stroke incidence and case fatality to those estimated between the 1991/92 and 2002/03 studies. RESULTS: A total of 5,200 first-ever strokes were estimated to have occurred in NZ in 2001. Rates of stroke rose exponentially with increasing age and were 20% higher among males than females at most ages. Nevertheless, the lifetable risk of stroke was lower for males (16%) than females (18%). On average, males survived a year longer than females after a first-ever stroke (9.0 vs. 8.2 years). The incidence rates of first-ever stroke declined by approximately 1% per year between 1991 and 2003. The lifetable risk of stroke remained stable for females but increased for males (from 14% to 16%) over this period. Stroke prevalence also increased by approximately 1% per year, whereas stroke-related mortality fell by 4% per year. If these trends continue, approximately 6,000 first-ever strokes (2% annual increase), 45,000 stroke survivors (2% annual increase) and 2,000 stroke-related deaths (1% annual decline) are expected in 2011. CONCLUSION: Stroke mortality is falling faster than stroke incidence. This, together with population growth and ageing, will lead to a rising burden of stroke-related disability over the next decade.     

Myocardial Ischemia Induced by 5-Fluorouracil: A Prospective Electrocardiographic and Cardiac Biomarker Study

BackgroundCardiotoxicity induced by 5‐fluorouracil (5‐FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5‐FU to increase our understanding of the cardiotoxicity.Subjects, Materials, and MethodsPatients with colorectal or anal cancer that received first‐time treatment with 5‐FU‐based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12‐lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5‐FU treatment (intervention).ResultsA total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5‐FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5‐FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5‐FU treatment.Conclusion5‐FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5‐FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%–6% of the patients developed acute coronary syndromes during treatment with 5‐FU.Implications for PracticeSymptomatic 5‐fluorouracil (5‐FU) cardiotoxicity occurs in 0.6%–19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5‐FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5‐FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5‐FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5‐FU.     

Cervical Cancer in Sub-Saharan Africa: A Multinational Population-Based Cohort Study of Care and Guideline Adherence

BackgroundCervical cancer (CC) is the most common female cancer in many countries of sub‐Saharan Africa (SSA). We assessed treatment guideline adherence and its association with overall survival (OS).MethodsOur observational study covered nine population‐based cancer registries in eight countries: Benin, Ethiopia, Ivory Coast, Kenya, Mali, Mozambique, Uganda, and Zimbabwe. Random samples of 44–125 patients diagnosed from 2010 to 2016 were selected in each. Cancer‐directed therapy (CDT) was evaluated for degree of adherence to National Comprehensive Cancer Network (U.S.) Guidelines.ResultsOf 632 patients, 15.8% received CDT with curative potential: 5.2% guideline‐adherent, 2.4% with minor deviations, and 8.2% with major deviations. CDT was not documented or was without curative potential in 22%; 15.7% were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease. Adherence was not assessed in 46.9% (no stage or follow‐up documented, 11.9%, or records not traced, 35.1%). The largest share of guideline‐adherent CDT was observed in Nairobi (49%) and the smallest in Maputo (4%). In patients with FIGO stage I–III disease (n = 190), minor and major guideline deviations were associated with impaired OS (hazard rate ratio [HRR], 1.73; 95% confidence interval [CI], 0.36–8.37; HRR, 1.97; CI, 0.59–6.56, respectively). CDT without curative potential (HRR, 3.88; CI, 1.19–12.71) and no CDT (HRR, 9.43; CI, 3.03–29.33) showed substantially worse survival.ConclusionWe found that only one in six patients with cervical cancer in SSA received CDT with curative potential. At least one‐fifth and possibly up to two‐thirds of women never accessed CDT, despite curable disease, resulting in impaired OS. Investments into more radiotherapy, chemotherapy, and surgical training could change the fatal outcomes of many patients.Implications for PracticeDespite evidence‐based interventions including guideline‐adherent treatment for cervical cancer (CC), there is huge disparity in survival across the globe. This comprehensive multinational population‐based registry study aimed to assess the status quo of presentation, treatment guideline adherence, and survival in eight countries. Patients across sub‐Saharan Africa present in late stages, and treatment guideline adherence is remarkably low. Both factors were associated with unfavorable survival. This report warns about the inability of most women with cervical cancer in sub‐Saharan Africa to access timely and high‐quality diagnostic and treatment services, serving as guidance to institutions and policy makers. With regard to clinical practice, there might be cancer‐directed treatment options that, although not fully guideline adherent, have relevant survival benefit. Others should perhaps not be chosen even under resource‐constrained circumstances.     

Inferring past pesticide exposures: a matrix of individual active ingredients in home and garden pesticides used in past decades

BACKGROUND: In retrospective studies of the health effects of home and garden pesticides, self-reported information typically forms the basis for exposure assessment. Study participants generally find it easier to remember the types of pests treated than the specific pesticides used. However, if the goal of the study is to assess disease risk from specific chemicals, the investigator must be able to link the pest type treated with specific chemicals or products. OBJECTIVES: Our goal was to develop a "pesticide-exposure matrix" that would list active ingredients on the market for treating different types of pests in past years, and provide an estimate of the probability that each active ingredient was used. METHODS: We used several different methods for deriving the active ingredient lists and estimating the probabilities. These methods are described in this article, along with a sample calculation and data sources for each. RESULTS: The pesticide-exposure matrix lists active ingredients and their probabilities of use for 96 distinct scenarios defined by year (1976, 1980, 1990, 2000), applicator type (consumer, professional), and pest type (12 categories). Calculations and data sources for all 96 scenarios are provided online. CONCLUSIONS: Although we are confident that the active ingredient lists are reasonably accurate for most scenarios, we acknowledge possible sources of error in the probability estimates. Despite these limitations, the pesticide-exposure matrix should provide valuable information to researchers interested in the chronic health effects of residential pesticide exposure.