Suppression of star formation in dwarf galaxies by photoelectric grain heating feedback.

Photoelectric heating--heating of dust grains by far-ultraviolet photons--has long been recognized as the primary source of heating for the neutral interstellar medium. Simulations of spiral galaxies have shown some indication that photoelectric heating could suppress star formation; however, simulations that include photoelectric heating have typically shown that it has little effect on the rate of star formation in either spiral galaxies or dwarf galaxies, which suggests that supernovae are responsible for setting the gas depletion time in galaxies. This result is in contrast with recent work indicating that a star formation law that depends on galaxy metallicity--as is expected with photoelectric heating,but not with supernovae--reproduces the present-day galaxy population better than does a metallicity-independent one. Here we report a series of simulations of dwarf galaxies, the class of galaxy in which the effects of both photoelectric heating and supernovae are expected to be strongest. We simultaneously include space and time-dependent photoelectric heating in our simulations, and we resolve the energy-conserving phase of every supernova blast wave, which allows us to directly measure the relative importance of feedback by supernovae and photoelectric heating in suppressing star formation. We find that supernovae are unable to account for the observed large gas depletion times in dwarf galaxies. Instead, photoelectric heating is the dominant means by which dwarf galaxies regulate their star formation rate at any given time,suppressing the rate by more than an order of magnitude relative to simulations with only supernovae.

Evaluation of an emergency prevention program for mother to child transmission of HIV in British Columbia.

INTRODUCTION: The objective of this study was to evaluate a province-wide program designed to identify HIV infection accurately and to prevent mother to child transmission among high-risk pregnant women of unknown serostatus. METHODS: Between 2000 and 2007, 347 high-risk women were identified through the Prevention of Mother to Child Transmission (PMTCT) program implemented in 27 hospitals across British Columbia. Rates of HIV transmission and details of the implementation of prophylaxis kits were assessed. RESULTS: Of the 346 high-risk mother-infant pairs identified and included in the provincial program, 35.4% of the mothers and 95.7% of infants received antiretroviral therapy for prevention of vertical transmission. Of 309 pairs who subsequently underwent HIV testing, five mothers were found to be HIV positive, an infection rate of 16.2/1000 in this cohort; the overall rate in BC is 0.68/1000 births. One of the five infants born to an HIV positive mother was infected with HIV. DISCUSSION: The program was successful in identifying a subgroup of pregnant women at increased risk of HIV infection; however, mother to child transmission occurred in one of five cases (20%). To reduce the risk of mother to child HIV transmission in BC to the lowest possible level, additional strategies such as increasing uptake of prenatal screening and point-of-care testing in labour and delivery may need to be explored.

Preterm Birth and Antiretroviral Exposure in Infants HIV-exposed Uninfected.

BACKGROUND: Infants HIV-exposed and uninfected (IHEU) who are born to women living with HIV are at an increased risk of preterm birth (PTB). Antenatal exposure to certain maternal antiretroviral therapy (ART) regimens has been associated with PTB, although existing studies in this domain are limited and report discordant findings. We determined odds of PTB among IHEU by antenatal ART regimens and timing of exposure, adjusting for maternal risk factors. METHODS: We retrospectively studied IHEU born in British Columbia (BC), Canada between 1990 and 2012 utilizing provincial health administrative databases. We included data from a control group of infants HIV-unexposed and uninfected (IHUU) matched ~3:1 for each IHEU on age, sex and geocode. RESULTS: A total of 411 IHEU and 1224 IHUU were included in univariable analysis. PTB was more frequent among IHEU (20%) compared with IHUU (7%). IHEU were more often antenatally exposed to alcohol, tobacco, as well as prescription, nonprescription, and illicit drugs (IHEU: 36%, 8% and 35%; vs. IHUU: 3%, 1% and 9%, respectively). After adjusting for maternal substance use and smoking exposure, IHEU remained at increased odds of PTB [adjusted odds ratio (aOR) (95% CI): 2.66; (1.73, 4.08)] compared with matched IHUU controls. ART-exposed IHEU (excluding those with NRTIs only ART) had lower adjusted odds of PTB compared with IHEU with no maternal ART exposure, regardless of regimen [aOR range: 0.16-0.29 (0.02-0.95)]. Odds of PTB between IHEU exposed to ART from conception compared with IHEU exposed to ART postconception did not differ [aOR: 0.91 (0.47, 1.76)]; however, both groups experienced lower odds of PTB compared with IHEU with no maternal ART [preconception: aOR: 0.28 (0.08, 0.89); postconception: aOR 0.30 (0.11, 0.83)]. CONCLUSIONS: BC IHEU were over twice as likely to be born preterm compared with demographically matched controls. Maternal substance use in pregnancy modulated this risk; however, we found no adverse associations of PTB with exposure to antenatal ART.

Investigation of factors associated with spontaneous preterm birth in pregnant women living with HIV.

OBJECTIVE: To investigate factors contributing to preterm birth (PTB), including cART use and clinical and social determinants of health, in women living with HIV (WLWH) from British Columbia, Canada. DESIGN: Retrospective observational cohort. METHODS: We investigated the effect of cART use and other clinical and demographic factors on spontaneous PTB (sPTB) rates (<37 weeks gestational age) among 631 singleton pregnancies between 1997 and 2018. Exposure to cART was modelled in comparison to no exposure, exposure in the first trimester, and between regimens. Differences in sPTB risk were estimated using time-dependent Cox's proportional hazards models. RESULTS: Overall, the sPTB rate was 16%. Cumulative cART use was associated with lower risk of PTB (Wald test P = 0.02; hazard ratio = 0.98, 95% CI = 0.96-0.99) and specific cART regimens were not associated with increased risk of sPTB. Exposure in the first trimester was not associated with sPTB and for each week of cART exposure, the risk of sPTB decreased by 2%. In a multivariable model, HIV viral load and substance use remained associated with risk of sPTB, but not cART exposure. CONCLUSION: The sPTB rate among pregnant WLWH was more than three times higher than in the general population. However, sPTB was not related specifically to use of cART; in fact, cART appeared to reduce the risk of sPTB. Uncontrolled HIV replication and substance use were associated with increased risk of sPTB among pregnant WLWH. This emphasizes the important role of prenatal care, access to cART, and smoking cessation and harm reduction to reduce the risk of sPTB in WLWH.

Neurodevelopmental outcomes and in-utero antiretroviral exposure in HIV-exposed uninfected children.

OBJECTIVES: To assess and compare neurodevelopmental disorders in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children in British Columbia, Canada. To determine associations between these outcomes and in-utero exposure to antiretroviral drugs. DESIGN: Retrospective controlled cohort study. METHODS: Data were collected on 446 HEU children and 1323 HUU children (matched ∼1 : 3 for age, sex, and geocode) born between 1990 and 2012. Multivariable logistic regressions determined odds ratios of neurodevelopmental disorder diagnoses. RESULTS: HEUs had three times higher odds of being born preterm (P < 0.0001), and a more than two-fold increase in odds for autism, disturbance of emotions, hyperkinetic syndrome, and developmental delay compared with matched HUUs (P < 0.02) in unadjusted analysis. This association was reduced [adjusted neurodevelopmental disorder odds ratio (AOR) = 1.67; 95% confidence interval: 1.12-2.48; P = 0.011] after adjusting for maternal substance use and/or smoking (children born after April 2000). Regardless of antiretroviral exposure type (i.e. none, treatment with one or multiple drug classes), HEUs had higher odds of any neurodevelopmental disorders compared with matched HUUs; however, there was no evidence suggesting any specific classes of antiretroviral drugs or exposure durations increased their likelihood of neurodevelopmental disorders. CONCLUSION: The results suggest no adverse associations between antiretroviral drugs and neurodevelopmental disorders within antiretroviral-exposed HEU children in our cohort. Prevalence of neurodevelopmental disorders is higher in HEUs; however, maternal substance use plays a role, as could other environmental factors not captured. These findings highlight a need for holistic support for pregnant women as well as careful developmental monitoring of HEUs past infancy, and access to early interventions, particularly among those born preterm and those exposed to addictive substances.

Vibrio cholerae motility exerts drag force to impede attack by the bacterial predator Bdellovibrio bacteriovorus.

The bacterial predator Bdellovibrio bacteriovorus is evolved to attack and kill other bacteria, including the human intestinal pathogen Vibrio cholerae. Although B. bacteriovorus exhibit a broad prey range, little is known about the genetic determinants of prey resistance and sensitivity. Here we perform a genetic screen on V. cholerae and identify five pathways contributing to predation susceptibility. We find that the essential virulence regulators ToxR/S increase susceptibility to predation, as mutants of these genes are more resistant to predation. We observe by flow cytometry that lipopolysaccharide is a critical defense, as mutants lacking O-antigen are rapidly attacked by predatory B. bacteriovorus. Using polymer solutions to alter media viscosity, we find that when B. bacteriovorus attacks motile V. cholerae, increased drag forces slow its ability to prey. These results provide insights into key prey resistance mechanisms, and may be useful in the application of B. bacteriovorus in treating infections.

Blood Mitochondrial DNA Content in HIV-Exposed Uninfected Children with Autism Spectrum Disorder.

Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort.

Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women.

INTRODUCTION: Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period. METHODS: This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR. RESULTS: Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001). CONCLUSIONS: In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.

Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy.

OBJECTIVE: To investigate potential mitochondrial toxicity in HIV-uninfected infants exposed to highly active antiretroviral therapy (HAART) in utero and/or neonatal zidovudine. DESIGN: A prospective observational study performed in a tertiary referral center for HIV-infected women and their infants and children. METHODS: Plasma lactate was measured repeatedly during the first 6 months of life in a consecutive cohort of infants exposed to HAART in utero and/or neonatal zidovudine. Maternal CD4, HIV RNA concentration, antiretroviral and substance use histories, mode of delivery, infant gender, cord pH, Apgar score and birth weight were collected. RESULTS: The plasma lactate was above normal on at least 1 occasion in 35 of 38 (92%) infants and reached levels > or =5 mmol/l in 10 (26%) infants. Overall 78 of 117 (68%) lactate measurements were elevated, with 11 (10%) in the serious (> or =5 mmol/l) range. None of the infants received antiretrovirals beyond 6 weeks, yet elevated lactates persisted up to age 6 months. Two infants had reversible symptoms consistent with those of lactic acidemia. No association was found between the infant peak lactate and the type of therapy during pregnancy, its duration or maternal substance use. CONCLUSION: Transient lactic acidemia was observed in the majority of HIV uninfected infants exposed to HAART in utero and/or zidovudine neonatally. We hypothesize that the hyperlactatemia is a consequence of persistent, primarily subclinical, mitochondrial toxicity from the transplacental and neonatal exposure to antiretrovirals and of impaired hepatic lactate clearance. Although the clinical relevance of our findings is unknown, we recommend lactate monitoring in these infants, considering discontinuation of neonatal zidovudine in symptomatic infants with lactate > or =5 mmol/l and careful long term follow up of these children.

A national review of vertical HIV transmission.

OBJECTIVES: Prevention of vertical HIV transmission has evolved significantly in Canada over the last two decades. The aim of this analysis is to describe the surveillance programme used, rate of vertical HIV transmission and changing epidemiology of HIV-affected pregnancies in Canada. DESIGN: National perinatal HIV surveillance programme. METHODS: From 1990, annual retrospective data was collected on demographic and clinical characteristics of HIV-infected mothers and their infants referred to 22 participating sites across Canada either before/during pregnancy or within 3 months after delivery. Factors impacting HIV transmission and demographic features were explored. RESULTS: Two thousand, six hundred and ninety-two mother-infant pairs were identified. The overall rate of vertical HIV transmission was 5.2%, declining to 2.9% since 1997. The rate of transmission for mothers who received HAART was 1%, and 0.4% if more than 4 weeks of HAART was given. Forty percent of women delivered by caesarean section, with no difference in transmission rate compared with vaginal delivery for women treated with HAART (1.4 vs. 0.6%, P = 0.129) but significant risk reduction for those who did not receive HAART (3.8 vs. 10.3%, P = 0.016). Black women were the largest group; proportions of black and aboriginal women increased significantly over time (P < 0.001 for both). Heterosexual contact was the most common risk category for maternal infection (65%), followed by injection drug use (IDU) (25%). CONCLUSION: Vertical HIV transmission in Canada has decreased dramatically for women treated with HAART therapy. All pregnant women should be evaluated for HIV infection and programmes expanded to reach vulnerable populations including aboriginal, immigrant and IDU women.

Blood mitochondrial DNA mutations in HIV-infected women and their infants exposed to HAART during pregnancy.

OBJECTIVES: Nucleo(s/t)ide reverse transcriptase inhibitors given to HIV-infected pregnant women to prevent vertical transmission may adversely affect mitochondrial DNA (mtDNA). We hypothesized that HAART-exposed/HIV-uninfected infants may show higher blood mtDNA mutation burden than controls born to HIV-uninfected mothers. METHODS: Blood was collected from in-utero HIV/HAART-exposed infants and controls, as well as from a subset of their mothers. The presence of mtDNA A→C/T→G (AC/TG) mutations was measured by cloning and sequencing D-loop PCR amplicons. Relationships with maternal characteristics were examined. RESULTS: No significant difference was found between the percentage of HIV/HAART-exposed infants with AC/TG mutations (N = 15/57, 26.3%) and controls (N = 10/70, 14.3%) before (P = 0.090) or after controlling for covariates (P = 0.058), although a tendency was observed. However, significantly more HIV/HAART-exposed mothers (N = 18/42, 42.9%) harboured AC/TG mutations compared with controls (N = 7/39, 17.9%) before (P = 0.015) and after (P = 0.012) controlling for covariates. AC/TG mutations were more prevalent in HIV/HAART-exposed mothers than in their infants (N = 42, 42.9 vs. 23.8%, P = 0.033), however, this difference disappeared after controlling for covariates. No difference was seen between control mothers and their infants (N = 39, both 17.9%). In HIV/HAART-exposed mothers, only a detectable HIV plasma viral load near delivery predicted AC/TG mutations. CONCLUSION: Our results suggest that HIV and/or HAART exposure are associated with increased prevalence of AC/TG mtDNA mutations in mothers and show a similar tendency in infants exposed during pregnancy. As accumulation of mtDNA mutations has been linked with aging and age-associated diseases, this may raise concerns in the long term for HIV and HAART-exposed populations.

Leukocyte telomere length in HIV-infected pregnant women treated with antiretroviral drugs during pregnancy and their uninfected infants.

OBJECTIVES: HIV disease can lead to accelerated telomere attrition, although certain drugs used as part of antiretroviral therapy (ART) can inhibit telomerase reverse transcriptase activity. This could in turn lead to shorter telomeres. We hypothesized that HIV and ART exposure would be associated with shorter leukocyte telomere length (TL) in exposed mother/infant pairs compared with controls. METHODS: In these retrospective and prospective observational cohort studies, TL was evaluated in peripheral blood leukocytes obtained from HIV-infected pregnant women treated with ART and their uninfected infants, and compared with HIV untreated (retrospective cohort) or HIV mothers and their infants (prospective cohort). RESULTS: In HIV-infected ART-exposed mothers, leukocyte TL was not significantly shorter than that in HIV untreated mothers or HIV controls, nor was their infants' TL significantly different. Cord blood of ART-exposed infants exhibited TL shorter than that from infants born to HIV-negative mothers. Placenta also showed evidence of shorter TL after adjustment for relevant covariates. Factors associated with shorter maternal and infant TL included smoking and the use of drugs of addiction in pregnancy. CONCLUSIONS: These results suggest that maternal HIV infection or exposure to ART has minimal effect on infant leukocyte TL, a reassuring finding. In contrast, tissues that express higher telomerase activity such as umbilical cord blood and placenta appear comparatively more affected by ART. Smoking and the use of drugs of addiction have a negative impact on maternal and infant leukocyte TL, possibly through oxidative telomere damage.

Perinatal exposure to antiretroviral therapy is associated with increased blood mitochondrial DNA levels and decreased mitochondrial gene expression in infants.

BACKGROUND: The effects of perinatal antiretroviral therapy (ART) on infant mitochondrial function are not well known. We compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in human immunodeficiency virus (HIV)-uninfected, ART-exposed infants born to HIV-positive mothers with mtDNA levels and mtDNA gene expression in control infants born to uninfected women. METHODS: In this prospective cohort study, longitudinal mtDNA:nuclear DNA and mtRNA:beta-actin mRNA ratios were compared in blood samples obtained at various time points from birth to 8 months, using generalized estimating equation linear regression models. RESULTS: Log(10) mtDNA levels at birth were higher in ART-exposed infants, compared with levels in control infants, although the difference did not reach statistical significance (P = .07 for comparison of samples obtained 0-3 days after birth). ART-exposed infants' mtDNA levels increased further during the zidovudine prophylaxis period-from age 4 days to age 6 weeks-(P = .001) and remained significantly higher than the levels observed in control infants until the end of the study. In contrast, log(10) mtRNA levels at birth were lower in ART-exposed infants than in control infants (P = .03), but were not statistically different later. CONCLUSIONS: When control infants and ART-exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in ART-exposed infants. These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/or expression take place during and after ART exposure. These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long-term impact of these alterations must be studied.

A prospective controlled study of neurodevelopment in HIV-uninfected children exposed to combination antiretroviral drugs in pregnancy.

OBJECTIVE: Our intent was to investigate the neurodevelopment of HIV-uninfected children exposed to combination highly active antiretroviral therapy in pregnancy compared with children not exposed to highly active antiretroviral therapy but with similar socioeconomic backgrounds. PATIENTS AND METHODS: A prospective controlled cross-sectional study of the neurodevelopment of children exposed to highly active antiretroviral therapy versus those not exposed was performed by using the Bayley Scales of Infant Development and Vineland Adaptive Behavior Scales at 18 to 36 months of age. The highly active antiretroviral therapy-exposed children were born to HIV-infected women but were uninfected themselves. The control children were born to HIV-uninfected women with similar anticipated socioeconomic background (hepatitis C infected and high proportion of substance use). Sociodemographic, clinical, highly active antiretroviral therapy (antenatal, intrapartum, neonatal), and substance-use histories were collected. Results were compared by using analyses of covariance and chi2 analysis. RESULTS: Thirty-nine highly active antiretroviral therapy-exposed and 24 control children were assessed. All mean scores were lower for those in the highly active antiretroviral therapy-exposed group than those in the control group (Bayley Mental Development Index: 85.4 vs 94.3; Bayley Psychomotor Development Index: 93.4 vs 96.6; Vineland mean communication score: 90.1 vs 94.4; Vineland mean daily-living score: 91.2 vs 93.6; Vineland mean socialization score: 97.1 vs 98.4). However, when maternal substance use during pregnancy was controlled for, there were no significant differences between the groups in any domains assessed. Children in both groups exposed to maternal substance use scored significantly lower than children not exposed in all domains except communication skills. It is important to note that there were no differences between the highly active antiretroviral therapy-exposed children with no substance exposure and the control children with no substance exposure in any of the scores. CONCLUSIONS: HIV- and highly active antiretroviral therapy-exposed HIV-uninfected children had lower development and adaptive behavior scores when compared with children who had not been exposed. However, these differences were not significant after correcting for maternal substance use, which had a greater impact on neurodevelopment than highly active antiretroviral therapy exposure. These results suggest that perinatal highly active antiretroviral therapy exposure is not associated with altered development and behavior at 18 to 36 months of age.

Life-threatening human metapneumovirus pneumonia requiring extracorporeal membrane oxygenation in a preterm infant.

We present the first report in the literature of a child with human metapneumovirus pneumonia who required extracorporeal membrane oxygenation for survival. This was a 3-month-old premature boy from British Columbia, Canada, who developed severe respiratory failure, experienced failure of high-frequency oscillatory mechanical ventilation, and required extracorporeal membrane oxygenation support for 10 days. This case illustrates the importance of including this newly discovered pathogen among the causes of childhood pneumonia.