Juneteenth in STEMM and the barriers to equitable science.

We are 52 Black scientists. Here, we establish the context of Juneteenth in STEMM and discuss the barriers Black scientists face, the struggles they endure, and the lack of recognition they receive. We review racism's history in science and provide institutional-level solutions to reduce the burdens on Black scientists.

Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3ß.

Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 ß activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 ß during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.SIGNIFICANCE STATEMENT Premature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurologic outcomes. Because of its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study uses perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.

Locus coeruleus in memory formation and Alzheimer's disease.

Catecholamine neurons of the locus coeruleus (LC) in the dorsal pontine tegmentum innervate the entire neuroaxis, with signaling actions implicated in the regulation of attention, arousal, sleep-wake cycle, learning, memory, anxiety, pain, mood, and brain metabolism. The co-release of norepinephrine (NE) and dopamine (DA) from LC terminals in the hippocampus plays a role in all stages of hippocampal-memory processing. This catecholaminergic regulation modulates the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. LC neurons in awake animals have two distinct firing modes: tonic firing (explorative) and phasic firing (exploitative). These two firing modes exert different modulatory effects on post-synaptic dendritic spines. In the hippocampus, the firing modes regulate long-term potentiation (LTP) and long-term depression, which differentially regulate the mRNA expression and transcription of plasticity-related proteins (PRPs). These proteins aid in structural alterations of dendritic spines, that is, structural long-term potentiation (sLTP), via expansion and structural long-term depression (sLTD) via contraction of post-synaptic dendritic spines. Given the LC's role in all phases of memory processing, the degeneration of 50% of the LC neuron population occurring in Alzheimer's disease (AD) is a clinically relevant aspect of disease pathology. The loss of catecholaminergic regulation contributes to dysfunction in memory processes along with impaired functions associated with attention and task completion. The multifaceted role of the LC in memory and general task performance and the close correlation of LC degeneration with neurodegenerative disease progression together implicate it as a target for new clinical assessment tools.

Active travelling to school is not associated with increased total daily physical activity levels, or reduced obesity and cardiovascular/pulmonary health parameters in 10-12-year olds: a cross-sectional cohort study.

BACKGROUND/OBJECTIVES: Childhood obesity has increased enormously. Several lifestyle factors have been implicated, including decreased physical activity, partially involving a decline in active travel to school. We aimed to establish the association between school transport mode and physical activity levels of primary 6 and 7 children (aged 10-12). Secondary outcomes were body mass index standard deviation scores, blood pressure levels and lung function. SUBJECTS/METHODS: A cross-sectional study was conducted with a total number of 432 children from three primary schools in North East Scotland. Actigraph accelerometers were used to provide objective measures of physical activity. Ninety-two children in primary 6 and 90 children in primary 7 (40 in common) had adequate data. Modes of transport to school were assessed by a questionnaire. Two hundred and seventeen children in primary 6 and one hundred and sixty-five in primary 7 returned adequate questionnaires. Children who used active transport modes for >70% of their journeys to school over the week were coded as active travellers and <30% were coded as passive travellers. All children also had height, weight, blood pressure levels and lung function measured. RESULTS: Children who lived further away from school, and in more expensive properties were more likely to travel passively to school. Actively commuting children (70% walking) had significantly higher activity levels than passive commuters during the 30 min that encompassed their journey to and from school. However, there were no significant differences between active and passive school travellers in total daily physical activity, BMI SDS, and both systolic and diastolic blood pressure and lung function. CONCLUSIONS: There was no evidence that more days of active travel to school had a significant influence on total physical activity, obesity and related health parameters. Public health interventions promoting active travel to school may have limited success in quelling the childhood obesity epidemic.

Astrocytic Endocannabinoids Mediate Hippocampal Transient Heterosynaptic Depression.

Astrocytes are highly dynamic cells that modulate synaptic transmission within a temporal domain of seconds to minutes in physiological contexts such as Long-Term Potentiation (LTP) and Heterosynaptic Depression (HSD). Recent studies have revealed that astrocytes also modulate a faster form of synaptic activity (milliseconds to seconds) known as Transient Heterosynaptic Depression (tHSD). However, the mechanism underlying astrocytic modulation of tHSD is not fully understood. Are the traditional gliotransmitters ATP or glutamate released via hemichannels/vesicles or are other, yet, unexplored pathways involved? Using various approaches to manipulate astrocytes, including the Krebs cycle inhibitor fluoroacetate, connexin 43/30 double knockout mice (hemichannels), and inositol triphosphate type-2 receptor knockout mice, we confirmed early reports demonstrating that astrocytes are critical for tHSD. We also confirmed the importance of group II metabotropic glutamate receptors (mGluRs) in astrocytic modulation of tHSD using a group II agonist. Using dominant negative SNARE mice, which have disrupted glial vesicle function, we also found that vesicular release of gliotransmitters and activation of adenosine A1 receptors are not required for tHSD. As astrocytes can release lipids upon receptor stimulation, we asked if astrocyte-derived endocannabinoids are involved in tHSD. Interestingly, a cannabinoid receptor 1 (CB1R) antagonist blocked and an inhibitor of the endogenous endocannabinoid 2-arachidonyl glycerol (2-AG) degradation potentiates tHSD in hippocampal slices. Taken together, this study provides the first evidence for group II mGluR-mediated astrocytic endocannabinoids in transiently suppressing presynaptic neurotransmitter release associated with the phenomenon of tHSD.

Neuronal transgene expression in dominant-negative SNARE mice.

Experimental advances in the study of neuroglia signaling have been greatly accelerated by the generation of transgenic mouse models. In particular, an elegant manipulation that interferes with astrocyte vesicular release of gliotransmitters via overexpression of a dominant-negative domain of vesicular SNARE (dnSNARE) has led to documented astrocytic involvement in processes that were traditionally considered strictly neuronal, including the sleep-wake cycle, LTP, cognition, cortical slow waves, depression, and pain. A key premise leading to these conclusions was that expression of the dnSNARE was specific to astrocytes. Inconsistent with this premise, we report here widespread expression of the dnSNARE transgene in cortical neurons. We further demonstrate that the activity of cortical neurons is reversibly suppressed in dnSNARE mice. These findings highlight the need for independent validation of astrocytic functions identified in dnSNARE mice and thus question critical evidence that astrocytes contribute to neurotransmission through SNARE-dependent vesicular release of gliotransmitters.

The effects of surface stripping ZnO nanorods with argon bombardment.

ZnO nanorods are used in devices including field effects transistors, piezoelectric transducers, optoelectronics and gas sensors. However, for efficient and reproducible device operation and contact behaviour, surface contaminants must be removed or controlled. Here we use low doses of argon bombardment to remove surface contamination and make reproducible lower resistance contacts. Higher doses strip the surface of the nanorods allowing intrinsic surface measurements through a cross section of the material. Photoluminescence finds that the defect distribution is higher at the near-surface, falling away in to the bulk. Contacts to the n-type defect-rich surface are near-Ohmic, whereas stripping away the surface layers allows more rectifying Schottky contacts to be formed. The ability to select the contact type to ZnO nanorods offers a new way to customize device behaviour.

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca(2+) photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.

Photolysis of caged Ca2+ but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release.

Astrocytes in hippocampal slices can dynamically regulate synaptic transmission in a process mediated by increases in intracellular Ca(2+). However, it is debated whether astrocytic Ca(2+) signals result in release of glutamate. We here compared astrocytic Ca(2+) signaling triggered by agonist exposure versus photolysis side by side. Using transgenic mice in which astrocytes selectively express the MrgA1 receptor, we found that receptor-mediated astrocytic Ca(2+) signaling consistently triggered neuronal hyperpolarization and decreased the frequency of miniature excitatory postsynaptic currents (EPSCs). In contrast, photolysis of caged Ca(2+) (o-nitrophenyl-EGTA) in astrocytes led to neuronal depolarization and increased the frequency of mEPSCs through a metabotropic glutamate receptor-mediated pathway. Analysis of transgenic mice in which astrocytic vesicular release is suppressed (dominant-negative SNARE mice) and pharmacological manipulations suggested that glutamate is primarily released by opening of anion channels rather than exocytosis. Combined, these studies show that photolysis but not by agonists induced astrocytic Ca(2+) signaling triggers glutamate release.

D-ß-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.

1.The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-P-hydroxybutyrate (D-ßHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ßHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential (AP) properties, while D- PHb rescued neuronal functions associated with axonal conduction, synchronization and LTP.

D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.

The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-ꞵ-hydroxybutyrate (D-ꞵHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ꞵHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential properties, while D-ꞵHb rescued neuronal functions associated with axonal conduction, synchronization, and LTP.

Food insecurity and disasters: predicting disparities in total and first-time food pantry visits during the COVID-19 pandemic.

In the U.S. state of Arizona, nearly one-third of households experienced food insecurity during the COVID-19 pandemic, an increase from one-fourth of households before the pandemic. Previous research on food insecurity in the wake of natural and human-instigated disasters demonstrates that groups vulnerable to food insecurity before a disaster are more susceptible to food insecurity during and after that disaster; however, less is known about whether this relationship also holds true during health-related disasters, such as the COVID-19 pandemic. We explore how the COVID-19 pandemic influenced urban food insecurity patterns by analyzing the socio-demographic characteristics of food pantry clients in Maricopa County, Arizona. Using data from Phoenix Rescue Mission (PRM), a local non-profit food service provider, two binomial logistic regression models compare the socio-demographic composition of total and first-time food pantry users before and during the pandemic. In addition to an overall increase in food pantry usage during the pandemic, we find that, while certain socio-demographic groups historically vulnerable to food insecurity experienced the predicted uptick in insecurity during the pandemic, other socio-demographic disparities were attenuated. These somewhat disparate findings illustrate the complex relationship between disasters and food insecurity in an urban context, offering several avenues for future research. Supplementary Information: The online version contains supplementary material available at 10.1007/s12571-022-01336-2.

Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults.

Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (D-ßHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of D-ßHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of D-ßHB compared to active control glucose (N = 26). Effect of age and blood levels of D-ßHB and glucose were used to further explore the effect of D-ßHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of D-ßHB. Importantly, the effect was specific to D-ßHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of D-ßHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging.

Distinct astrocytic modulatory roles in sensory transmission during sleep, wakefulness, and arousal states in freely moving mice.

Despite extensive research on astrocytic Ca2+ in synaptic transmission, its contribution to the modulation of sensory transmission during different brain states remains largely unknown. Here, by using two-photon microscopy and whole-cell recordings, we show two distinct astrocytic Ca2+ signals in the murine barrel cortex: a small, long-lasting Ca2+ increase during sleep and a large, widespread but short-lasting Ca2+ spike when aroused. The large Ca2+ wave in aroused mice was inositol trisphosphate (IP3)-dependent, evoked by the locus coeruleus-norepinephrine system, and enhanced sensory input, contributing to reliable sensory transmission. However, the small Ca2+ transient was IP3-independent and contributed to decreased extracellular K+, hyperpolarization of the neurons, and suppression of sensory transmission. These events respond to different pharmacological inputs and contribute to distinct sleep and arousal functions by modulating the efficacy of sensory transmission. Together, our data demonstrate an important function for astrocytes in sleep and arousal states via astrocytic Ca2+ waves.

Mobile Pantries Can Serve the Most Food Insecure Populations.

Purpose: Food insecurity is an urgent crisis in the United States, with one in nine people lacking a consistent source of the food necessary for an active and healthy lifestyle. This crisis is particularly dire in Maricopa County, Arizona, where 1 in 5 children experience food insecurity, and >1 in 10 residents experience poverty. Mobile food pantries offer an additional resource to address food insecurity; however, there is minimal knowledge about how communities utilize these food distributors. Background: Research on the elderly (people >60 years) and immigrant populations shows that these populations are especially vulnerable to food insecurity. The risk these groups face is compounded in Maricopa County, the 15th largest county in the country with minimal public transit to extant resources. Mobile food pantries offer one solution to this issue, bringing groceries and other important items directly to communities. Methods: This study utilizes data from a food pantry called "Phoenix Rescue Mission" (PRM) on food insecure people's use of PRM's mobile and brick-and-mortar pantries, as well as census data. Using GIS mapping and a multinomial logistic regression model, this research identifies how different demographic groups engage with PRM's brick-and-mortar or mobile pantries. Results: Findings indicate that people aged 60-80 years and immigrant people of color are more likely to use both mobile and brick-and-mortar pantries. Conclusions: This research suggests that mobile pantries can reach the most food insecure populations and local nonprofits and governments can consider implementing mobile pantries to reach food insecure communities.

NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse.

Retinal ganglion cells (RGCs) project topographically to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Spontaneous activity plays a critical role in retinotopic mapping in both regions; however, the molecular mechanisms underlying activity-dependent refinement remain unclear. Previous pharmacologic studies implicate NMDA receptors (NMDARs) in the establishment of retinotopy. In other brain regions, NMDARs are expressed on both the presynaptic and postsynaptic side of the synapse, and recent work suggests that presynaptic and postsynaptic NMDARs play distinct roles in retinotectal developmental dynamics. To directly test the role of NMDARs expressed by RGCs in retinofugal map formation, we took a conditional genetic knock-out approach to delete the obligate GluN1 subunit of NMDARs in RGCs. Here, we demonstrate reduced GluN1 expression in the retina of Chrnb3-Cre;GluN1flox/flox (pre-cKO) mice without altered expression in the SC. Anatomical tracing experiments revealed no significant changes in termination zone size in the SC and dLGN of pre-cKO mice, suggesting NMDAR function in RGCs is not an absolute requirement for topographic refinement. Further, we observed no change in the eye-specific organization of retinal inputs to the SC nor dLGN. To verify that NMDA induces activity in RGC terminals, we restricted GCaMP5 expression to RGCs and confirmed induction of calcium transients in RGC terminals. Together, these findings demonstrate that NMDARs expressed by RGCs are not required for retinofugal topographic map formation nor eye-specific segregation in the mouse.

Lipophilic nanocrystal prodrug-release defines the extended pharmacokinetic profiles of a year-long cabotegravir.

A once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.

Prevention of diarrhoea in children with HIV infection or exposure to maternal HIV infection.

BACKGROUND: Diarrhoea is a major cause of morbidity and mortality among infants and children worldwide, especially in low- and middle-income countries. Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is a condition that similarly disproportionately affects low- and middle-income countries; of the nearly 2.1 million children under age 15 years living with HIV/AIDS, the large majority reside in sub-Saharan Africa. Infants and children with HIV infection have more frequent and more severe diarrhoea than children without HIV. Interventions including vitamin A, zinc and cotrimoxazole may contribute substantially to preventing diarrhoea in children with HIV infection or exposure to HIV. OBJECTIVES: We perform a systematic review of randomised controlled trials and nonrandomised studies that examine the effectiveness of vitamin A, zinc and cotrimoxazole on mortality and morbidity from diarrhoea in HIV-infected and -exposed infants and children. SEARCH STRATEGY: Electronic databases including Pubmed, Central and EMBASE were searched without limits to language from 1980 to April 2010. Conference database searches were performed, experts were contacted and bibliographies were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs) and nonrandomised studies (NRSs) that examined the effectiveness of the three interventions were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed citations for eligibility and double-extracted included studies. Assessment of bias of individual studies was performed independently by both reviewers. Only two summary estimates were performed due to heterogeneity in study design and interventions. MAIN RESULTS: Four RCTs were identified for vitamin A. One RCT was identified for zinc. One RCT and two NRSs were identified for cotrimoxazole. Vitamin A reduced mortality overall in children with HIV infection (four studies). A pooled estimate of three studies for reduction in mortality from vitamin A compared to placebo had a relative risk (DerSimonian and Laird method, random effects) of 0.50 (95% confidence interval (CI): 0.31 to 0.79) in 267 patients. Diarrheoa-specific mortality did not reach statistical significance and diarrhoeal morbidity outcomes were variable in three trials. Zinc supplementation reduced the number of physician visits for watery diarrhoea in one trial. Cotrimoxazole reduced mortality and hospitalisations compared to placebo in one RCT, although diarrhoea-specific morbidities were not significant. AUTHORS' CONCLUSIONS: Vitamin A shows benefits in reduction of mortality in HIV-infected children. The effect of vitamin A on children with HIV exposure is not clear and needs further review. Zinc and combination vitamin A, zinc and micronutrient supplementation did not show an effect compared to vitamin A alone in children with HIV infection. Cotrimoxazole reduced mortality and some morbidity in children with HIV infection. Further research may clarify the effects of these interventions on morbidity from diarrhoea and in the population of children with HIV exposure.

Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research.

INTRODUCTION: Despite significant advances in treatment and prevention of HIV-1 infection, poor adherence to daily combination antiretroviral therapy (ART) regimens remains a major obstacle toward achieving sustained viral suppression and prevention. Adherence to ART could also be compromised by adverse drug reactions and societal factors that limit access to therapy. Therefore, medicines that aim to improve adherence by limiting ART side effects, frequency of dosing and socially acceptable regimens are becoming more attractive. AREAS COVERED: This review highlights recent advances and challenges in the development of long-acting drug delivery strategies for HIV prevention and treatment. Approaches for extended oral and transdermal deliveries, microbicides, broadly neutralizing antibodies, and long-acting implantable and injectable deliveries are reviewed. EXPERT OPINION: Emerging approaches on long-acting antiretroviral therapies and broadly neutralizing antibody technologies are currently at various stages of development. Such efforts, if successful and become broadly accepted by clinicians and users, will provide newer and simpler options for prevention and treatment of HIV infection.