Safety Data Timelines for Pregnant Individuals with HIV on Antiretroviral Therapy.

Antiretrovirals are often approved by the Food and Drug Administration without sufficient safety data regarding their use in pregnancy. To quantify this delay, we calculated the interval from the approval date to their inclusion in the Antiretroviral Pregnancy Registry prospective analysis (≥ 200 first trimester exposures); median delay was six years.

Identifying Effective Durations of Antibiotic Therapy for the Treatment of Carbapenem-resistant Enterobacterales Bloodstream Infections: A Multicenter Observational Study.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

Infectious Diseases Consultation Associated With Reduced Mortality in Gram-Negative Bacteremia.

Gram-negative bacteremia (GN-BSI) can cause significant morbidity and mortality, but the benefit of infectious diseases consultation (IDC) is not well defined. A 24-site observational cohort study of unique hospitalized patients with 4861 GN-BSI episodes demonstrated a 40% decreased risk of 30-day mortality in patients with IDC compared to those without IDC.

Weight changes in patients with sustained viral suppression switching tenofovir disoproxil fumarate to tenofovir alafenamide.

OBJECTIVE: Switching from tenofovir disoproxil fumarate (TDF)- to tenofovir alafenamide (TAF)-containing antiretroviral therapy may negatively influence weight, cholesterol, and atherosclerotic cardiovascular disease risk. The extent of these changes and their association with TAF remain unclear. METHODS: This retrospective cohort evaluated metabolic changes in virologically suppressed patients with HIV infection who switched from TDF to TAF without switching other antiretroviral therapy medications. Adult patients on TDF and with no HIV viral load values >200 copies/mL for ≥2 years prior to and following a TAF switch were included. Weight and other variables were collected for 2 years before and after the switch. Longitudinal linear mixed-effects models evaluated changes at 1 and 2 years after the switch. RESULTS: In the unadjusted analysis, there were increases in weight, BMI, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, fasting glucose, and atherosclerotic cardiovascular disease risk scores 2 years after switching to TAF (each p ≤ 0.03). However, only increases in total and low-density lipoprotein cholesterol were associated with TAF and were significantly different from expected changes predicted in the adjusted longitudinal models. CONCLUSIONS: Despite observing significant unadjusted metabolic changes after switching to TAF, only changes in cholesterol were associated with TAF and were different from changes expected in time-trend adjusted models.

Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal.

Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

Adolescent and adult nicotine exposure differentially impacts oral nicotine and oral saccharin self-administration in mice.

Smokers that begin during adolescence are more likely to develop nicotine dependence than those who begin as adults. However, the factors that contribute to this remain largely unknown. Here we utilized a novel operant oral nicotine self-administration procedure in mice to assess the consequences of adolescent nicotine exposure on nicotine and saccharin (non-drug) reinforcement in adults. Animals were given non-contingent exposure to either saline or nicotine using the osmotic minipumps during both adolescence and adulthood for 2 weeks. Reinforcing efficacy for oral nicotine and saccharin was assessed using the progressive ratio schedule 2-weeks following the washout period in adults. Non-contingent nicotine exposure in adolescence drastically increased operant responding for oral nicotine but reduced responding for oral saccharin in the group re-exposed to nicotine in adulthood. Interestingly, adolescent nicotine-exposed mice that received saline exposure as adults exhibited higher preference for oral saccharin. However, breakpoints for oral nicotine in these mice remained comparable to control animals. Surprisingly, both adolescent and adult nicotine exposure increased inactive lever responding during self-administration presumably reflecting impulsive responding. Our data suggest that adolescent nicotine exposure produces an increase in reinforcement sensitivity in adulthood as reflected by increased saccharin self-administration but this sensitivity becomes biased towards nicotine self-administration when re-exposed to nicotine in adulthood. Moreover, nicotine/saccharin reinforcement could be impacted by changes in cognitive control, such as increased impulsivity. These distinct behavioral mechanisms may act in concert to facilitate maladaptive nicotine taking in smokers that initiate nicotine use during adolescence.