The North American Monsoon buffers forests against the ongoing megadrought in the Southwestern United States.

The US Southwest has been entrenched in a two-decade-long megadrought (MD), the most severe since 800 CE, which threatens the long-term vitality and persistence of regional montane forests. Here, we report that in the face of record low winter precipitation and increasing atmospheric aridity, seasonal activity of the North American Monsoon (NAM) climate system brings sufficient precipitation during the height of the summer to alleviate extreme tree water stress. We studied seasonally resolved, tree-ring stable carbon isotope ratios across a 57-year time series (1960-2017) in 17 Ponderosa pine forests distributed across the NAM geographic domain. Our study focused on the isotope dynamics of latewood (LW), which is produced in association with NAM rains. During the MD, populations growing within the core region of the NAM operated at lower intrinsic and higher evaporative water-use efficiencies (WUEi and WUEE , respectively), compared to populations growing in the periphery of the NAM domain, indicating less physiological water stress in those populations with access to NAM moisture. The disparities in water-use efficiencies in periphery populations are due to a higher atmospheric vapor pressure deficit (VPD) and reduced access to summer soil moisture. The buffering advantage of the NAM, however, is weakening. We observed that since the MD, the relationship between WUEi and WUEE in forests within the core NAM domain is shifting toward a drought response similar to forests on the periphery of the NAM. After correcting for past increases in the atmospheric CO2 concentration, we were able to isolate the LW time-series responses to climate alone. This showed that the shift in the relation between WUEi and WUEE was driven by the extreme increases in MD-associated VPD, with little advantageous influence on stomatal conductance from increases in atmospheric CO2 concentration.

Perturbation of the developmental potential of preimplantation mouse embryos by hydroxyurea.

Women are advised not to attempt pregnancy while on hydroxyurea (HU) due to the teratogenic effects of this agent, based on results obtained from animal studies. Several case reports suggest that HU may have minimal or no teratogenic effects on the developing human fetus. Fourteen cases of HU therapy in pregnant patients diagnosed with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease (SCD) have been reported. Three pregnancies were terminated by elective abortion; 1 woman developed eclampsia and delivered a phenotypically normal stillborn infant. All other patients delivered live, healthy infants without congenital anomalies. We contend that case studies such as these have too few patients and cannot effectively address the adverse effect of HU on preimplantation embryo or fetuses. The objective of this study was to assess the risks associated with a clinically relevant dose of HU used for the treatment of SCD, on ovulation rate and embryo development, using adult C57BL/6J female mice as a model. In Experiment 1, adult female mice were randomly assigned to a treatment or a control group (N = 20/group). Treatment consisted of oral HU (30 mg/kg) for 28 days; while control mice received saline (HU vehicle). Five days to the cessation of HU dosing, all mice were subjected to folliculogenesis induction with pregnant mare serum gonadotropin (PMSG). Five mice/group were anesthetized at 48 hours post PMSG to facilitate blood collection via cardiac puncture for estradiol-17beta (E(2)) measurement by RIA. Ovulation was induced in the remaining mice at 48 hours post PMSG with human chorionic gonadotropin (hCG) and immediately caged with adult males for mating. Five plugged female mice/group were sacrificed for the determination of ovulation rate. The remaining mated mice were sacrificed about 26 hours post hCG, ovaries excised and weighed and embryos harvested and cultured in Whitten's medium (WM) supplemented with CZBt. In Experiments 2 and 3, (N = 10/Experiment) folliculogenesis and ovulation were induced in untreated mice followed by mating. Recovered embryos were either exposed continuously (Experiment 2) or intermittently (Experiment 3) to bioavailable HU (18 microg HU/mL of WM + CZBt) or WM + CZBt only (control). Treated mice sustained decreased ovarian wt, ovulation rate and circulating E(2) compared with controls (P < 0.05). Fewer embryos retrieved from HU-treated mice developed to blastocyst stage (32%) compared with those from controls (60%; P < 0.05). Furthermore, continuous or intermittent in vitro exposures of embryos to HU also resulted in reduced development to blastocyst stage (continuous HU, 9 vs. control, 63%; P < 0.05; intermittent HU, 20 vs. control, 62%; P < 0.05) with embryos exposed continuously to HU in vitro fairing worse. Even though HU is well tolerated, our data suggest that it compromises folliculogenesis and the ability of generated embryos to develop. Therefore, designed studies with larger numbers of patients receiving HU during pregnancy, with longer follow-up of exposed children and more careful assessment of embryo/fetotoxic effects, are required before this agent can be promoted as safe in pregnancy.

Pediatric uptake of a newly available antipsychotic medication.

OBJECTIVE: The uptake of new antipsychotic medications among children has not been studied adequately. Although ziprasidone received Food and Drug Administration approval for the treatment of psychotic disorders among children in June 2009, it first became available for off-label use by children in 2001 and presented an excellent case study for off-label market entry. The objective of this study was to determine the pattern of initiation and switching for off-label use of ziprasidone among Michigan children who were insured by Medicaid in the first year that ziprasidone was available. METHODS: We conducted a retrospective study by using Michigan Medicaid data for patients who were aged <21 years and had 2 years of continuous enrollment and at least 1 prescription for ziprasidone in the first year the medication was available. The main outcome measures were proportion of children prescribed ziprasidone as their first antipsychotic, with evidence of treatment resistance, and by a psychiatrist. RESULTS: In the first year, 292 individuals who met criteria were prescribed ziprasidone. Approximately 53% had a diagnosis of psychosis. Explosive personality disorder and oppositional defiant disorder were the next most common diagnoses. For 33% of individuals, this was the first antipsychotic medication. Only 12% of individuals showed evidence of treatment resistance to other antipsychotic medications before switching to ziprasidone. CONCLUSIONS: During the period when ziprasidone had no approved pediatric usages, a small percentage of patients who were prescribed ziprasidone showed evidence of treatment resistance, the primary expected indication. Some prescribing for ziprasidone in the first year in this population could be considered inappropriate considering what was known about the safety and efficacy of ziprasidone in children and adolescents at the time. "Fail first" and prior authorization policies may be appropriate in the first year a medication is available so as to protect children from potential serious harm.

Monitoring pediatric antidepressant use.

The PhaST system was developed to improve monitoring efforts of pediatric antidepressant use and is currently being tested in a clinical trial. The design of PhaST reflects both the FDA recommendations and consideration of system and family resources. Pilot and preliminary results of the current study data have shown that participants can be reached by telephone and necessary monitoring calls can be completed over a period of time. PTS clinicians were also able to respond to "positive calls" and determine level of concern as well as action steps needed. Physicians and other ongoing providers received monitoring call reports and PTS clinician follow-up as indicated. Given the promising findings of the pilot study and preliminary trial data, PhaST appears to be a sensitive method for monitoring outpatients for adverse effects of antidepressants. Because it uses inexpensive IVR technology and physician extenders, it may prove to increase communication between health providers and patients and shows promise for improving patient safety and quality of care. Beyond medication safety, it could also be utilized to enhance medication and/or treatment adherence, as well as assist clinicians in helping patients implement behavior management plans.

Spatio-temporal clusters of new psychotropic medications among Michigan children insured by Medicaid.

PURPOSE: The prescription of psychotropic medications to children and adolescents has increased dramatically over the last decade. However, the development of disparities in prescribing is poorly understood. We examined whether clustering of utilization is a common phenomenon among early adopters of medications described the characteristics of clusters. METHODS: We obtained the complete Medicaid Analytic Extract (MAX) files for the State of Michigan between 1 January 2000 and 31 December 2003. We tracked the adoption of: aripiprazole, atomoxetine, escitalopram, methylphenidate OROS, and ziprasidone. We conducted retrospective, space-time analyses, scanning for clusters with high rates of prescribing. Chi(2) analyses were used to compare the attributes of patients living within clusters to patients living in the rest of the state for each medication. Clusters of utilization were identified via the spatial scan statistic. Analysis of variance (ANOVA) was then used to compare the numbers of mental health professionals per capita in geographic areas that did and did not demonstrate clustering of prescriptions for new psychotropic medications. RESULTS: All five medications exhibited space-time clustering within the first 90 days following the US Food and Drug Administration (FDA) approval. The Medicaid population surrounding Kalamazoo was more likely to receive a prescription on multiple occasions. Excluding ziprasidone, clusters were not associated with greater geographic access to mental health care professionals. CONCLUSIONS: Clustering of new prescriptions for psychotropic medications was a common phenomenon in this population. Surveillance and cluster identification allow the development of disparities to be studied. This information permits interventions to be targeted to locations prospectively.

Once-daily treatment of ADHD with guanfacine: patient implications.

The standard of care for treating ADHD is to use a psychostimulant as the first line agent. Recent medical literature reports that approximately 70%-90% of patients with ADHD received some benefit from a stimulant medication. Even though psychostimulants have a high rate of efficacy, an estimated 30%-50% of children and adults may discontinue psychostimulants secondary to adverse effects or inadequate response. Guanfacine has been used for a number of years as an off label alternative to psychostimulants. This article reviews the current literature on the effectiveness of guanfacine in treating ADHD. It also introduces the preliminary data for guanfacine extended release and its effectiveness in decreasing the symptoms of ADHD.