Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses.

OBJECTIVES: To review evidence from systematic reviews and/or meta-analyses (SR/MAs) regarding neuraminidase inhibitor (NI) safety and effectiveness. METHODS: We conducted an SR of SR/MAs of randomized control and/or observational studies. We searched eight electronic databases for SR/MAs that examined the effectiveness or safety of NIs administered for influenza (i.e. influenza-like illness or lab-confirmed) treatment or prophylaxis. RESULTS: We identified 27 (0.7%) eligible SR/MAs of 3723 articles reviewed. NI (n = 2) or oseltamivir (n = 1) versus no treatment were consistently associated with a decrease in mortality odds among the hospitalized, general population (OR range 0.2 - 0.8). Oseltamivir versus no treatment was associated with a decrease in hospitalization and pneumonia risk/odds in 2/4 SR/MAs. Oseltamivir (n = 4) and zanamivir (n = 3) were consistently associated with a 0.5 - 1 day decrease in symptom duration. Oseltamivir (n = 4) or zanamivir (n = 4) versus no prophylaxis were consistently associated with a decrease in the odds/risk of symptomatic secondary transmission (OR/RR range 0.1 - 0.5). Oseltamivir versus no treatment was consistently associated with a 1.5- to 2.5-fold increase in the odds/risk of nausea (n = 4) and vomiting (n = 5). CONCLUSIONS: NI treatment is likely to be effective at reducing mortality among hospitalized patients, and symptom duration by up to 1 day in the general population. Oseltamivir or zanamivir prophylaxis are likely to be effective at reducing secondary symptomatic influenza transmission. Increased nausea and vomiting are likely associated with oseltamivir use. We recommend that decisions regarding NI use are made in consideration of potential adverse events, particularly for the general population at low risk of complications. Among hospitalized patients, NI administration seems warranted to reduce mortality risk.

Safety and effectiveness of neuraminidase inhibitors in situations of pandemic and/or novel/variant influenza: a systematic review of the literature, 2009-15.

Objectives: To review systematically the published literature evaluating neuraminidase inhibitor (NI) safety and effectiveness in situations of pandemic and novel/variant influenza. Methods: We searched six online databases using comprehensive search criteria for observational studies and randomized controlled trials investigating the effects of NI treatment, prophylaxis or outbreak control in patients of all ages. Results: Overall, 165 studies were included (95% observational), which were generally of low methodological quality due to lack of adjustment for confounding variables. In studies reporting adjusted estimates in general populations, NI treatment appeared likely to be effective against mortality (primarily if administered within 48 h of symptom onset) and potentially effective in reducing pneumonia. NIs appeared effective in reducing secondary transmission when indicated for prophylaxis. Limited, low-quality data suggest NIs are likely safe in general populations and may be safe in pregnant women and children. Data are scarce regarding safety of NIs in adults and high-risk individuals. Conclusions: Most included studies were observational, statistically underpowered and at high risk of reporting biased and/or confounded effect estimates. NI treatment appeared likely effective in reducing mortality (cause unspecified) and pneumonia in general populations, with increasing benefit when administered with 48 h of symptom onset. NI pre- or post-exposure prophylaxis is likely effective in reducing secondary transmission of influenza in a general population. Our evidence suggests NIs are likely safe to use in the general population; however, data for children and pregnant women are limited. Knowledge gaps persist in specific populations such as Aboriginals, high-risk individuals and the elderly.

Electron- and proton-impact excitation of hydrogenlike uranium in relativistic collisions.

The K shell excitation of H-like uranium (U(91+)) in relativistic collisions with different gaseous targets has been studied at the experimental storage ring at GSI Darmstadt. By performing measurements with different targets as well as with different collision energies, we were able to observe for the first time the effect of electron-impact excitation (EIE) process in the heaviest hydrogenlike ion. The large fine-structure splitting in H-like uranium allowed us to unambiguously resolve excitation into different L shell levels. State-of-the-art calculations performed within the relativistic framework which include excitation mechanisms due to both protons (nucleus) and electrons are in good agreement with the experimental findings. Moreover, our experimental data clearly demonstrate the importance of including the generalized Breit interaction in the treatment of the EIE process.

Metals leaching from common residential and commercial roofing materials across four years of weathering and implications for environmental loading.

Urban stormwater is a major source of chemical pollution to receiving waters. Anthropogenic materials in the built environment can be an important source of chemicals to stormwater runoff. Roofing materials can leach significant amounts of metals, which vary over the life of the roof. We report concentrations of three metals (As, Cu, Zn) leaching into runoff from experimental panels of 14 roofing materials over 4.5 years of weathering. Ten roofing materials leached metals. Several leached >10 ppb during one or more study periods. The most common correlate with metal concentration was panel age, followed by precipitation amount. Extrapolating from these observations, we estimated the loading of metals from each roofing material during the first 10 years following installation. Eight materials were predicted to leach metals above background at the end of the 10 years. In combination with information on the prevalence of different roofing materials in the Puget Sound region of the Pacific Northwest, we estimated the relative amount of metals contributed from roofing materials in this basin. Most arsenic and copper was estimated to be contributed by residential roofing; nearly all arsenic from wood shakes manufactured with copper chromated arsenic, and copper contributed mainly from treated wood shakes followed by copper granule-containing asphalt shingles. Most zinc was estimated to be contributed by commercial roofs, including Zincalume and painted metal roofs. Overall our data shows that roofing materials can be an important long-term source of As, Cu, and Zn to stormwater runoff. Compared with atmospheric deposition, roof materials were a significant source, particularly of As and Cu. To get a complete picture of metals sourced from buildings, there is a need to study whole roof systems, including gutters, downspouts, and HVAC systems, as well as metals contributed from homeowner-applied treatments to their roofs.

Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.

OBJECTIVE: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. METHOD: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. RESULTS: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. CONCLUSIONS: Paroxetine is generally well tolerated and effective for major depression in adolescents.

The role of the pancreas in intestinal zinc secretion in metallothionein-null mice.

The distribution and excretion of endogenous Zn, including the role of the pancreas, were examined in fasted MT+/+ and MT-/- mice. At 3 and 6 h after receiving 65Zn tracer by subcutaneous injection, 65Zn levels were compared in tissues of MT+/+ and MT-/- mice. 65Zn levels were significantly higher in the liver and pancreas of the MT+/+ mice, whereas in the MT-/- mice, 65Zn levels were significantly higher in muscle, skin, and most of the gastrointestinal tract other than the stomach and upper small intestine. In MT-/- mice, 3% of the injected 65Zn was recovered in the luminal contents of the small intestine over 3-6 h, compared with <1.5% in the MT+/+ mice. A loading dose of Zn (150 microg, s.c.) sufficient to raise the plasma Zn concentration by fourfold to fivefold in both MT+/+ and MT-/- mice resulted in similar increases in pancreatic Zn levels in each genotype, although more Zn appeared in the lower small intestine of MT-/- mice. Pancreatectomy decreased the level of 65Zn in the small intestine of MT-/- but not MT+/+ mice. Longer-term studies over 4 days demonstrated few differences in tissue 65Zn between MT+/+ and MT-/- mice, with the exception of the pancreas, where 65Zn retention after fasting in MT-/- mice was half that of MT+/+ mice. MT-/- mice also had significantly lower Zn concentrations in the pancreas. Fecal excretion of 65Zn in MT-/- mice was greater than that of MT+/+ mice in the first 24 h (24.7 vs. 18.2% of injected dose; p < 0.05). Besides metallothionein (MT), there were no significant differences in the molecular weight distribution of Zn binding ligands in the lumen of the small intestine between MT+/+ and MT-/- mice. Mice lacking MT I and II lose more endogenous Zn into the gut because of a relative failure of the pancreas to retain Zn. However, increased Zn secretion via the small intestinal mucosa may also contribute to intestinal Zn loss in MT-/- mice.

Effects of muscimol inactivation of the cerebellar interposed-dentate nuclear complex on the performance of the nictitating membrane response in the rabbit.

Intracranial microinjections of the GABAA agonist muscimol were used to assess the involvement of the dentato-interposed cerebellar nuclear complex in the performance of the conditioned (CR) and unconditioned (UR) nictitating membrane responses in the rabbit. Specifically, the experiments test the hypothesis that the cerebellar nuclei are involved in the performance of both the CRs and URs. The experiments employed temporary nuclear lesions to disrupt the CRs in order to examine parallel effects on URs. Animals were conditioned in a standard delay conditioning paradigm. Injection sites at which the muscimol application disrupted execution of the CRs were identified in each rabbit. Once these sites were found, the effects of muscimol and saline injections were evaluated while alternating paired trials with unpaired trials in which only the unconditioned stimuli were applied. There are two main findings in the present study. First, the activation of the GABAA receptors in the dentato-interposed cerebellar nuclear region reduced the amplitude and increased the latency of the UR. This change in the UR closely paralleled the disruption of the CR. This observation is consistent with the notion that the cerebellum is involved in the regulation of defensive flexion reflexes. Second, cerebellar nuclear inactivation did not eliminate the tone-induced enhancement of the UR. This finding suggests the presence of cerebellum-independent circuits subserving the intermodal interaction between the conditioned and unconditioned stimuli.

Disbanding a multidisciplinary clinic: effects on the health care of myelomeningocele patients.

A multidisciplinary clinic for the evaluation and care of children with central nervous system malformations was established at our hospital in 1963 and disbanded in 1988. Three years later, a retrospective telephone survey of myelomeningocele patients (n = 87) was used to identify the effect of clinic closing on the health and care of these patients. After the clinic was disbanded, 45-66% of myelomeningocele patients failed to have regular medical and specialty care, despite the continued availability of the same specialty care in the same location. The most significant correlation was that older patients had less frequent care; this failure in health care utilization was not related to the patients' insurance status. This lack of care is not benign. An increase in serious morbidity, including amputation and nephrectomy, was detected in those patients with the least follow-up, but not in the control group. A significant problem with coordination of the patients' care exists; neither the patient, the family, nor the local physician assumes the duties of coordinator of care. This review indicates that if a multidisciplinary clinic is disbanded, a large proportion of patients will fail to maintain adequate medical follow-up, and that significant morbidity can occur within several years. It is unrealistic to expect the continuation of effective care by merely maintaining the individual services of the disbanded clinic, without some coordinator of care.