In particular research domains, the randomized control trial (RCT) is considered to be the only means for obtaining reliable estimates of the true impact of an intervention. However, an RCT design ...would often not be considered ethical, politically feasible, or appropriate for evaluating the impact of many policy, programme, or structural changes common in public health research. As such, researchers must use alternative yet robust research methods for determining the impact of such interventions. The evaluation of natural experiments (i.e. an intervention not controlled or manipulated by researchers), using various experimental and non-experimental design options can provide an alternative to the RCT. The following review highlights (a) the importance of evaluating natural experiments; (b) design considerations associated with evaluating natural experiments; (c) methods for reducing bias in natural experimental studies; and (d) the potential benefits of targeted systems to enable natural experiments in emerging priority domains moving forward.
The benefits of antipsychotic medications are sometimes obscured by their adverse effects. These effects range from relatively minor tolerability issues (e.g., mild sedation or dry mouth) to very ...unpleasant (e.g., constipation, akathisia, sexual dysfunction) to painful (e.g., acute dystonias) to disfiguring (e.g., weight gain, tardive dyskinesia) to life‐threatening (e.g., myocarditis, agranulocytosis). Importantly, adverse effect profiles are specific to each antipsychotic medication and do not neatly fit into first‐ and second‐generation classifications. This paper reviews management strategies for the most frequent side effects and identifies common principles intended to optimize net antipsychotic benefits. Only use antipsychotics if the indication is clear; only continue antipsychotics if a benefit is discernible. If an antipsychotic is providing substantial benefit, and the adverse effect is not life‐threatening, then the first management choice is to lower the dose or adjust the dosing schedule. The next option is to change the antipsychotic; this is often reasonable unless the risk of relapse is high. In some instances, behavioral interventions can be tried. Finally, concomitant medications, though generally not desirable, are necessary in many instances and can provide considerable relief. Among concomitant medication strategies, anticholinergic medications for dystonias and parkinsonism are often effective; beta‐blockers and anticholinergic medications are useful for akathisia; and metformin may lead to slight to moderate weight loss. Anticholinergic drops applied sublingually reduce sialorrhea. Usual medications are effective for constipation or dyslipidemias. The clinical utility of recently approved treatments for tardive dyskinesia, valbenazine and deutetrabenazine, is unclear.
The extracellular-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that are involved in regulating cellular signaling in both normal and pathological ...conditions. Their expression is critical for development and their hyperactivation is a major factor in cancer development and progression. Since their discovery as one of the major signaling mediators activated by mitogens and Ras mutation, we have learned much about their regulation, including their activation, binding partners and substrates. In this review I will discuss some of what has been discovered about the members of the Ras to ERK pathway, including regulation of their activation by growth factors and cell adhesion pathways. Looking downstream of ERK activation I will also highlight some of the many ERK substrates that have been discovered, including those involved in feedback regulation, cell migration and cell cycle progression through the control of transcription, pre-mRNA splicing and protein synthesis.
Highlights • Tubulin modifications contribute to functional diversity of microtubules (MTs). • Post-translational modifications (PTMs) affect MT dynamics, organization, and interactions with other ...cellular components. • Various PTMs overlap or localize to specific MT domains demonstrating heterogeneity. • PTMs vary with time, cell type, subcellular compartment, and physiological state.
For many decades, river research has been focused on perennial rivers. Intermittent river research has a shorter history, and recent studies suggest that alternating dry and wet conditions alter ...virtually all biotic communities and biogeochemical processes in these rivers. Intermittent rivers constitute more than half of the length of the global river network and are increasing in number and length in response to climate change, land-use alteration, and water abstraction. Our views of the roles that rivers play in maintaining biodiversity and controlling material fluxes will change substantially when intermittent rivers are fully integrated into regional and global analyses. Concepts, questions, and methodologies from lotic, lentic, and terrestrial ecology need to be integrated and applied to intermittent rivers to increase our knowledge and effective management of these rivers.
Nurses work in stressful and demanding settings and often suffer from depression and burnout. Despite overlapping symptoms, research has been inconclusive regarding the discriminant validity of ...measures of burnout with regard to measures of depression. Such inconclusive discriminant validity might cause clinicians to fail to recognize and manage depression separately from burnout.
This meta-analysis aimed to clarify the distinctiveness of burnout as a separate construct by examining the size of the relationship between burnout and depression among nurses as well as potential moderators.
A stepwise method was used by searching 4 databases (PubMed, CINAHL, PsycINFO, and EMBASE) to retrieve published papers in English examining the relationship between burnout and depression among nurses and reporting the effect sizes of their findings.
We identified a total of 37 eligible studies. The pooled estimate showed a positive association between burnout and depression among nurses (r = 0.403, 95% CI 0.327, 0.474, p < 0.0001) and a slightly higher correlation coefficient for the Emotional Exhaustion subscale of the Maslach Burnout Inventory (MBI) measure (0.494, 95% CI 0.41, 0.57).
This review confirms a large burnout - depression correlation in nursing samples, adding to existing literature encompassing a variety of occupations. Future studies should focus on path analysis to assess the causal relationship as well as investigate potential moderators.
Although adults with schizophrenia have a significantly increased risk of premature mortality, sample size limitations of previous research have hindered the identification of the underlying causes.
...To describe overall and cause-specific mortality rates and standardized mortality ratios (SMRs) for adults with schizophrenia compared with the US general population.
We identified a national retrospective longitudinal cohort of patients with schizophrenia 20 to 64 years old in the Medicaid program (January 1, 2001, to December 31, 2007). The cohort included 1,138,853 individuals, 4,807,121 years of follow-up, and 74,003 deaths, of which 65,553 had a known cause.
Mortality ratios for the schizophrenia cohort standardized to the general population with respect to age, sex, race/ethnicity, and geographic region were estimated for all-cause and cause-specific mortality. Mortality rates per 100,000 person-years and the mean years of potential life lost per death were also determined. Death record information was obtained from the National Death Index.
Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI, 3.7-3.7) as likely to die in the follow-up period as were adults in the general population. Cardiovascular disease had the highest mortality rate (403.2 per 100,000 person-years) and an SMR of 3.6 (95% CI, 3.5-3.6). Among 6 selected cancers, lung cancer had the highest mortality rate (74.8 per 100,000 person-years) and an SMR of 2.4 (95% CI, 2.4-2.5). Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9; 95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4). Accidental deaths (119.7 per 100,000 person-years) accounted for more than twice as many deaths as suicide (52.0 per 100,000 person-years). Nonsuicidal substance-induced death, mostly from alcohol or other drugs, was also a leading cause of death (95.2 per 100,000 person-years).
In a US national cohort of adults with schizophrenia, excess deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk factors, including especially tobacco use. Excess deaths directly attributable to alcohol or other drugs highlight threats posed by substance abuse. More aggressive identification and management of cardiovascular risk factors, as well as reducing tobacco use and substance abuse, should be leading priorities in the medical care of adults with schizophrenia.
OBJECTIVE: To determine both the negative and positive predictive values of comprehensive chromosome screening (CCS) results for clinical outcome. DESIGN: Data obtained from two prospective, ...double-blinded, nonselection studies. SETTING: Academic center for reproductive medicine. PATIENT(S): One hundred forty-six couples with a mean maternal age of 34.0 ± 4.4 years and a mean paternal age of 37.3 ± 5.8 years. INTERVENTION(S): Embryo biopsy for DNA fingerprinting and aneuploidy assessment. MAIN OUTCOME MEASURE(S): Failure rate of embryos predicted aneuploid by CCS (negative predictive value) and success rate of embryos predicted euploid by CCS (positive predictive value). RESULT(S): A total of 255 IVF-derived human embryos were cultured and selected for transfer without influence from CCS analysis. Embryos were biopsied before transfer, including 113 blastomeres at the cleavage stage and 142 trophectoderm biopsies at the blastocyst stage. Comprehensive chromosome screening was highly predictive of clinical outcome, with 96% of aneuploid predicted embryos failing to sustain implantation and 41% sustained implantation from embryos predicted to be euploid. CONCLUSION(S): These nonselection data provide the first prospective, blinded, clinical study directly measuring the predictive value of aneuploidy screening for clinical outcome. The clinical error rate of an aneuploidy designation is very low (4%), whereas implantation and delivery rates of euploid embryos are increased relative to the entire cohort of transferred embryos.
The ability to modulate brain states using targeted stimulation is increasingly being employed to treat neurological disorders and to enhance human performance. Despite the growing interest in brain ...stimulation as a form of neuromodulation, much remains unknown about the network-level impact of these focal perturbations. To study the system wide impact of regional stimulation, we employ a data-driven computational model of nonlinear brain dynamics to systematically explore the effects of targeted stimulation. Validating predictions from network control theory, we uncover the relationship between regional controllability and the focal versus global impact of stimulation, and we relate these findings to differences in the underlying network architecture. Finally, by mapping brain regions to cognitive systems, we observe that the default mode system imparts large global change despite being highly constrained by structural connectivity. This work forms an important step towards the development of personalized stimulation protocols for medical treatment or performance enhancement.
PDF
