ABSTRACT
BACKGROUND
Previous studies have reported that health literacy limitations are associated with poorer disease control for chronic conditions, but have not evaluated potential associations ...with medication adherence.
OBJECTIVE
To determine whether health literacy limitations are associated with poorer antidepressant medication adherence.
DESIGN
Observational new prescription cohort follow-up study.
PARTICIPANTS
Adults with type 2 diabetes who completed a survey in 2006 and received a new antidepressant prescription during 2006–2010 (
N
= 1,366) at Kaiser Permanente Northern California.
MAIN MEASURES
Validated three-item self-report scale measured health literacy. Discrete indices of adherence based on pharmacy dispensing data according to validated methods: primary non-adherence (medication never dispensed); early non-persistence (dispensed once, never refilled); non-persistence at 180 and 365 days; and new prescription medication gap (NPMG; proportion of time that the person is without medication during 12 months after the prescription date).
KEY RESULTS
Seventy-two percent of patients were classified as having health literacy limitations. After adjusting for sociodemographic and clinical covariates, patients with health literacy limitations had significantly poorer adherence compared to patients with no limitations, whether measured as early non-persistence (46 % versus 38 %,
p
< 0.05), non-persistence at 180 days (55 % versus 46 %,
p
< 0.05), or NPMG (41 % versus 36%,
p
< 0.01). There were no significant associations with primary adherence or non-persistence at 365 days.
CONCLUSIONS
Poorer antidepressant adherence among adults with diabetes and health literacy limitations may jeopardize the continuation and maintenance phases of depression pharmacotherapy. Findings underscore the importance of national efforts to address health literacy, simplify health communications regarding treatment options, improve public understanding of depression treatment, and monitor antidepressant adherence.
The nonhomologous end-joining (NHEJ) pathway is the primary repair pathway for DNA double strand breaks (DSBs) in humans. Repair is mediated by a core complex of NHEJ factors that includes a ligase ...(DNA Ligase IV; L4) that relies on juxtaposition of 3΄ hydroxyl and 5΄ phosphate termini of the strand breaks for catalysis. However, chromosome breaks arising from biological sources often have different end chemistries, and how these different end chemistries impact the way in which the core complex directs the necessary transitions from end pairing to ligation is not known. Here, using single-molecule FRET (smFRET), we show that prior to ligation, differences in end chemistry strongly modulate the bridging of broken ends by the NHEJ core complex. In particular, the 5΄ phosphate group is a recognition element for L4 and is critical for the ability of NHEJ factors to promote stable pairing of ends. Moreover, other chemical incompatibilities, including products of aborted ligation, are sufficient to disrupt end pairing. Based on these observations, we propose a mechanism for iterative repair of DSBs by NHEJ.
Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's ...abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a "knockin" of a cocaine-insensitive but functional DAT did not self-administer cocaine intravenously despite normal food-maintained responding and normal intravenous self-administration of amphetamine and a direct dopamine agonist. Our results have three implications. First, they imply a crucial role for high-affinity DAT binding of cocaine in mediating its reinforcing effects, reconciling mouse genetic engineering approaches with data from classic pharmacological studies. Second, they demonstrate the usefulness of knockin strategies that modify specific amino acid sequences within a protein. Third, they show that it is possible to alter the DAT protein sequence in such a way as to selectively target its interaction with cocaine, while sparing other behaviors dependent on DAT function. Thus, molecular engineering technology could advance the development of highly specialized compounds such as a dopamine-sparing "cocaine antagonist."
Dixon and Goldman present a debate on the future of Medicaid's so-called institutions for mental diseases (IMD) exclusion rule. The debate has particular salience for the larger policy debate on ...whether the United States has enough psychiatric inpatient beds and the types of facilities and services needed in a comprehensive system of psychiatric services. The IMD exclusion rule was part of the original Medicaid policy from 1965. Understanding the IMD rule requires understanding what is meant by "institutions for mental diseases." For purposes of current Medicaid policy, IMDs are hospitals, nursing homes, or other institutions with more than 16 beds that are primarily engaged in providing diagnosis, treatment, or care of persons with mental diseases other than dementia or intellectual disabilities.
Tumor-derived exosomes have documented roles in accelerating the initiation and outgrowth of metastases, as well as in therapy resistance. Little information supports the converse, that exosomes or ...similar vesicles can suppress metastasis. We investigated the NME1 (Nm23-H1) metastasis suppressor as a candidate for metastasis suppression by extracellular vesicles. Exosomes derived from two cancer cell lines (MDA-MB-231T and MDA-MB-435), when transfected with the NME1 (Nm23-H1) metastasis suppressor, secreted exosomes with NME1 as the predominant constituent. These exosomes entered recipient tumor cells, altered their endocytic patterns in agreement with NME1 function, and suppressed in vitro tumor cell motility and migration compared to exosomes from control transfectants. Proteomic analysis of exosomes revealed multiple differentially expressed proteins that could exert biological functions. Therefore, we also prepared and investigated liposomes, empty or containing partially purified rNME1. rNME1 containing liposomes recapitulated the effects of exosomes from NME1 transfectants in vitro. In an experimental lung metastasis assay the median lung metastases per histologic section was 158 using control liposomes and 15 in the rNME1 liposome group, 90.5% lower than the control liposome group (P = 0.016). The data expand the exosome/liposome field to include metastasis suppressive functions and describe a new translational approach to prevent metastasis.
Determine whether continuous glucose monitor (CGM) metrics can provide actionable advance warning of an emergency department (ED) visit or hospitalization for hypoglycemic or hyperglycemic ...(dysglycemic) events.
Two nested case-control studies were conducted among insulin-treated diabetes patients at Kaiser Permanente, who shared their CGM data with their providers. Cases included dysglycemic events identified from ED and hospital records (2016-2021). Controls were selected using incidence density sampling. Multiple CGM metrics were calculated among patients using CGM >70% of the time, using CGM data from two lookback periods (0-7 and 8-14 days) before each event. Generalized estimating equations were specified to estimate odds ratios and C-statistics.
Among 3626 CGM users, 108 patients had 154 hypoglycemic events and 165 patients had 335 hyperglycemic events. Approximately 25% of patients had no CGM data during either lookback; these patients had >2 × the odds of a hypoglycemic event and 3-4 × the odds of a hyperglycemic event. While several metrics were strongly associated with a dysglycemic event, none had good discrimination.
Several CGM metrics were strongly associated with risk of dysglycemic events, and these can be used to identify higher risk patients. Also, patients who are not using their CGM device may be at elevated risk of adverse outcomes. However, no CGM metric or absence of CGM data had adequate discrimination to reliably provide actionable advance warning of an event and thus justify a rapid intervention.
Alzheimer's disease (AD) is associated with disrupted circadian rhythms and sleep, which are thought to reflect an impairment of internal circadian timekeeping that contribute to clinical symptoms ...and disease progression. To evaluate these hypotheses, a suitable preclinical model of AD is needed. We performed a comprehensive assessment of circadian rhythms and sleep in the APPswe/PS1dE9 (APP/PS1) mouse model using long-term in vivo electroencephalogram (EEG) monitoring and behavioral assays from 5 to 22 months of age. APP/PS1 mice were crossed with a PERIOD2::LUCIFERASE (PER2::LUC) mouse model to evaluate synchrony among peripheral circadian oscillators. The APP/PS1 mice exhibited a mild but persistent phase delay of nocturnal activity onset in 12:12h light:dark conditions, as well as a shift toward higher frequencies in the EEG power spectra compared to littermate controls. Our results suggest that APP/PS1 mice may not be the optimal preclinical model for studying the specific circadian changes associated with AD but that quantitative EEG may offer a sensitive measure of AD-associated changes in sleep quality that can be modeled in APP/PS1 mice.
•APPswe/PS1dE9 exhibited a persistent phase delay of nocturnal activity onset but no differences in most other circadian variables explored, even in aged mice with extensive amyloid pathology.•APPswe/PS1dE9 x PERIOD2::LUCIFERASE show no evidence of internal circadian misalignment.•APPswe/PS1dE9 mice exhibit a shift toward higher frequencies in the EEG power spectra during wake and nonrapid eye movement sleep (NREM).
There are currently no treatments for empathy deficits in neuropsychiatric disorders. Acute administration of the hormone oxytocin has been associated with symptomatic improvements across animal ...models and several neuropsychiatric disorders, but results of the majority of oxytocin randomised controlled trials (RCTs) of longer duration have been negative or inconclusive. This lack of efficacy of may be due to rapid habituation to oxytocin with chronic dosing. The objective of the present study is to describe the design of a phase 2 adaptive randomised controlled crossover trial of intranasal oxytocin in frontotemporal dementia (FOXY) as an efficient model for future investigations of symptomatic treatments in neuropsychiatric and neurodegenerative disorders.
Stage 1 will identify which of three dose schedules is most promising based on change in the primary outcome measure, the Neuropsychiatric Inventory apathy/indifference domain score, over 6 weeks of treatment. In stage 2, additional patients are enrolled at the most promising dose for preliminary efficacy analysis when combined with stage 1 to determine if a phase 3 trial is warranted. Objective measures include facial expression recognition, cerebrospinal fluid (CSF) oxytocin levels, and behavioural ratings of videotaped interactions.
A total of 20 patients per arm will be entered into stage 1 for a total of 60 patients. In stage 2, an additional 40 patients will be enrolled in the most promising dose arm.
The use of adaptive, crossover designs and inclusion of objective measures of change in CSF oxytocin levels and social behaviour will improve the efficiency and conclusiveness of RCTs of oxytocin and other symptomatic treatments in neuropsychiatric disorders.
ClinicalTrials.gov, NCT03260920 . Registered on August 24, 2017.
Impaired sensorimotor control, as a common feature of autism spectrum disorder (ASD), could be a driving factor to handwriting problems. This study examined the Chinese and English handwriting and ...sensorimotor skills of 15 ASD and 174 typically developing Chinese adolescents. Participants with ASD had lower writing speed and poor manual dexterity (MD) than the typically developing participants. MD was a significant mediator between ASD and handwriting speed. Ground time and airtime represent the length of time when the pen touches the paper and is held in air, respectively. Participants with ASD who had better performance in MD showed shorter ground time in Chinese handwriting and shorter airtime in English handwriting. Training for adolescents with ASD on their MD may improve their handwriting performance.
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