Pharmacogenetics of hypoglycemia associated with sulfonylurea therapy in usual clinical care.
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ABSTRACT:
SUBMITTER: Mitchell SL
PROVIDER: S-EPMC8174577 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportancePostpartum depression (PPD) affects as many as 20% of mothers, yet just 1 in 10 of these women receives evidence-based treatment. The COVID-19 pandemic has increased PPD risk, reduced treatment access, and shifted preferences toward virtual care.ObjectiveTo determine whether an online 1-day cognitive behavioral therapy (CBT)-based workshop added to treatment as usual improves PPD, anxiety, social support, mother-infant relationship quality, and infant temperament more than treatment as usual alone.Design, setting, and participantsThis randomized clinical trial included 403 women with PPD who were recruited across Ontario, Canada, during the COVID-19 pandemic (April 20 to October 4, 2020). Women with Edinburgh Postnatal Depression Scale (EPDS) scores of at least 10 who were 18 years or older and had an infant younger than 12 months were eligible.InterventionsWomen were randomly assigned to receive a live, interactive online 1-day CBT-based workshop delivered by a registered psychotherapist, psychiatrist, or clinical psychology graduate student in addition to treatment as usual (n = 202) or to receive treatment as usual and wait-listed to receive the workshop 12 weeks later (n = 201).Main outcomes and measuresThe primary outcome was change in PPD (EPDS scores) in experimental and wait list control groups 12 weeks after baseline. Secondary outcomes included maternal anxiety (7-item Generalized Anxiety Disorder Questionnaire [GAD-7]), social support (Social Provisions Scale), quality of the mother-infant relationship (Postpartum Bonding Questionnaire), and infant temperament (Infant Behavior Questionnaire-Revised Very Short Form).ResultsParticipants all identified as women with a mean (SD) age of 31.8 (4.4) years. The workshop led to significant mean (SD) reductions in EPDS scores (from 16.47 [4.41] to 11.65 [4.83]; B = -4.82; P < .001) and was associated with a higher odds of exhibiting a clinically significant decrease in EPDS scores (odds ratio, 4.15; 95% CI, 2.66-6.46). The mean (SD) GAD-7 scores decreased from 12.41 (5.12) to 7.97 (5.54) after the workshop (B = -4.44; 95% CI, -5.47 to -3.38; P < .001) and participants were more likely to experience a clinically significant change (odds ratio, 3.09; 95% CI, 1.99-4.81). Mothers also reported improvements in bonding (B = -3.22; 95% CI, -4.72 to -1.71; P < .001), infant-focused anxiety (B = -1.64; 95% CI, -2.25 to 1.00; P < .001), social support (B = 3.31; 95% CI, 1.04 to 5.57; P < .001), and positive affectivity/surgency in infants (B = 0.31; 95% CI, 0.05 to 0.56; P < .001).Conclusions and relevanceIn this randomized clinical trial, an online 1-day CBT-based workshop for PPD provides an effective, brief option for mothers, reducing PPD and anxiety as well as improving social support, the mother-infant relationship, and positive affectivity/surgency in offspring.Trial registrationClinicalTrials.gov Identifier: NCT04485000.
| S-EPMC8427485 | biostudies-literature
Project description:Drug-drug interactions causing severe hypoglycemia due to antidiabetic drugs is a major clinical and public health problem. We assessed whether sulfonylurea use with a statin or fibrate was associated with severe hypoglycemia. We conducted cohort studies of users of glyburide, glipizide, and glimepiride plus a statin or fibrate within a Medicaid population. The outcome was a validated, diagnosis-based algorithm for severe hypoglycemia. Among 592,872 persons newly exposed to a sulfonylurea+antihyperlipidemic, the incidence of severe hypoglycemia was 5.8/100 person-years. Adjusted hazard ratios (HRs) for sulfonylurea+statins were consistent with no association. Most overall HRs for sulfonylurea+fibrate were elevated, with sulfonylurea-specific adjusted HRs as large as 1.50 (95% confidence interval (CI): 1.24-1.81) for glyburide+gemfibrozil, 1.37 (95% CI: 1.11-1.69) for glipizide+gemfibrozil, and 1.63 (95% CI: 1.29-2.06) for glimepiride+fenofibrate. Concomitant therapy with a sulfonylurea and fibrate is associated with an often delayed increased rate of severe hypoglycemia.
| S-EPMC4828264 | biostudies-other
Project description:Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium's therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future.
| S-EPMC4220538 | biostudies-literature
Project description: Not available
| S-EPMC2746285 | biostudies-literature
Project description:OBJECTIVE:Test if therapy dogs reduce anxiety in emergency department (ED) patients. METHODS:In this controlled clinical trial (NCT03471429), medically stable, adult patients were approached if the physician believed that the patient had "moderate or greater anxiety." Patients were allocated on a 1:1 ratio to either 15 min exposure to a certified therapy dog and handler (dog), or usual care (control). Patient reported anxiety, pain and depression were assessed using a 0-10 scale (10 = worst). Primary outcome was change in anxiety from baseline (T0) to 30 min and 90 min after exposure to dog or control (T1 and T2 respectively); secondary outcomes were pain, depression and frequency of pain medication. RESULTS:Among 93 patients willing to participate in research, 7 had aversions to dogs, leaving 86 (92%) were willing to see a dog six others met exclusion criteria, leaving 40 patients allocated to each group (dog or control). Median and mean baseline anxiety, pain and depression scores were similar between groups. With dog exposure, median anxiety decreased significantly from T0 to T1: 6 (IQR 4-9.75) to T1: 2 (0-6) compared with 6 (4-8) to 6 (2.5-8) in controls (P<0.001, for T1, Mann-Whitney U and unpaired t-test). Dog exposure was associated with significantly lower anxiety at T2 and a significant overall treatment effect on two-way repeated measures ANOVA for anxiety, pain and depression. After exposure, 1/40 in the dog group needed pain medication, versus 7/40 in controls (P = 0.056, Fisher's exact test). CONCLUSIONS:Exposure to therapy dogs plus handlers significantly reduced anxiety in ED patients.
| S-EPMC6326463 | biostudies-literature
Project description:ImportanceThe incidence rate of neck pain is increasing worldwide, and the disease is associated with a high social burden. Manual therapy has been widely applied in the treatment of neck pain, but a high-quality, pragmatic randomized clinical trial for this treatment has not been conducted to date.ObjectiveThis study aimed to compare the effectiveness of Chuna manual therapy with that of usual care for patients with chronic neck pain.Design, setting, and participantsA multicenter, assessor-blinded, pragmatic, randomized clinical trial was conducted between October 18, 2017, and June 28, 2019. This intention-to-treat analysis included 108 patients with chronic neck pain persisting for at least 3 months; patients were recruited from 5 hospitals in Korea.InterventionsTen sessions (2 sessions per week for 5 weeks) of Chuna manual therapy or usual care (electrotherapy and oral medication) were conducted.Main outcomes and measuresThe main outcome was the difference in visual analog scale (VAS) score for chronic neck pain between baseline and 5 weeks after randomization.ResultsThis randomized clinical trial recruited 108 patients (mean [SD] age, 38.4 [9.3] years; 73 women [67.6%]). Fifty-four patients were allocated to the Chuna therapy group, and 54 received usual care. At 5 weeks after randomization, manual therapy showed statistically superior results compared with usual care in terms of pain (difference in chronic neck pain VAS, 16.8 mm; 95% CI, 10.1-23.5 mm), function (difference in Neck Disability Index, 8.6%; 95% CI, 4.2%-13.1%), and quality of life (difference in the European Quality of Life-5 Dimension 5 Levels (EQ-5D-5L) scores, -0.07 points; 95% CI, -0.11 to -0.02 points). Regarding the 1-year cumulative values measured using area under the curve analyses, superior outcomes were attained in the manual therapy group in terms of the numerical rating scale for chronic neck pain (1.3 points; 95% CI, 0.5-2.0 points), Neck Disability Index (6.7%; 95% CI, 2.5%-10.9%), Neck Pain Questionnaire (7.4%; 95% CI, 2.3%-12.6%), and EQ-5D-5L scores (-0.03 points; -0.07 to 0.00 points).Conclusions and relevanceIn this randomized clinical trial, for patients with chronic neck pain, Chuna manual therapy was more effective than usual care in terms of pain and functional recovery at 5 weeks and 1 year after randomization. These results support the need to consider recommending manual therapies as primary care treatments for chronic neck pain.Trial registrationClinicalTrials.gov identifier: NCT03294785.
| S-EPMC8280970 | biostudies-literature
Project description: Not available
| S-EPMC8832170 | biostudies-literature
Project description:BackgroundThe association between the SLCO1B1 rs4149056 variant and statin-associated muscle symptoms (SAMS) is well validated, but the clinical utility of its implementation in patient care is unknown.DesignThe Integrating Pharmacogenetics in Clinical Care (I-PICC) Study is a pseudo-cluster randomized controlled trial of SLCO1B1 genotyping among statin-naïve primary care and women's health patients across the Veteran Affairs Boston Healthcare System. Eligible patients of enrolled primary care providers are aged 40-75 and have elevated risk of cardiovascular disease by American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Patients give consent by telephone in advance of an upcoming appointment, but they are enrolled only if and when their provider co-signs an order for SLCO1B1 testing, performed on a blood sample already collected in clinical care. Enrolled patients are randomly allocated to have their providers receive results through the electronic health record at baseline (PGx + arm) versus after 12 months (PGx- arm). The primary outcome is the change in low-density lipoprotein cholesterol (LDL-C) after one year. Secondary outcomes are concordance with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for simvastatin prescribing, concordance with ACC/AHA guidelines for statin use, and incidence of SAMS. With 408 patients, the study has >80% power to exclude a between-group LDL-C difference of 10 mg/dL (non-inferiority design) and to detect between-group differences of 15% in CPIC guideline concordance (superiority design).ConclusionThe outcomes of the I-PICC Study will inform the clinical utility of preemptive SLCO1B1 testing in the routine practice of medicine, including its proposed benefits and unforeseen risks.
| S-EPMC8119226 | biostudies-literature
Project description:Recent advances have provided unprecedented opportunities to identify prognostic and predictive markers of efficacy of cancer therapy. Genetic markers can be used to exclude patients who will not benefit from therapy, exclude patients at high risk of severe toxicity and adjust dosing. Genomic approaches for marker discovery now include genome-wide association studies and tumor DNA sequencing. The challenge is now to select markers for which there is enough evidence to transition them to the clinic. The hurdles include the inherent low frequency of many of these markers, the lengthy validation process through trials, as well as legislative and economic hurdles. Attempts to answer questions about certain markers more quickly have led to an increased popularity of trials with enrichment design, especially in light of the dramatic phase I results seen in recent months. Personalized medicine in oncology is a step closer to reality.
| S-EPMC3858908 | biostudies-literature
Project description:The ATP-sensitive potassium channel (K(ATP)) regulates insulin secretion in pancreatic beta cells. Loss of functional K(ATP) channels because of mutations in either the SUR1 or Kir6.2 channel subunit causes persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We investigated the molecular mechanism by which a single phenylalanine deletion in SUR1 (DeltaF1388) causes PHHI. Previous studies have shown that coexpression of DeltaF1388 SUR1 with Kir6.2 results in no channel activity. We demonstrate here that the lack of functional expression is due to failure of the mutant channel to traffic to the cell surface. Trafficking of K(ATP) channels requires that the endoplasmic reticulum-retention signal, RKR, present in both SUR1 and Kir6.2, be shielded during channel assembly. To ask whether DeltaF1388 SUR1 forms functional channels with Kir6.2, we inactivated the RKR signal in DeltaF1388 SUR1 by mutation to AAA (DeltaF1388 SUR1(AAA)). Inactivation of similar endoplasmic reticulum-retention signals in the cystic fibrosis transmembrane conductance regulator has been shown to partially overcome the trafficking defect of a cystic fibrosis transmembrane conductance regulator mutation, DeltaF508. We found that coexpression of DeltaF1388 SUR1(AAA) with Kir6.2 led to partial surface expression of the mutant channel. Moreover, mutant channels were active. Compared with wild-type channels, the mutant channels have reduced ATP sensitivity and do not respond to stimulation by MgADP or diazoxide. The RKR --> AAA mutation alone has no effect on channel properties. Our results establish defective trafficking of K(ATP) channels as a molecular basis of PHHI and show that F1388 in SUR1 is critical for normal trafficking and function of K(ATP) channels.
| S-EPMC30234 | biostudies-literature