In this study involving 2103 men with elevated PSA levels, the use of both MRI-targeted and 12-core systematic biopsies was more effective at detecting clinically significant prostate cancers than ...either biopsy method alone.
Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health ...problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10−16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Maternal smoking during pregnancy, especially when sustained, leads to numerous adverse health outcomes in offspring. Pregnant women disproportionately underreport smoking and smokers tend to have ...lower follow-up rates to repeat questionnaires. Missing, incomplete, or inaccurate data on presence and duration of smoking in pregnancy impairs identification of novel health effects and limits adjustment for smoking in studies of other pregnancy exposures. An objective biomarker in newborns of maternal smoking during pregnancy would be valuable.
We developed a biomarker of sustained maternal smoking in pregnancy using common DNA methylation platforms.
Using a dimension reduction method, we developed and tested a numeric score in newborns to reflect sustained maternal smoking in pregnancy from data on cotinine, a short-term smoking biomarker measured mid-pregnancy, and Illumina450K cord blood DNA methylation from newborns in the Norwegian Mother and Child Cohort Study (MoBa).
This score reliably predicted smoking status in the training set (
= 1,057; accuracy = 96%, sensitivity = 80%, specificity = 98%). Sensitivity (58%) was predictably lower in the much smaller test set (
= 221), but accuracy (91%) and specificity (97%) remained high. Reduced birth weight, a well-known effect of maternal smoking, was as strongly related to the score as to cotinine. A three-site score had lower, but acceptable, performance (accuracy
= 82%, accuracy
= 83%).
Our smoking methylation score represents a promising novel biomarker of sustained maternal smoking during pregnancy easily calculated with Illumina450K or IlluminaEPIC data. It may help identify novel health impacts and improve adjustment for smoking when studying other risk factors with more subtle effects.
Objective: Despite the heightened urgency of the current prescription opioid crisis, few psychotherapies have been evaluated for chronic pain patients receiving long-term opioid analgesics. Current ...psychological pain treatments focus primarily on ameliorating negative affective processes, yet basic science suggests that risk for opioid misuse is linked with a dearth of positive affect. Interventions that modulate positive psychological processes may produce therapeutic benefits among patients with opioid-treated chronic pain. The aim of this study was to conduct a theory-driven mechanistic analysis of proximal outcome data from a Stage 2 randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE), an integrative intervention designed to promote positive psychological health. Method: Patients with opioid-treated chronic pain (N = 95; age = 56.8 ± 11.7; 66% female) were randomized to 8 weeks of therapist-led MORE or support group (SG) interventions. A latent positive psychological health variable comprised of positive affect, meaning in life, and self-transcendence measures was examined as a mediator of the effect of MORE on changes in pain severity at posttreatment and opioid misuse risk by 3-month follow-up. Results: Participants in MORE reported significantly greater reductions in pain severity by posttreatment (p = .03) and opioid misuse risk by 3-month follow-up (p = .03) and significantly greater increases in positive psychological health (p < .001) than SG participants. Increases in positive psychological health mediated the effect of MORE on pain severity by posttreatment (p = .048), which in turn predicted decreases in opioid misuse risk by follow-up (p = .02). Conclusions: Targeting positive psychological mechanisms via MORE and other psychological interventions may reduce opioid misuse risk among chronic pain patients receiving long-term opioid therapy.
What is the public health significance of this article?
Current pharmacological and psychological pain treatments focus largely on reducing negative emotional reactions to pain. This study suggests that a new psychological treatment, Mindfulness-Oriented Recovery Enhancement, decreases risk for prescription opioid misuse among patients with chronic pain by increasing positive psychological factors like positive emotions and meaning in life.
Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) ...or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and EM, and examined how conformation regulated interactions with AMPA-type and NMDA-type glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration. PSD95 associated with AMPARs (via transmembrane AMPAR regulatory protein subunits) or NMDARs via glutamate ionotropic receptor NMDA-type subunit 2B (GluN2B) subunits only in its palmitoylated and extended conformation. In contrast, in its extended conformation, SAP97 associates with NMDARs, but not with AMPARs. Within PSDs, PSD95 and SAP97 were largely in the extended conformation, but had different orientations. PSD95 oriented perpendicular to the PSD membrane, with its palmitoylated, N-terminal domain at the membrane. SAP97 oriented parallel to the PSD membrane, likely as a dimer through interactions of its N-terminal L27 domain. Changing PSD95 palmitoylation in PSDs altered PSD95 and AMPAR levels but did not affect NMDAR levels. These results indicate that in PSDs, PSD95 palmitoylation, conformation, and its interactions are dynamic when associated with AMPARs and more stable when associated with NMDARs. Altogether, our results are consistent with differential regulation of PSD95 palmitoylation in PSDs resulting from the clustering of palmitoylating and depalmitoylating enzymes into AMPAR nanodomains segregated away from NMDAR nanodomains.
Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 ...variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose.
A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5-7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network
examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021
to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.
IMPORTANCE: Successful treatment of opioid misuse among people with chronic pain has proven elusive. Guidelines recommend nonopioid therapies, but the efficacy of mindfulness-based interventions for ...opioid misuse is uncertain. OBJECTIVE: To evaluate the efficacy of Mindfulness-Oriented Recovery Enhancement (MORE) for the reduction of opioid misuse and chronic pain. DESIGN, SETTING, AND PARTICIPANTS: This interviewer-blinded randomized clinical trial enrolled patients from primary care clinics in Utah between January 4, 2016, and January 16, 2020. The study included 250 adults with chronic pain receiving long-term opioid therapy who were misusing opioid medications. INTERVENTIONS: Treatment with MORE (comprising training in mindfulness, reappraisal, and savoring positive experiences) or supportive group psychotherapy (control condition) across 8 weekly 2-hour group sessions. MAIN OUTCOMES AND MEASURES: Primary outcomes were (1) opioid misuse assessed by the Drug Misuse Index (self-report, interview, and urine screen) and (2) pain severity and pain-related functional interference, assessed by subscale scores on the Brief Pain Inventory through 9 months of follow-up. Secondary outcomes were opioid dose, emotional distress, and ecological momentary assessments of opioid craving. The minimum intervention dose was defined as 4 or more completed sessions of MORE or supportive group psychotherapy. RESULTS: Among 250 participants (159 women 63.6%; mean SD age, 51.8 11.9 years), 129 were randomized to the MORE group and 121 to the supportive psychotherapy group. Overall, 17 participants (6.8%) were Hispanic or Latino, 218 (87.2%) were White, and 15 (6.0%) were of other races and/or ethnicities (2 American Indian, 3 Asian, 1 Black, 2 Pacific Islander, and 7 did not specify). At baseline, the mean duration of pain was 14.7 years (range, 1-60 years), and the mean (SD) morphine-equivalent opioid dose was 101.0 (266.3) mg (IQR, 16.0-90.0 mg). A total of 203 participants (81.2%) received the minimum intervention dose (mean SD, 5.7 2.2 sessions); at 9 months, 92 of 250 participants (36.8%) discontinued the study. The overall odds ratio for reduction in opioid misuse through the 9-month follow-up period in the MORE group compared with the supportive psychotherapy group was 2.06 (95% CI, 1.17-3.61; P = .01). At 9 months, 36 of 80 participants (45.0%) in the MORE group were no longer misusing opioids compared with 19 of 78 participants (24.4%) in the supportive psychotherapy group. Mixed models demonstrated that MORE was superior to supportive psychotherapy through 9 months of follow-up for pain severity (between-group effect: 0.49; 95% CI, 0.17-0.81; P = .003) and pain-related functional interference (between-group effect: 1.07; 95% CI, 0.64-1.50; P < .001). Participants in the MORE group reduced their opioid dose to a greater extent than those in the supportive psychotherapy group. The MORE group also had lower emotional distress and opioid craving. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, among adult participants in a primary care setting, the MORE intervention led to sustained improvements in opioid misuse and chronic pain symptoms and reductions in opioid dosing, emotional distress, and opioid craving compared with supportive group psychotherapy. Despite attrition caused by the COVID-19 pandemic and the vulnerability of the sample, MORE appeared to be efficacious for reducing opioid misuse among adults with chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02602535
AbstractObjectiveTo estimate the effectiveness of mRNA vaccines against moderate and severe covid-19 in adults by time since second, third, or fourth doses, and by age and immunocompromised ...status.DesignTest negative case-control study.SettingHospitals, emergency departments, and urgent care clinics in 10 US states, 17 January 2021 to 12 July 2022.Participants893 461 adults (≥18 years) admitted to one of 261 hospitals or to one of 272 emergency department or 119 urgent care centers for covid-like illness tested for SARS-CoV-2.Main outcome measuresThe main outcome was waning of vaccine effectiveness with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine during the omicron and delta periods, and the period before delta was dominant using logistic regression conditioned on calendar week and geographic area while adjusting for age, race, ethnicity, local virus circulation, immunocompromised status, and likelihood of being vaccinated.Results45 903 people admitted to hospital with covid-19 (cases) were compared with 213 103 people with covid-like illness who tested negative for SARS-CoV-2 (controls), and 103 287 people admitted to emergency department or urgent care with covid-19 (cases) were compared with 531 168 people with covid-like illness who tested negative for SARS-CoV-2. In the omicron period, vaccine effectiveness against covid-19 requiring admission to hospital was 89% (95% confidence interval 88% to 90%) within two months after dose 3 but waned to 66% (63% to 68%) by four to five months. Vaccine effectiveness of three doses against emergency department or urgent care visits was 83% (82% to 84%) initially but waned to 46% (44% to 49%) by four to five months. Waning was evident in all subgroups, including young adults and individuals who were not immunocompromised; although waning was morein people who were immunocompromised. Vaccine effectiveness increased among most groups after a fourth dose in whom this booster was recommended.ConclusionsEffectiveness of mRNA vaccines against moderate and severe covid-19 waned with time after vaccination. The findings support recommendations for a booster dose after a primary series and consideration of additional booster doses.
Background:Health disparities between Native Americans and white Americans persist due to a variety of factors, including colonization, poverty, and racism. Racist interpersonal interactions between ...nurses and other healthcare providers and tribal members may also contribute to reluctance among Native Americans to engage with Western healthcare systems. Purpose: The purpose of this study was to better understand the healthcare experiences of members of a state-recognized Gulf Coast tribe. Methods: In partnership with a community advisory board, 31 semistructured interviews were conducted, transcribed, and analyzed utilizing a qualitative description approach. Results: All participants mentioned their preferences, views about, or experiences of using natural or traditional medicine approaches (referenced 65 times). Emergent themes include (a) preference for and use of traditional medicine; (b) resistance to western healthcare systems; (c) preference for holistic approaches to health; and (d) negative provider interpersonal interactions contributing to reluctance in seeking care. Conclusion: These findings suggest that integrating a holistic conceptualization of health and traditional medicine practices into Western healthcare settings would benefit Native Americans.
Native American/American Indian (NA/AI) people have higher rates of chronic disease, including substance use and mental health disorders, compared to White Americans. Though pharmaceuticals can be ...helpful in addressing many chronic healthcare conditions, many people do not take medications as prescribed. NA/AI identity has been found to be associated with lower rates of medication adherence compared to White Americans.
The purpose of this study is to better understand NA/AI women's perceptions, beliefs, and experiences related to medication.
Thirty-one semi-structured interviews were conducted with NA/AI women from a state-recognized tribe located in the Gulf South. Interviews were transcribed and analyzed using a qualitative description approach.
Eighteen women discussed their experiences using medications when asked about their healthcare experiences. Participants identified the following themes in their discussion of medication: (a) Cost of Medication as a Barrier; (b) Negative Side Effects of Western Medication; (c) Fear of Resistance and Dependence; (d) Preference for Traditional Medicine or None; and (e) Lack of Communication around Medications from Providers.
Our findings support the growing call for cultural safety within medical settings and integrating NA/AI conceptualizations of health and well-being and traditional practices into western healthcare settings to better support NA/AI people.
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