NDRGs in Breast Cancer: A Review and In Silico Analysis.

The N-myc downstream regulated gene family (NDRGs) includes four members: NDRG1, NDRG2, NDRG3, and NDRG4. These members exhibit 53-65% amino acid identity. The role of NDRGs in tumor growth and metastasis appears to be tumor- and context-dependent. While many studies have reported that these family members have tumor suppressive roles, recent studies have demonstrated that NDRGs, particularly NDRG1 and NDRG2, function as oncogenes, promoting tumor growth and metastasis. Additionally, NDRGs are involved in regulating different signaling pathways and exhibit diverse cellular functions in breast cancers. In this review, we comprehensively outline the oncogenic and tumor suppressor roles of the NDRG family members in breast cancer, examining evidence from in vitro and in vivo breast cancer models as well as tumor tissues from breast cancer patients. We also present analyses of publicly available genomic and transcriptomic data from multiple independent cohorts of breast cancer patients.

An individual segmented trajectory approach for identifying opioid use patterns using longitudinal dispensing data.

PURPOSE: The aim of this study is to use electronic opioid dispensing data to develop an individual segmented trajectory approach for identifying opioid use patterns. The resulting opioid use patterns can be used for examining the association between opioid use and drug overdose. METHODS: We retrospectively assembled a cohort of members on long-term opioid therapy (LTOT) between January 1, 2006 and June 30, 2019 who were 18 years and older and enrolled in one of three health care systems in the US. We have developed an individual segmented trajectory analysis for identifying various opioid use patterns by scanning over the follow-up and finding distinct opioid use patterns based on variability measured with coefficient of variation and trends of milligram morphine equivalents levels. RESULTS: Among 31, 865 members who were on LTOT between January 1, 2006 and June 30, 2019, 58.3% were female, and the average age was 55.4 years (STD = 15.4). The study population had 152 557 person-years of follow-up, with an average follow-up of 4.4 years per enrollment per person (STD = 3.4). This novel approach identified up to 13 distinct patterns including 88 756 episodes of "stable" pattern (42.1%) with an average follow-up of 11.2 months, 29 140 episodes of "increasing" pattern (13.8%) with an average follow-up of 6.0 months, 13 201 episodes of ≤10% dose reduction (6.3%) with an average follow-up of 10.4 months, 7286 episodes of 11%-20% dose reduction (3.5%) with an average follow-up of 5.3 months, 4457 episodes of 21%-30% dose reduction (2.1%) with an average follow-up of 4.0 months, and 9903 episodes of >30% dose reduction (4.7%) with an average follow-up of 2.6 months. CONCLUSIONS: A novel approach was developed to identify 13 distinct opioid use patterns using each individual's longitudinal dispensing data and these patterns can be used in examining overdose risk during the time that these patterns are ongoing.

Associations between Missed Colonoscopy Appointments and Multiple Prior Adherence Behaviors in an Integrated Healthcare System: An Observational Study.

BACKGROUND: Missed colonoscopy appointments delay screening and treatment for gastrointestinal disorders. Prior nonadherence with other care components may be associated with missed colonoscopy appointments. OBJECTIVE: To assess variability in prior adherence behaviors and their association with missed colonoscopy appointments. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients scheduled for colonoscopy in an integrated healthcare system between January 2016 and December 2018. MAIN MEASURES: Prior adherence behaviors included: any missed outpatient appointment in the previous year; any missed gastroenterology clinic or colonoscopy appointment in the previous 2 years; and not obtaining a bowel preparation kit pre-colonoscopy. Other sociodemographic, clinical, and system characteristics were included in a multivariable model to identify independent associations between prior adherence behaviors and missed colonoscopy appointments. KEY RESULTS: The median age of the 57,590 participants was 61 years; 52.8% were female and 73.4% were white. Of 77,684 colonoscopy appointments, 3,237 (4.2%) were missed. Individuals who missed colonoscopy appointments were more likely to have missed a previous primary care appointment (62.5% vs. 38.4%), a prior gastroenterology appointment (18.4% vs. 4.7%) or not to have picked up a bowel preparation kit (42.4% vs. 17.2%), all p < 0.001. Correlations between the three adherence measures were weak (phi < 0.26). The rate of missed colonoscopy appointments increased from 1.8/100 among individuals who were adherent with all three prior care components to 24.6/100 among those who were nonadherent with all three care components. All adherence variables remained independently associated with nonadherence with colonoscopy in a multivariable model that included other covariates; adjusted odds ratios (with 95% confidence intervals) were 1.6 (1.5-1.8) for outpatient appointments, 1.9 (1.7-2.1) for gastroenterology appointments, and 3.1 (2.9-3.4) for adherence with bowel preparation kits, respectively. CONCLUSIONS: Three prior adherence behaviors were independently associated with missed colonoscopy appointments. Studies to predict adherence should use multiple, complementary measures of prior adherence when available.

Association of initial opioid prescription duration and an opioid refill by pain diagnosis: Evidence from outpatient settings in ten US health systems.

OBJECTIVE: The Centers for Disease Control and Prevention's 2022 Clinical Practice Guideline for Prescribing Opioids for Pain cautioned that inflexible opioid prescription duration limits may harm patients. Information about the relationship between initial opioid prescription duration and a subsequent refill could inform prescribing policies and practices to optimize patient outcomes. We assessed the association between initial opioid duration and an opioid refill prescription. METHODS: We conducted a retrospective cohort study of adults ≥19 years of age in 10 US health systems between 2013 and 2018 from outpatient care with a diagnosis for back pain without radiculopathy, back pain with radiculopathy, neck pain, joint pain, tendonitis/bursitis, mild musculoskeletal pain, severe musculoskeletal pain, urinary calculus, or headache. Generalized additive models were used to estimate the association between opioid days' supply and a refill prescription. RESULTS: Overall, 220,797 patients were prescribed opioid analgesics upon an outpatient visit for pain. Nearly a quarter (23.5%) of the cohort received an opioid refill prescription during follow-up. The likelihood of a refill generally increased with initial duration for most pain diagnoses. About 1 to 3 fewer patients would receive a refill within 3 months for every 100 patients initially prescribed 3 vs. 7 days of opioids for most pain diagnoses. The lowest likelihood of refill was for a 1-day supply for all pain diagnoses, except for severe musculoskeletal pain (9 days' supply) and headache (3-4 days' supply). CONCLUSIONS: Long-term prescription opioid use increased modestly with initial opioid prescription duration for most but not all pain diagnoses examined.

Association Between Opioid Dose Reduction Rates and Overdose Among Patients Prescribed Long-Term Opioid Therapy.

BACKGROUND: Tapering long-term opioid therapy is an increasingly common practice, yet rapid opioid dose reductions may increase the risk of overdose. The objective of this study was to compare overdose risk following opioid dose reduction rates of ≤10%, 11% to 20%, 21% to 30%, and >30% per month to stable dosing. METHODS: We conducted a retrospective cohort study in three health systems in Colorado and Wisconsin. Participants were patients ≥18 years of age prescribed long-term opioid therapy between January 1, 2006, and June 30, 2019. Five opioid dosing patterns and drug overdoses (fatal and nonfatal) were identified using electronic health records, pharmacy records, and the National Death Index. Cox proportional hazard regression was conducted on a propensity score-weighted cohort to estimate adjusted hazard ratios (aHRs) for follow-up periods of 1, 3, 6, 9, and 12 months after a dose reduction. RESULTS: In a cohort of 17 540 patients receiving long-term opioid therapy, 42.7% of patients experienced a dose reduction. Relative to stable dosing, a dose reduction rate of >30% was associated with an increased risk of overdose and the aHR estimates decreased as the follow-up increased; the aHRs for the 1-, 6- and 12-month follow-ups were 5.33 (95% CI, 1.98-14.34), 1.81 (95% CI,1.08-3.03), and 1.49 (95% CI, 0.97-2.27), respectively. The slower tapering rates were not associated with overdose risk. CONCLUSIONS: Patients receiving long-term opioid therapy exposed to dose reduction rates of >30% per month had increased overdose risk relative to patients exposed to stable dosing. Results support the use of slow dose reductions to minimize the risk of overdose.

Update of a Multivariable Opioid Overdose Risk Prediction Model to Enhance Clinical Care for Long-term Opioid Therapy Patients.

BACKGROUND: Clinical opioid overdose risk prediction models can be useful tools to reduce the risk of overdose in patients prescribed long-term opioid therapy (LTOT). However, evolving overdose risk environments and clinical practices in addition to potential harmful model misapplications require careful assessment prior to widespread implementation into clinical care. Models may need to be tailored to meet local clinical operational needs and intended applications in practice. OBJECTIVE: To update and validate an existing opioid overdose risk model, the Kaiser Permanente Colorado Opioid Overdose (KPCOOR) Model, in patients prescribed LTOT for implementation in clinical care. DESIGN, SETTING, AND PARTICIPANTS: The retrospective cohort study consisted of 33, 625 patients prescribed LTOT between January 2015 and June 2019 at Kaiser Permanente Colorado, with follow-up through June 2021. MAIN MEASURES: The outcome consisted of fatal opioid overdoses identified from vital records and non-fatal opioid overdoses from emergency department and inpatient settings. Predictors included demographics, medication dispensings, substance use disorder history, mental health history, and medical diagnoses. Cox proportional hazards regressions were used to model 2-year overdose risk. KEY RESULTS: During follow-up, 65 incident opioid overdoses were observed (111.4 overdoses per 100,000 person-years) in the study cohort, of which 11 were fatal. The optimal risk model needed to risk-stratify patients and to be easily interpreted by clinicians. The original 5-variable model re-validated on the new study cohort had a bootstrap-corrected C-statistic of 0.73 (95% CI, 0.64-0.85) compared to a C-statistic of 0.80 (95% CI, 0.70-0.88) in the updated model and 0.77 (95% CI, 0.66-0.87) in the final adapted 7-variable model, which was also well-calibrated. CONCLUSIONS: Updating and adapting predictors for opioid overdose in the KPCOOR Model with input from clinical partners resulted in a parsimonious and clinically relevant model that was poised for integration in clinical care.

Ensuring equitable access to guideline-based asthma care across the lifespan: Tips and future directions to the successful implementation of the new NAEPP 2020 guidelines, a Work Group Report of the AAAAI Asthma, Cough, Diagnosis, and Treatment Committee.

The most recent recommendations from the 2020 National Asthma Education and Prevention Program Update and Global Initiative for Asthma 2021 guide evidence-based clinical decision making. However, given the present state of health disparities by age, income, and race, the equitable implementation and dissemination of these guidelines will be unlikely without further guidance. This work group report reviews the current state of the new asthma guideline implementation; presents updated evidence-based therapeutic options with attention to specific patient populations; and addresses barriers to the implementation of these guidelines in minoritized, historically marginalized, and underresourced communities. Allergists and immunologists can use practical ways to accomplish the goals of improved asthma care access and advanced asthma care across the life span, with specific considerations to historically marginalized populations. Modifiable barriers to guideline implementation include financial barriers, environmental factors, and allergy subspecialty access and care coordination. Various programs to improve access to guideline-based asthma care include community programs, school-based asthma programs, and digital health solutions, with an emphasis on reducing disparities by race.

The association between buprenorphine treatment duration and mortality: a multi-site cohort study of people who discontinued treatment.

BACKGROUND AND AIMS: Buprenorphine is an effective medication for opioid use disorder that reduces mortality; however, many patients are not retained in buprenorphine treatment, and an optimal length of treatment after which patients can safely discontinue treatment has not been identified. This study measured the association between buprenorphine treatment duration and all-cause mortality among patients who discontinued treatment. Secondary objectives were to measure the association between treatment duration and drug overdose and opioid-related overdoses. DESIGN: Multi-site cohort study. SETTING: Eight US health systems. PARTICIPANTS: Patients who initiated and discontinued buprenorphine treatment between 1 January 2012 and 31 December 2018 (n = 6550). Outcomes occurring after patients discontinued buprenorphine treatment were compared between patients who initiated and discontinued treatment after 8-30, 31-90, 91-180, 181-365 and > 365 days. MEASUREMENTS: Covariate data were obtained from electronic health records (EHRs). Mortality outcomes were derived from EHRs and state vital statistics. Non-fatal opioid and drug overdoses were obtained from diagnostic codes. Four sites provided cause-of-death data to identify fatal drug and opioid-related overdoses. Adjusted frailty regression was conducted on a propensity-weighted cohort to assess associations between duration of the final treatment episode and outcomes. FINDINGS: The mortality rate after buprenorphine treatment was 1.82 per 100 person-years (n = 191 deaths). In regression analyses with > 365 days as the reference group, treatment duration was not associated with all-cause mortality and drug overdose (P > 0.05 for both). However, compared with > 365 days of treatment, 91-180 days of treatment was associated with increased opioid overdose risk (hazard ratio = 2.94, 95% confidence interval = 1.11-7.79). CONCLUSIONS: Among patients who discontinue buprenorphine treatment, there appears to be no treatment duration period associated with a reduced risk for all-cause mortality. Patients who discontinue buprenorphine treatment after 91-180 days appear to be at heightened risk for opioid overdose compared with patients who discontinue after > 365 days of treatment.

Opioid Dose Trajectories and Associations With Mortality, Opioid Use Disorder, Continued Opioid Therapy, and Health Plan Disenrollment.

Importance: Uncertainty remains about the longer-term benefits and harms of different opioid management strategies, such as tapering and dose escalation. For instance, opioid tapering could help patients reduce opioid exposure to prevent opioid use disorder, but patients may also seek care elsewhere and engage in nonprescribed opioid use. Objective: To evaluate the association between opioid dose trajectories observed in practice and patient outcomes. Design, Setting, and Participants: This retrospective cohort study was conducted in 3 health systems in Colorado and Wisconsin. The study population included patients receiving long-term opioid therapy between 50 and 200 morphine milligram equivalents between August 1, 2014, and July 31, 2017. Follow-up ended on December 31, 2019. Data were analyzed from January 2020 to August 2022. Exposures: Group-based trajectory modeling identified 5 dosing trajectories over 1 year: 1 decreasing, 1 high-dose increasing, and 3 stable. Main Outcomes and Measures: Primary outcomes assessed after the trajectory period were 1-year all-cause mortality, incident opioid use disorder, continued opioid therapy at 1 year, and health plan disenrollment. Associations were tested using Cox proportional hazards regression and log-binomial models, adjusting for baseline covariates. Results: A total of 3913 patients (mean [SD] age, 59.2 [14.4] years; 2767 White non-Hispanic [70.7%]; 2237 female patients [57.2%]) were included in the study. Compared with stable trajectories, the decreasing dose trajectory was negatively associated with opioid use disorder (adjusted hazard ratio [aHR], 0.40; 95% CI, 0.29-0.55) and continued opioid therapy (site 1: adjusted relative risk [aRR], 0.39; 95% CI, 0.34-0.44), but was positively associated with health plan disenrollment (aHR, 1.66; 95% CI, 1.24-2.22). The decreasing trajectory was not associated with mortality (aHR, 1.28; 95% CI, 0.87-1.86). In contrast, the high-dose increasing trajectory was positively associated with mortality (aHR, 2.19; 95% CI, 1.44-3.32) and opioid use disorder (aHR, 1.81; 95% CI, 1.39-2.37) but was not associated with disenrollment (aHR, 0.90; 95% CI, 0.56-1.42) or continued opioid therapy (site 1: aRR, 0.98; 95% CI, 0.94-1.03). Conclusions and Relevance: In this cohort study, decreasing opioid dose was associated with reduced risk of opioid use disorder and continued opioid therapy but increased risk of disenrollment compared with stable dosing, whereas the high-dose increasing trajectory was associated with an increased risk of mortality and opioid use disorder. These findings can inform opioid management decision-making.

Successful treatment of neurocysticercosis with albendazole desensitization.

BACKGROUND: Neurocysticercosis is a growing public health problem in the United States. Albendazole is a mainstay of medical therapy for neurocysticercosis, and here we present a case of hypersensitivity to albendazole leading to life-threatening disease progression. OBJECTIVE: To report the first successful albendazole desensitization protocol. METHODS: An oral albendazole 12-step desensitization protocol was developed, starting with 0.001 mg and progressing at 15 minutes intervals. Dosage for each subsequent step was as follows: 0.003 mg, 0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, 300mg. RESULTS: The patient rapidly improved from a symptomatic standpoint, and repeat MRI showed a dramatic improvement in lesions. CONCLUSIONS: This successful desensitization protocol to albendazole can be of value to other patients with history suggestive of IgE-mediated allergy needing treatment for parasitic infections.

Restrictive opioid prescribing policies and evolving risk environments: A qualitative study of the perspectives of patients who experienced an accidental opioid overdose.

BACKGROUND: Despite policy efforts to prevent overdose, accidental overdoses among individuals prescribed opioids continue to occur. Guided by Rhodes' Risk Environment Framework, we examined the unintended consequences of restrictive policies by identifying macro policy and micro-level contextual factors that patients prescribed opioids for pain identified as contributing to overdose events. METHODS: Semi-structured interviews were conducted with 31 patients prescribed opioids who experienced an accidental opioid overdose between April 2017 and June 2019 in two health systems. RESULTS: We identified three interrelated factors that emerged within an evolving risk environment and may have increased patients' vulnerability for an accidental opioid overdose: desperation from persistent pain and comorbidities; limited knowledge about opioid medication safety and effectiveness; and restrictive opioid prescribing policies that exacerbated stigma, fear and mistrust and prevented open patient-clinician communication. When experiencing persistent pain, patients took matters into their own hands by taking more medications or in different intervals than prescribed, mixing them with other substances, or using illicitly obtained opioids. CONCLUSION: For some patients, macro-level policies and guidelines designed to reduce opioid overdoses by restricting opioid supply may have paradoxically created a micro-level risk environment that contributed to overdose events in a subset of patients.

The association of criminal justice supervision setting with overdose mortality: a longitudinal cohort study.

BACKGROUND AND AIMS: Despite the high prevalence of substance use among people in the US criminal justice system, little is known about the incidence of overdose mortality by use patterns, drug convictions and supervision setting. We examined the associations between these characteristics and overdose mortality. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Individuals sentenced to prison, jail, probation or jail plus probation for a felony conviction in Michigan, USA from 2003 to 2006. MEASUREMENTS: Using the National Death Index, we assessed overdose mortality to December 2012. We calculated overdose mortality rates by pre-sentence opioid use, drug convictions and supervision setting. Multivariable analyses were conducted using competing risks regression with time-varying covariates. FINDINGS: Among 140 266 individuals followed over a mean of 7.84 years [standard deviation (SD) = 1.52], 14.9% of the 1131 deaths were due to overdose (102.8 per 100 000 person-years). Over the follow-up, more than half of overdose deaths occurred in the community (57.7%), nearly a third (28.8%) on probation and 12.8% on parole. The adjusted risk of overdose death was lower on probation [hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.60, 0.85] than in the community without probation or parole (HR = 1.00) but not significantly different on parole (HR = 1.13, 95% CI = 0.87, 1.47). Pre-sentence daily opioid use (HR = 3.54, 95% CI = 3.24, 3.87) was associated with an increased risk. Drug possession (HR = 1.11, 95% CI = 0.93, 1.31) and delivery convictions (HR = 0.92, 95% CI = 0.77, 1.09) were not significantly associated with overdose mortality. CONCLUSIONS: Based on the absolute or relative risk, parole, probation and community settings are appropriate settings for enhanced overdose prevention interventions. Ensuring that individuals with pre-sentence opioid use have access to harm reduction and drug treatment services may help to prevent overdose among people involved with the criminal justice system.

Author Correction: A natural experiment study of the effects of imprisonment on violence in the community.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Breath carbonyl levels in a human population of seven hundred participants.

Oxidative stress is associated with numerous health conditions and disorders, and aldehydes are known biomarkers of oxidative stress that can be non-invasively measured in exhaled human breath. Few studies report breath aldehyde levels in human populations, and none claim participant numbers in the hundreds or more. Further, the breath community must first define the existing aldehyde concentration variance in a normal population to understand when these levels are significantly perturbed by exogenous stressors or health conditions. In this study, we collected breath samples from 692 participants and quantified C4-C10 straight chain aldehyde levels. C9 aldehyde was the most abundant in breath, followed by C6. C4 and C5 appear to have bimodal distributions. Post hoc, we mined our dataset for other breath carbonyls captured by our assay, which involves elution of breath samples onto a solid phase extraction cartridge, derivatization and liquid chromatography-quadrupole time of flight mass spectrometry (LC-qTOF). We found a total of 21 additional derivatized compounds. Using self-reported demographic factors from our participants, we found no correlation between these breath carbonyls and age, gender, body mass index (BMI), ethnicity or smoking habit (tobacco and marijuana). This work was preceded by a small confounders study, which was intended to refine our breath collection procedure. We found that breath aldehyde levels can be affected by participants' using scented hygiene products such as lotions and mouthwashes, while collecting consecutive breath samples, rinsing the mouth with water, and filtering inspired air did not have an effect. Using these parameters to guide our sampling, subjects were instructed to avoid the prior conditions to provide a breath sample for our study.

Association of Opioids Prescribed to Family Members With Opioid Overdose Among Adolescents and Young Adults.

Importance: Family members are cited as a common source of prescription opioids used for nonmedical reasons. However, the overdose risk associated with exposure to opioids prescribed to family members among adolescents and young adults is not well established. Objective: To assess the association of opioids prescribed to family members with pharmaceutical opioid overdose among youth. Design, Setting, and Participants: This cohort study included 45 145 family units with a total of 72 040 adolescents and young adults aged 11 to 26 years enrolled in a Kaiser Permanente Colorado health plan in 2006 and observed through June 2018. Exposures: Opioid prescriptions and dosage dispensed to family members and youth in the past month. Main Outcomes and Measures: Fatal pharmaceutical opioid overdoses identified in vital records and nonfatal pharmaceutical opioid overdoses identified in emergency department and inpatient settings. Time to first overdose was modeled using Cox regression. Results: The study population consisted of 72 040 adolescents and young adults (mean [SD] age across follow-up, 19.3 [3.7] years; 36 646 [50.9%] girls and women) nested in 45 145 family units. Youth were more commonly exposed to prescription opioids dispensed to a family member than through their own prescriptions. During follow-up, 26 284 youth (36.5%) filled at least 1 opioid prescription, and 47 461 youth (65.9%) had at least 1 family member with a prescription. Exposure to family members with opioid prescriptions in the past month was associated with increased risk of pharmaceutical opioid overdose (adjusted hazard ratio [aHR], 2.17; 95% CI, 1.24-3.79) independent of opioids prescribed to youth (aHR, 6.62; 95% CI, 3.39-12.91). Concurrent exposure to opioid prescriptions from youth and family members was associated with substantially increased overdose risk (aHR, 12.99; 95% CI, 5.08-33.25). High dosage of total morphine milligram equivalents (MME) prescribed to family members in the past month was associated with youth overdose (0 MME vs >0 to <200 MME: aHR, 1.39; 95% CI, 0.51-3.81; 0 MME vs 200 to <600 MME: aHR, 1.49; 95% CI, 0.59-3.77; 0 MME vs ≥600 MME: aHR, 2.93; 95% CI, 1.55-5.56). Conclusions and Relevance: In this study of youth linked to family members, exposure to family members' prescribed opioids was associated with increased risk of pharmaceutical opioid overdose, independent of opioids prescribed to youth. Further interventions targeting youth and families are needed, including counseling patients about the risks of opioids to youth in their families.

A natural experiment study of the effects of imprisonment on violence in the community.

One of the goals of imprisonment is to reduce violence1. Although imprisonment has risen dramatically since the 1970s, its effects on future violent crime are poorly understood2. This study's objective was to examine the effect of imprisonment on violent crime in the community among individuals on the policy margin between prison and probation sentences. Drawing on data from a population-based cohort of individuals convicted of a felony in Michigan between 2003 and 2006 (n = 111,110) and followed through June 2015, we compared the rates of commission of violent crime committed by individuals sentenced to prison with those of individuals sentenced to probation using a natural experiment based on the random assignment of judges to criminal cases. Being sentenced to prison had no significant effects on arrests or convictions for violent crimes after release from prison, but imprisonment modestly reduced the probability of violence if comparisons included the effects of incapacitation during imprisonment. These results suggest that for individuals on the current policy margin between prison and probation, imprisonment is an ineffective long-term intervention for violence prevention, as it has, on balance, no rehabilitative or deterrent effects after release.