Patient risk screening to improve transitions of care in surgical opioid prescribing: a qualitative study of provider perspectives.

INTRODUCTION: In patients undergoing surgical procedures, transitions in opioid prescribing occur across multiple providers during the months before and after surgery. These transitions often result in high-risk and uncoordinated prescribing practices, especially for surgical patients with prior opioid exposure. However, perspectives of relevant providers about screening and care coordination to address these risks are unknown. METHODS: We conducted qualitative interviews with 24 surgery, primary care, and anesthesia providers in Michigan regarding behaviors and attitudes about screening surgical patients to inform perioperative opioid prescribing in relation to transitions of care. We used an interpretive description framework to topically code interview transcripts and synthesize underlying themes in analytical memos. RESULTS: Providers believed that coordinated, multidisciplinary approaches to identify patients at risk of poor pain and opioid-related outcomes could improve transitions of care for surgical opioid prescribing. Anesthesia and primary care providers saw value in knowing patients' preoperative risk related to opioid use, while surgeons' perceptions varied widely. Across specialties, most providers favored a screening tool if coupled with actionable recommendations, sufficient resources, and facilitated coordination between specialties. Providers identified a lack of pain specialists and a dearth of actionable guidelines to direct interventions for patients at high opioid-related risk as major limitations to the value of patient screening. DISCUSSION: These findings provide context to address risk from prescription opioids in surgical transitions of care, which should include identifying high-risk patients, implementing a coordinated plan, and emphasizing actionable recommendations.

Piloting a statewide emergency department take-home naloxone program: Improving the quality of care for patients at risk of opioid overdose.

BACKGROUND: Emergency department (ED) patients with nonfatal opioid overdose are at high risk for subsequent fatal overdose, yet ED programs aimed at reducing harm from opioid use remain underdeveloped. OBJECTIVES: The objective was to pilot a statewide ED take-home naloxone program and improve the care of patients with opioid use disorder (OUD) and risky drug use through training and interprofessional network building. METHODS: Nine hospital EDs with pharmacy, nurse, and physician champions were recruited, surveyed, and trained. Take-home naloxone rescue kits were developed, disseminated, and tracked. Two overdose prevention summits were convened prior to the COVID pandemic, and two X-waiver training courses aimed at emergency physicians and advanced practice providers were arranged, both in person and virtual. RESULTS: A total of 872 naloxone rescue kits were distributed to ED patients at risk of opioid overdose during the first phase of this project, and more than 140 providers were trained in the use of medications for OUD in acute care settings. CONCLUSIONS: A statewide ED take-home naloxone program was shown to be feasible across a range of different hospitals with varying maturity in preexisting OUD resources and capabilities. Future work will be aimed at both expanding and measuring the effectiveness of this work.

Statewide Prehabilitation Program and Episode Payment in Medicare Beneficiaries.

BACKGROUND: Prehabilitation has been shown to improve postoperative outcomes in a variety of patient populations undergoing major operations. The feasibility, generalizability, and value of broad implementation of prehabilitation outside the research environment are unknown. METHODS: Medicare claims data from 2014 to 2017 were used to conduct a multicenter (21 Michigan hospitals) pragmatic cohort study. Patients and controls were followed for the duration of their index surgical hospitalization and for 90 days postoperatively. Medicare beneficiaries older than 18 years who underwent inpatient surgical procedures at a participating hospital during the study time period were eligible for inclusion. The prehabilitation program involved a home-based walking program with supplementary education on nutrition, smoking cessation, and psychological preparation for surgical procedure. Data were analyzed with an intention-to-treat approach using t-tests and Wilcoxon rank sum tests. Propensity score matching used comorbidities and demographic factors to match controls to patients in a 2:1 manner with an exact match required for operation type. RESULTS: Patients (n = 523) and controls (n = 1,046) had no significant differences in demographic factors or comorbidities. Patients had significantly shorter median hospital length of stay (6 vs 7 days; p < 0.01) than controls and were more likely to be discharged to home (65.6% vs 57.0%, p < 0.01). Total episode payments were significantly lower for patients compared with controls ($31,641 vs $34,837; p = 0.04). Patients had significantly lower post-acute care payments for skilled nursing facility ($941 vs $1,566; p = 0.02) and home health ($829 vs $960; p = 0.03) services. CONCLUSIONS: Participation in a prehabilitation program in Michigan was associated with shorter length of stay and lower total episode payments after operation. Payers and hospitals should invest in the implementation of simple home-based prehabilitation programs.

Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK.

BACKGROUND: STARTMRK, a phase III noninferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naive patients, remained blinded until its conclusion at 5 years. We now report the final study results. METHODS: Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary end points stipulated at weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with viral RNA (vRNA) levels <50 copies per milliliter counting noncompleters as failures (NC=F). Changes from baseline CD4 count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at week 240. RESULTS: Overall, 71 of 281 raltegravir recipients (25%) and 98 of 282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the primary NC=F efficacy analysis at week 240, 198 of 279 (71.0%) raltegravir recipients and 171 of 279 (61.3%) efavirenz recipients had vRNA levels <50 copies per milliliter, yielding a treatment difference {Δ [95% confidence interval (CI)] = 9.5 (1.7 to 17.3)}. Generally comparable between-treatment differences were seen in both the protocol-stipulated sensitivity analyses and the prespecified subgroup analyses. The mean (95% CI) increments in baseline CD4 counts at week 240 were 374 and 312 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Δ(95% CI) = 62 (22 to 102)]. Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric side effects (39.1% vs 64.2%, P < 0.001) or drug-related clinical adverse events (52.0% vs 80.1%, P < 0.001). CONCLUSIONS: In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine seemed to have superior efficacy compared with efavirenz/tenofovir/emtricitabine.

Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK.

We compared 4 years of antiretroviral therapy with tenofovir/emtricitabine and either raltegravir or efavirenz from the ongoing STARTMRK study of treatment-naïve HIV-infected patients. Through 192 weeks, raltegravir produced durable and consistent viral suppression and immune restoration compared with efavirenz irrespective of baseline demographic and prognostic factors, including in patients with high viral loads.

Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner.

BACKGROUND: The small intestinal epithelium is highly sensitive to radiation and is a major site of injury during radiation therapy and environmental overexposure. OBJECTIVE: To examine probiotic bacteria as potential radioprotective agents in the intestine. METHODS: 8-week-old C57BL/6 wild-type or knockout mice were administered probiotic by gavage for 3 days before 12 Gy whole body radiation. The intestine was evaluated for cell-positional apoptosis (6 h) and crypt survival (84 h). RESULTS: Gavage of 5×107 Lactobacillus rhamnosus GG (LGG) improved crypt survival about twofold (p<0.01); the effect was observed when administered before, but not after, radiation. Conditioned medium (CM) from LGG improved crypt survival (1.95-fold, p<0.01), and both LGG and LGG-CM reduced epithelial apoptosis particularly at the crypt base (33% to 18%, p<0.01). LGG was detected in the distal ileal contents after the gavage cycle, but did not lead to a detectable shift in bacterial family composition. The reduction in epithelial apoptosis and improved crypt survival offered by LGG was lost in MyD88⁻/⁻, TLR-2⁻/⁻ and cyclo-oxygenase-2⁻/⁻ (COX-2) mice but not TLR-4⁻/⁻ mice. LGG administration did not lead to increased jejunal COX-2 mRNA or prostaglandin E2 levels or a change in number of COX-2-expressing cells. However, a location shift was observed in constitutively COX-2-expressing cells of the lamina propria from the villi to a position near the crypt base (villi to crypt ratio 80:20 for control and 62:38 for LGG; p<0.001). Co-staining revealed these COX-2-expressing small intestinal lamina propria cells to be mesenchymal stem cells. CONCLUSIONS: LGG or its CM reduce radiation-induced epithelial injury and improve crypt survival. A TLR-2/MyD88 signalling mechanism leading to repositioning of constitutive COX-2-expressing mesenchymal stem cells to the crypt base is invoked.

Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK.

BACKGROUND: We compared 3 years of antiretroviral therapy with raltegravir or efavirenz as part of a combination regimen in the ongoing STARTMRK study of treatment-naive patients infected with human immunodeficiency virus (HIV). METHODS: Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies/mL and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind, noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Outcomes included viral suppression, adverse events, and changes from baseline metabolic parameters. Dual energy X-ray absorptiometry scans were obtained on a convenience sample of patients at prespecified time points to assess changes in body fat composition. RESULTS: At week 156 counting noncompleters as failures, 212 (75.4%) of 281 versus 192 (68.1%) of 282 had vRNA levels <50 copies/mL in the raltegravir and efavirenz groups, respectively [Δ (95% CI) = 7.3% (-0.2, 14.7), noninferiority P < .001]. Mean changes from baseline CD4 count were 332 and 295 cells/mm³ in the raltegravir and efavirenz arms, respectively [Δ (95% CI) = 37 (4, 69)]. Consistent virologic and immunologic efficacy was maintained across prespecified demographic and baseline prognostic subgroups for both treatment groups. Fewer drug-related clinical adverse events (49% vs 80%; P < .001) occurred in raltegravir than efavirenz recipients, with discontinuations due to adverse events in 5% and 7%, respectively. Elevations in fasting lipid levels (including LDL- and HDL-cholesterol) were consistently lower in the raltegravir than efavirenz group (P < .005). Fat gain was 19% in 25 raltegravir recipients and 31% in 32 efavirenz recipients at week 156. CONCLUSIONS: When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir produced durable viral suppression and immune restoration that was at least equivalent to efavirenz through 156 weeks of therapy. Both regimens were well tolerated, but raltegravir was associated with fewer drug-related clinical adverse events and smaller elevations in lipid levels. Clinical Trials Registration. NCT00369941.

Antibody persistence ten years after first and second doses of 23-valent pneumococcal polysaccharide vaccine, and immunogenicity and safety of second and third doses in older adults.

In a study of older adults, first and second doses of 23-valent pneumococcal polysaccharide vaccine (PN23) induced IgG increases for all 8 vaccine serotypes tested. Participants (N=143, mean age 76 years) were re-enrolled to study antibody levels after ten years, and safety and immunogenicity of another PN23 dose. Ten years after first or second doses, mean IgG concentrations exceeded vaccine-naïve levels for 7 of 8 serotypes tested. Second and third doses administered at this time were generally well tolerated and were immunogenic, inducing similar postvaccination levels. Immunogenicity is preserved after multiple PN23 doses without evidence of a lower than expected immune response (i.e., without hyporesponsiveness).

Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials.

BACKGROUND: To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy. METHODS: The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729. FINDINGS: 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group. INTERPRETATION: Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir. FUNDING: Merck.

Growth factor regulation of prostaglandin-endoperoxide synthase 2 (Ptgs2) expression in colonic mesenchymal stem cells.

We previously found that a population of colonic stromal cells that constitutively express high levels of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2) altered their location in the lamina propria in response to injury in a Myd88-dependent manner (Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., and Stappenbeck, T. S. (2007) J. Clin. Invest. 117, 258-269). At the time of this study, the identity of these cells and the mechanism by which they expressed high levels of Ptgs2 were unknown. Here we found that these colonic stromal cells were mesenchymal stem cells (MSCs). These colonic MSCs expressed high Ptgs2 levels not through interaction with bacterial products but instead as a consequence of mRNA stabilization downstream of Fgf9 (fibroblast growth factor 9), a growth factor that is constitutively expressed by the intestinal epithelium. This stabilization was mediated partially through a mechanism involving endogenous CUG-binding protein 2 (CUGbp2). These studies suggest that Fgf9 is an important factor in the regulation of Ptgs2 in colonic MSCs and may be a factor involved in its constitutive expression in vivo.

The incidence and course of depression in bereaved youth 21 months after the loss of a parent to suicide, accident, or sudden natural death.

OBJECTIVE: This study examined effects of bereavement 21 months after a parent's death, particularly death by suicide. METHOD: The participants were 176 offspring, ages 7-25, of parents who died by suicide, accident, or sudden natural death. They were assessed 9 and 21 months after the death, along with 168 nonbereaved subjects. RESULTS: Major depression and alcohol or substance abuse 21 months after the parent's death were more common among bereaved youth than among comparison subjects. Offspring with parental suicide or accidental death had higher rates of depression than comparison subjects; those with parental suicide had higher rates of alcohol or substance abuse. Youth with parental suicide had a higher incidence of depression than those bereaved by sudden natural death. Bereavement and a past history of depression increased depression risk in the 9 months following the death, which increased depression risk between 9 and 21 months. Losing a mother, blaming others, low self-esteem, negative coping, and complicated grief were associated with depression in the second year. CONCLUSIONS: Youth who lose a parent, especially through suicide, are vulnerable to depression and alcohol or substance abuse during the second year after the loss. Depression risk in the second year is mediated by the increased incidence of depression within the first 9 months. The most propitious time to prevent or attenuate depressive episodes in bereaved youth may be shortly after the parent's death. Interventions that target complicated grief and blaming of others may also improve outcomes in symptomatic youth with parental bereavement.

Antecedents and sequelae of sudden parental death in offspring and surviving caregivers.

OBJECTIVES: To examine the psychiatric antecedents that put parents at risk for early death, and the psychological sequelae of bereavement in offspring and caregivers. DESIGN: A population-based study. SETTING: Bereaved families were recruited through the coroner's records and by advertisement. Control families were recruited by random-digit dialing and advertisement. PARTICIPANTS: Families with biological offspring from 7 to 25 years of age in which 1 parent died of suicide, accident, or sudden natural death were included (n = 140). Controls (n = 99) had 2 living parents and their biological offspring and had no death of a first-degree relative within the past 2 years. MAIN OUTCOME MEASURES: Lifetime psychiatric history for deceased parents (probands) and new-onset psychiatric disorders, self-reported symptoms, and functional status in offspring and surviving caregivers. RESULTS: Bipolar disorder, substance abuse, and personality disorders are more common in probands who died of suicide or accident than in control parents. Bereaved offspring and their caregivers were at increased risk for depression and posttraumatic stress disorder. Bereaved offspring had a 3-fold (95% confidence interval, 1.3-7.0) increased risk of depression, even after controlling for antecedent and concomitant risk factors. Offspring bereaved by suicide showed similar outcomes compared with those bereaved by other types of death. CONCLUSIONS: Bereavement conveys an increased risk of depression and posttraumatic stress disorder above and beyond other vulnerability factors. Better integration of medical and psychiatric care may prevent premature parental death, but once it occurs, physicians should be alert to the increased risk for depression and posttraumatic stress disorder in bereaved offspring and their caregivers.

Deciphering the 'black box' of the intestinal stem cell niche: taking direction from other systems.

PURPOSE OF REVIEW: Study of developmental signaling pathways suggests that the intestinal stem cell niche regulates the activity of the crypt-based epithelial progenitors during homeostasis and injury states. The cellular origin of these signals, however, remains poorly defined. Here, we examine the current state of knowledge regarding intestinal epithelial progenitor niches and highlight applicable lessons learned from other systems. RECENT FINDINGS: Cell-cell contact, regulatory factor delivery, stem cell polarity, and mesenchymal stem cells are considered. SUMMARY: Based on the findings in other niche systems as well as the overall complexity and unique organization of the intestinal progenitor niche, future studies will focus on defining peri-cryptal architecture, cellular sources of regulatory factors, and the dynamic nature of the niche during homeostasis and injury repair. These insights may lead to novel cell-based therapies for a variety of conditions that damage the mucosal lining of the gut.

Phenomenology and correlates of complicated grief in children and adolescents.

OBJECTIVE: To describe the phenomenology of complicated grief (CG) in parentally bereaved children and adolescents and to examine its correlates. METHOD: This is a preliminary report from an ongoing 5-year, population-based, longitudinal study of the impact of parental loss on family members. Analyses of cross-sectional data at intake are presented. The sample consists of 129 children and adolescents of parents who died by suicide, accident, or sudden natural death. Their average age is 13.3 +/- 3.1 years (range 7-18 years). A modified version of the Inventory of Complicated Grief-Revised (ICG-R) was administered and its factor structure, internal consistency, and convergent and discriminant validity were examined. RESULTS: CG was significantly related to functional impairment even after controlling for current depression, anxiety, and posttraumatic stress disorder. CG was also associated with other measures of psychopathology, including suicidal ideation. CONCLUSIONS: In this preliminary analysis, CG appears to be a clinically significant syndrome in children and adolescents. Longitudinal data will help to clarify the prognostic significance of CG as well as to examine the interrelationship of CG and other psychopathology over time.

Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury.

We identified cellular and molecular mechanisms within the stem cell niche that control the activity of colonic epithelial progenitors (ColEPs) during injury. Here, we show that while WT mice maintained ColEP proliferation in the rectum following injury with dextran sodium sulfate, similarly treated Myd88(-/-) (TLR signaling-deficient) and prostaglandin-endoperoxide synthase 2(-/-) (Ptgs2(-/-)) mice exhibited a profound inhibition of epithelial proliferation and cellular organization within rectal crypts. Exogenous addition of 16,16-dimethyl PGE(2) (dmPGE(2)) rescued the effects of this injury in both knockout mouse strains, indicating that Myd88 signaling is upstream of Ptgs2 and PGE(2). In WT and Myd88(-/-) mice, Ptgs2 was expressed in scattered mesenchymal cells. Surprisingly, Ptgs2 expression was not regulated by injury. Rather, in WT mice, the combination of injury and Myd88 signaling led to the repositioning of a subset of the Ptgs2-expressing stromal cells from the mesenchyme surrounding the middle and upper crypts to an area surrounding the crypt base adjacent to ColEPs. These findings demonstrate that Myd88 and prostaglandin signaling pathways interact to preserve epithelial proliferation during injury using what we believe to be a previously undescribed mechanism requiring proper cellular mobilization within the crypt niche.