Pharmacist interventions to deprescribe opioids and benzodiazepines in older adults: A rapid review.

BACKGROUND: Many older adults are prescribed opioids and benzodiazepines (BZDs), despite increased susceptibility to adverse events. Challenges of deprescribing include fragmented care and lack of knowledge or time. Pharmacists are well-positioned to overcome these challenges and facilitate deprescribing of these medications. OBJECTIVES: We sought to evaluate interventions utilizing pharmacists to deprescribe opioids and BZDs in older adults. METHODS: We conducted a rapid review following a comprehensive literature search to identify interventions with pharmacist involvement for deprescribing opioids and BZDs in older adults. Studies were included based on: (1) inclusion of patients ≥ 65 years old receiving BZDs and/or opioids, (2) evaluation of feasibility or outcomes following deprescribing (3) pharmacists as part of the intervention. We included randomized, observational, cohort, and pilot studies. Studies that did not report specific results for BZD or opioids were excluded. RESULTS: We screened 687 abstracts and included 17 studies. Most (n = 13) focused on BZD deprescribing. Few studies focused on opioids (n = 2) or co-prescribing of opioids and BZDs (n = 2). The most common intervention was educational brochures (n = 8), majority being the EMPOWER brochure for deprescribing BZDs. Other interventions included chart review with electronic notes (n = 4), pharmacist-led programs/services (n = 2), and multifactorial interventions (n = 3). Many studies were underpowered or lacked suitable control groups. Generally speaking, interventions utilizing educational materials and those in which pharmacists engaged with patients and providers were more effective. Interventions relying on electronic communication by pharmacists were less successful, due to low acceptance or acknowledgement. CONCLUSIONS: We identified a number of feasible interventions to reduce BZD use, but fewer interventions to reduce opioid use in older adults. An optimal approach for deprescribing likely requires pharmacists to engage directly with patients and providers. Larger well-designed studies are needed to evaluate the effectiveness of deprescribing interventions beyond feasibility.

Gastric bypass: why Roux-en-Y? A review of experimental data.

OBJECTIVE: To highlight the clinical and experimental rationales that support why the Roux-en-Y limb is an important surgical principle for bariatric gastric bypass. DATA SOURCES: We reviewed PubMed citations for open Roux-en-Y gastric bypass (RYGBP), laparoscopic RYGBP, loop gastric bypass, chronic alkaline reflux gastritis, and duodenoesophageal reflux. STUDY SELECTION: We reviewed clinical and experimental articles. Clinical articles included prospective, retrospective, and case series of patients undergoing RYGBP, laparoscopic RYGBP, or loop gastric bypass. Experimental articles that were reviewed included in vivo and in vitro models of chronic duodenoesophageal reflux and its effect on carcinogenesis. DATA EXTRACTION AND SYNTHESIS: No formal data extraction was performed. We reviewed published operative times, lengths of stay, and anastomotic leak rates for laparoscopic RYGBP and loop gastric bypass. For in vivo and in vitro experimental models of duodenoesophageal reflux, we reviewed the kinetics and potential molecular mechanisms of carcinogenesis. CONCLUSIONS: Recent data suggest that laparoscopic loop gastric bypass, performed without the creation of a Roux-en-Y gastroenterostomy, is a faster surgical technique that confers similarly robust weight loss compared with RYGBP or laparoscopic RYGBP. In the absence of a Roux limb, the long-term effects of chronic alkaline reflux are unknown. Animal models and in vitro analyses of chronic alkaline reflux suggest a carcinogenic effect.

Assessing the effectiveness and cost-effectiveness of drug intervention programs: UK case study.

The effectiveness and cost-effectiveness of the UK Drug Interventions Program which directs adult drug-misusing offenders out of crime and into treatment programs was established. Quality-adjusted life year estimates from the UK Drug Treatment Outcomes Research Study were collected and a cost-utility assessment of the Drug Interventions Program was conducted. Cost-utility assessment confirmed that the Drug Interventions Program is both effective and cost-effective with an average net cost saving of £668 (£6,207 including one case of homicide). This study provides evidence that drug intervention programs are cost-effective as they reduce crime, improve quality-of-life and reduce subsequent drug use.

Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling.

CONTEXT: Gastrointestinal (GI) carcinoid tumors elaborate serotonin and other vasoactive substances, causing the carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including achaete-scute complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI carcinoids. OBJECTIVE: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI carcinoids and model their interaction in a relevant GI carcinoid cell line. DESIGN: Fourteen GI carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth. SETTING: The study was conducted in an academic referral center. PATIENTS OR OTHER PARTICIPANTS: Deidentified archival pathology specimens were examined. RESULTS: Among a panel of six developmental transcription factors tested, only Ascl1 mRNA was overexpressed compared with surrounding normal tissue (seven of 10 GI carcinoid tumors and in BON cells, none of five normal tissues). Ascl1 protein was also expressed in four of four carcinoid tumors and BON cells). Notch pathway ligands, receptors, and downstream effectors were widely expressed in tumor and normal specimens. Overexpression of activated Notch1 in BON cells led to induction of the Notch effector hairy and enhancer of split 1 (Hes1), loss of Ascl1, reductions in neuron-specific enolase, synaptophysin, and chromogranin A, and most significantly, an 89% decrease in serotonin concentration and equivalent reductions in serotonin-reactive cells and repression of tryptophan hydroxylase 1 mRNA. CONCLUSIONS: The Notch signaling pathway is a significant regulator of neuroendocrine differentiation and serotonin production in GI carcinoid tumors.

Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer.

The basic helix-loop-helix transcription factor achaete-scute complex homologue 1 (ASCL1) is essential for the development of normal lung neuroendocrine cells as well as other endocrine and neural tissues. Small cell lung cancer (SCLC) and non-SCLC with neuroendocrine features express ASCL1, where the factor may play a role in the virulence and primitive neuroendocrine phenotype of these tumors. In this study, RNA interference knockdown of ASCL1 in cultured SCLC resulted in inhibition of soft agar clonogenic capacity and induction of apoptosis. cDNA microarray analyses bolstered by expression studies, flow cytometry, and chromatin immunoprecipitation identified two candidate stem cell marker genes, CD133 and aldehyde dehydrogenase 1A1 (ALDH1A1), to be directly regulated by ASCL1 in SCLC. In SCLC direct xenograft tumors, we detected a relatively abundant CD133(high)-ASCL1(high)-ALDH1(high) subpopulation with markedly enhanced tumorigenicity compared with cells with weak CD133 expression. Tumorigenicity in the CD133(high) subpopulation depended on continued ASCL1 expression. Whereas CD133(high) cells readily reconstituted the range of CD133 expression seen in the original xenograft tumor, CD133(low) cells could not. Our findings suggest that a broad range of SCLC cells has tumorigenic capacity rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC.

An anatomical study of external carotid artery vascular territories in face and midface flaps for transplantation.

BACKGROUND: The technical success of facial composite tissue allotransplantation demands full understanding of superficial and deep perfusion for reliable microvascular transfer. Candidates with composite midface defects require an appreciation of the circulatory patterns to design a composite midface allotransplant. METHODS: External carotid vascular territories were evaluated in 10 cadavers to determine the reliability of facial soft-tissue flaps based on a single vascular pedicle. The right common carotid artery was injected with red latex and the left was injected with blue latex. Dual perfusion was confirmed by purple, following two-color mixing. Vascular pedicles included the superficial temporal, transverse facial, and facial arteries. In five additional cadavers, the midface segment was isolated by Le Fort III osteotomy after two-color latex injection with inclusion of the internal maxillary vascular pedicle. Cadavers were imaged with three-dimensional computed tomographic reconstructions following latex injection to confirm perfusion patterns. RESULTS: In soft-tissue facial flaps, unilateral carotid dominance was seen in the nasal dorsum and tip, confirming reliable supply by a single external carotid artery. In midface flaps, bilateral perfusion was seen in the maxilla. Ipsilateral perfusion was observed at the zygomaticomaxillary complex without any contralateral contribution. CONCLUSIONS: Dual soft-tissue perfusion was confirmed in most specimens at the nasal, central face, and maxilla. The inclusion of the maxilla in the design of a facial composite allotransplant demands bilateral vascular pedicles based on the internal maxillary arteries. The authors highlight a procurement strategy for design of such flaps.

Desmoid tumors of the head and neck: a review.

Desmoid tumors of the head and neck are locally invasive neoplasms with a high propensity for inadequate resection and recurrence. The rarity of these neoplasms accounts for the fact that there are no prospective randomized data to evaluate the influence of adjuvant therapies, including radiotherapy, hormonal therapy, or cytotoxic chemotherapy. Several comprehensive retrospective series in the literature suggest that the margin status following resection does not necessarily correlate with local disease recurrence. As a result, we do not advocate the sacrifice of major neurovascular structures in an attempt to obtain negative margins. We present a review of desmoid tumors, emphasizing those occurring in the head and neck, and describe 3 cases that highlight the challenges that the anatomy of the head and neck presents in the management of this difficult disease.

Notch in lung development and lung cancer.

Although data regarding the role of the Notch pathway in human lung cancer are still limited, fetal lung developmental studies suggest that Notch signaling plays a critical role in regulating airway epithelial development. The moderate hypotrophic phenotype of lungs from animals bearing a Hes1 mutation, and the expression of Notch components in the distal lung bud during branching morphogenesis, together suggest that Notch may play a role in normal lung growth, especially in Clara cell precursors. Non-small cell lung cancers, including adenocarcinoma, appear to actively utilize this conserved developmental pathway. Pharmacologic inhibition of the Notch pathway is a potential experimental approach to lung cancer treatment.

Colorectal cancer mortality in first-degree relatives of early-onset colorectal cancer cases.

PURPOSE: Estimates of familial colorectal cancer risks are useful in genetic counseling and as a guide to determining entry into screening programs and trials of chemoprevention. Furthermore, they provide an insight into the contribution of the known colorectal cancer genes to the familial risk of the disease. There is a paucity of data about the familial colorectal cancer risk associated with early-onset disease outside the recognized cancer predisposition syndromes. METHODS: This was a retrospective cohort study. The parents and siblings of 205 patients with colorectal cancer aged less than 55 years at diagnosis were studied for mortality and cancer incidence. RESULTS: The overall standardized mortality ratio of colorectal cancer compared with the Northern Irish population was 3.54 (95 percent confidence interval, 2.59-4.79). There was some evidence that a family history of colorectal cancer is associated with a greater risk of colon (4.16; 95 percent confidence interval, 2.83-5.91) rather than rectal cancer (2.62; 95 percent confidence interval, 1.43-4.40). Risks in parents (2.54; 95 percent confidence interval, 1.45-3.72) were lower than in siblings (6.15; 95 percent confidence interval, 3.90-9.23). CONCLUSION: First-degree relatives of patients with early-onset disease are at a marked increase in risk. There is evidence that risks vary depending on the type of affected relative and by the site of colorectal cancer. This information should be considered in formulating screening strategies.