A randomized, pragmatic, pharmacist-led intervention reduced opioids following orthopedic surgery.

OBJECTIVES: To determine whether a pharmacist-led, patient-directed intervention can reduce opioid use following total hip arthroplasty (THA) or total knee arthroplasty (TKA). STUDY DESIGN: Randomized trial. METHODS: Patients scheduled to undergo THA or TKA (during 2015 and 2016) were randomized to usual care or intervention. We ranked patients according to predicted risk of persistent opioid use and selected the top 60% for inclusion (n = 561); all contributed to the analysis. Intervention patients were mailed materials 2 weeks before and after surgery, plus they received telephone intervention from specially trained pharmacists if they filled opioid prescriptions in the 28 to 90 days following surgery. Our primary outcome was the dispensed morphine equivalents (DME) in the 90 days following surgery, modeled using a natural log transformation. RESULTS: A total of 561 patients were randomized (286 usual care, 118 THA and 168 TKA; 275 intervention, 107 THA and 168 TKA); the mean age was 66 years, and 60% were female. Overall, we found no meaningful reduction in DME for intervention versus usual care (geometric mean ratio, 0.92 [95% CI, 0.69-1.21]). However, there was effect modification by whether the patient had TKA or THA (interaction P <.01). Those undergoing THA in the intervention group used significantly less DME than did those undergoing THA in the usual care group (geometric mean ratio, 0.52 [95% CI, 0.33-0.82]). CONCLUSIONS: Our pharmacist-led, patient-directed intervention to reduce opioid use demonstrated a reduction in opioid dispensings in the 90 days following THA but not TKA.

A qualitative study to develop materials educating patients about opioid use before and after total hip or total knee arthroplasty.

OBJECTIVE: The authors undertook a qualitative study with open-ended, structured interviews to understand patient)s educational needs for patients undergoing total hip and total knee arthroplasty (THA/TKA). DESIGN: Provider interviews explored their approach with THA/TKA patients on: pain management; barriers to opioid tapering; and recommendations/changes on educational materials to support pain management and opioid reduction. Patient interviews explored their experience, understanding, beliefs surrounding opioids, and recommendations on important content. A qualitative methodologist conducted interviews and content analysis to identify key themes. SETTING: Kaiser Permanente Northwest, community setting. PATIENTS, PARTICIPANTS: A purposeful sampling method identified interviewees (surgeons, advice nurses, physical therapists, physician assistants, and patients). Patients were recent THA/TKA cases in the top third of opioid use after surgery. INTERVENTIONS: N/A. MAIN OUTCOME MEASURE(S): Qualitative study. RESULTS: Recommendations for patient educational content included: (1) clear descriptions of how opioids work in the body, how to taper, nonopioid pain management options, and problems from overuse; (2) messaging on how long to expect to use opioids and type of pain to expect; (3) visual timeline to illustrate opioid tapering and exercise expectations; (4) emphasize that pain management is multimodal, and stress the balance between opioids for recovery versus overuse; (5) provide educational messaging multiple times prior to and after surgery. CONCLUSIONS: Patients and providers agreed that clearly stated verbal and written messaging is needed beyond what has typically been done regarding opioid expectations.

Evaluating Atypical Features of Femur Fractures: How Change in Radiological Criteria Influenced Incidence and Demography of Atypical Femur Fractures in a Community Setting.

Identification of atypical femoral fractures (AFFs) can be challenging. To assist in the radiological assessment, an American Society for Bone and Mineral Research (ASBMR) Task Force developed a case definition for AFFs in 2010, revising it in 2013. How the revised definition performs in a community setting compared with the 2010 definition is unknown. We applied the 2013 criteria to 372 femoral fractures that occurred between January 1, 1996, and June 30, 2009, employing two independent expert physician reviewers. We used radiographs that had been categorized in a previous study on the incidence of atypical fractures using 2010 ASMBR criteria (BEAK1). In this follow-up study (BEAK2), the same reviewers reviewed all previously identified femoral shaft fractures (FSFs) (n = 197) and distal femur fractures (n = 131) plus a 15% random sample of intertrochanteric fractures (n = 49). After initial review, agreement between the two reviewers ranged from 63% to 100% for specific features, and 84% of radiographs received the same overall classification. Fewer fractures met the 2013 compared with 2010 ASMBR case definition of AFFs (37 per 2013 criteria versus 74 per 2010 criteria). Forty-three radiographs (58%) categorized as AFFs according to 2010 criteria were no longer AFFs when 2013 criteria were applied, and an additional 12 non-atypical FSFs according to 2010 criteria were reclassified as AFFs according to 2013 criteria. The major cause of AFF reclassification was the change in the definition of transverse configuration. The modification of the comminution, non-traumatic, and periosteal/endosteal thickness criteria resulted in the reclassification of non-atypical FSFs to AFFs. Incidence rate of AFFs according to 2013 ASBMR criteria was lower overall during the 13 years of observation than when the 2010 ASBMR criteria were applied, although we saw a slight increase starting in 2000. As in BEAK1, we found that those with AFFs were younger, more often female, and had a higher exposure rate to bisphosphonates than those with non-atypical FSFs. As we continue to unravel the demographics of those who suffer from AFFs, our study adds information about how the change in criteria influences epidemiological work. © 2017 American Society for Bone and Mineral Research.

Mechanism of macromolecular structure evolution in self-assembled lipid nanoparticles for siRNA delivery.

Lipid nanoparticles (LNPs) are a leading platform for therapeutic delivery of small interfering RNAs (siRNAs). Optimization of LNPs as therapeutic products is enabled by the development of structure-activity relationships (SAR) linking LNP physiochemical and macromolecular properties to bioperformance. Methods by which LNP properties can be rationally manipulated are thus critical enablers of this fundamental knowledge build. In this work, we present a mechanistic study of LNP self-assembly via a rapid antisolvent precipitation process and identify critical physiochemical and kinetic parameters governing the evolution of LNP three-dimensional macromolecular structure as a biorelevant SAR feature. Using small-angle X-ray scattering, LNPs are shown to undergo a temporal evolution in macromolecular structure during self-assembly, rearranging from initially disordered phases after precipitation into well-ordered structures following a necessary annealing stage of the assembly sequence. The ability of LNPs to undergo structural reorganization is shown to be effected by the chemical nature of the aqueous antisolvent used for precipitation. Antisolvents of varying buffering species differentially influence LNP macromolecular features, revealing a new participatory role of buffer ions in LNP self-assembly. Furthermore, the formation of macromolecular structure in LNPs is shown to improve the efficiency of siRNA encapsulation, thereby offering a simple, nonchemical route for preparation of high-payload LNPs that minimize the dose of lipid excipients. The developed LNP precipitation process and mechanistic understanding of self-assembly are shown to be generalizable, enabling the production of LNPs with a tunable range of macromolecular features, as evidenced by the cubic, hexagonal, and oligo-lamellar phase LNPs exemplarily generated.

The development of an in vitro assay to screen lipid based nanoparticles for siRNA delivery.

In order to rapidly screen and select lead candidates for in vivo evaluation of lipid nanoparticles (LNPs) for systemic small interfering RNA (siRNA) delivery, an in vitro assay amenable to high-throughput screening (HTS) is developed. The strategy is to mimic the in vivo experience of LNPs after systemic administration, such as interactions with serum components, exposure to endosomal pH environments, and interactions with endosomal membrane lipids. It is postulated that the amount of siRNA released from LNPs after going through these treatments can be used as a screening tool to rank order the effectiveness of siRNA delivery by lipid nanoparticles in vivo. LNPs were incubated with 50% serum from different species (i.e. mouse, rat, or rhesus) at 37°C. The resulting samples were then reacted with anionic, endosomal-mimicking lipids at different pHs. The amount of siRNA released from LNPs was determined using spectrophotometry employing the fluorescent indicator SYBR Gold. Our results indicated that the amount of siRNA liberated was highly dependent upon the species of serum used and the pH to which it was exposed. LNPs treated with mouse serum showed higher levels of siRNA release, as did those subjected to endosomal pH (6.0), compared to physiological pH. Most interestingly, a good correlation between the amount of siRNA released and the in vivo efficacy was observed. In conclusion, an in vitro siRNA release assay was developed to screen and rank order LNPs for in vivo evaluation.

Incidence and demography of femur fractures with and without atypical features.

The case definition, community incidence, and characteristics of atypical femoral shaft fractures (FSFs) are poorly understood. This retrospective study utilized electronic medical records and radiograph review among women ≥50 years of age and men ≥65 years of age from January 1996 to June 2009 at Kaiser Permanente Northwest to describe the incidence rates and characteristics of subgroups of femur fractures. Fractures were categorized based on the American Society for Bone and Mineral Research (ASBMR) as atypical fracture major features (AFMs) (low force, shaft location, transverse or short oblique, noncomminuted) and AFMs with additional minor radiograph features (AFMms) (beaking, cortical thickening, or stress fracture). There were 5034 fractures in the study. The incidence rates of FSFs (without atypical features) and AFMs appeared flat (cumulative incidence: 18.2 per 100,000 person-years, 95% CI = 16.0-20.7; 5.9 per 100,000 person-years, 95% CI = 4.6-7.4; respectively) with 1,271,575 person-years observed. The proportion of AFMs that were AFMms increased over time. Thirty percent of AFMs had any dispensing of a bisphosphonate prior to the fracture, compared to 15.8% of the non-atypical FSFs. Years of oral glucocorticosteroid dispensing appeared highest in AFM and AFMm fractures. Those with AFMs only were older and had a lower frequency of bisphosphonate dispensing compared to those with AFMms. We conclude that rates of FSFs, with and without atypia, were low and stable over 13.5 years. Patients with only AFMs appear to be different from those with AFMms; it may be that only the latter group is atypical. There appear to be multiple associated risk factors for AFMm fractures.

Unicondylar knee arthroplasty in a patient with poliomyelitis.

Osteoarthritis in patients who have had poliomyelitis creates a significant challenge. The loss, or reduction of power in the quadriceps, combined with recurvatum and often patella baja can cause problems when considering total knee arthroplasty. The authors present the first case report of a unicondylar knee arthroplasty in such a patient. Functional knee scores improved, although some persistent degree of disability remained due to the preexisting poor muscle power.

Effectiveness of bisphosphonate therapy in a community setting.

BACKGROUND: Osteoporosis is a major cause of morbidity and mortality. Clinical trials have shown the effectiveness of bisphosphonates, the most commonly prescribed treatments, in reducing fracture risk. The population-based effectiveness of bisphosphonates in clinical practice is uncertain. METHODS: This retrospective cohort study used a matched design that compared time to clinical fracture in at-risk community women who initiated a bisphosphonate medication between 7/1/1996 and 6/30/2006 to those who did not. The study was conducted in an HMO in Oregon and Washington. Clinical electronic databases provided data. Eligible members were newly treated women aged > or = 55 years with either a BMD T-score of < or = -2.0 or a prior qualifying clinical fracture. They did not have contraindications for bisphosphonate therapy or a diagnosis associated with secondary osteoporosis (n=1829). They were matched to a similar comparison group (n=1829; total N=3658). The primary outcome was the first new incident fracture validated through chart review (closed clinical fracture of any bone except face, skull, finger, or toe or pathological fracture secondary to malignancy) during follow-up. An intention-to-treat analysis used Cox proportional hazards models to estimate the hazard ratio of fracture for treated relative to comparison patients, adjusting for differences in potential confounders. RESULTS: Treated and comparison patients were similar in mean age (72.0 years) and history of fracture (about 45%). The treated group had more women with T-scores of < or = -2.5 (67.3% vs. 54.7%) and a lower mean weight (146.6 lb vs. 151.8 lb). Only about 45% of treated patients had a bisphosphonate medication possession ratio (MPR) of > or = 0.80. During follow-up, 198 (10.8%) of patients in the treated group had incident fractures, vs. 179 (9.8%) of patients in the comparison group. After adjustments, patients in the treated group were 0.91 (95% CI 0.74-1.13) as likely to have an incident fracture as the comparison patients (p=0.388). The treatment effect remained non-significant after accounting for MPR. CONCLUSIONS: In this analysis of a community cohort of post-menopausal women at risk, the fracture risk of patients who received bisphosphonates did not differ significantly from those who did not. An enhanced understanding of this lack of treatment effect is urgently needed.

Physicochemical effects on uncontaminated kaolinite due to electrokinetic treatment using inert electrodes.

To determine the consequences of applying electrokinetics to clay soils, in terms of mechanisms acting and resulting effects on the clay, tests were conducted in which an electrical gradient was applied across controlled specimens of English China Clay (ECC) using 'inert' electrodes and a 'Reverse Osmosis' water feed to the electrodes (i.e., to mimic electrokinetic stabilisation without the stabiliser added or electrokinetic remediation without the contaminant being present). The specimens in which electromigration was induced over time periods of 3, 7, 14 and 28 days were subsequently tested for Atterberg Limits, undrained shear strength using a hand shear vane, water content, pH, conductivity and zeta potential. Water flowed through the system from anode to cathode and directly affected the undrained shear strength of the clay. Acid and alkali fronts were created around the anode and cathode, respectively, causing changes in the pH, conductivity and zeta potential of the soil. Variations in zeta potential were linked to flocculation and dispersion of the soil particles, thus raising or depressing the Liquid Limit and Plastic Limit, and influencing the undrained shear strength. Initial weakening around the anode and cathode was replaced by a regain of strength at the anode once acidic conditions had been created, while highly alkaline conditions at the cathode induced a marked improvement in strength. A novel means of indicating strength improvement by chemical means, i.e., free from water content effects, is presented to assist in interpretation of the results.