Mirogabalin: a novel gabapentinoid or another false dawn?

PURPOSE OF REVIEW: Mirogabalin is a novel gabapentinoid medication for the treatment of neuropathic pain. The purpose of this review is to discuss current evidence for its use. Gabapentinoids are widely prescribed for neuropathic pain. Mirogabalin offers theoretical advantages over traditional gabapentinoids due to its specificity for the α2δ-1 subunit of voltage-gated calcium channels. It is theorised that this specificity may reduce adverse drug reactions by minimising binding to the α2δ-2 subunit which is responsible for many of the gabapentinoid side effects. RECENT FINDINGS: Mirogabalin's slower dissociation from the α2δ-1 compared with α2δ-2, and its higher potency may also impart an efficacy benefit over traditional gabapentinoids. These theoretical advantages of mirogabalin remain inconclusive in clinical practice, with mixed evidence regarding mirogabalin versus traditional gabapentinoids. Some studies suggest a reduced side effect profile yet, others fail to demonstrate significant differences. Regarding efficacy, mirogabalin may be superior to placebo for several neuropathic pain syndromes, but evidence of widespread benefit over traditional gabapentinoids is currently lacking. SUMMARY: Mirogabalin offers theoretical promise, but large, independent studies are required to further assess its performance versus traditional gabapentinoids.

What Are the Relative Associations of Surgeon Performance and Prosthesis Quality With THA Revision Rates?

BACKGROUND: Many factors, including some related to the patient, implant selection, and the surgeon's skill and expertise, likely contribute to the risk of THA revision. However, surgeon factors have not been extensively analyzed in national joint replacement registries, and there is limited insight into their potential as a confounding variable for revision outcomes; for example, if surgeons with higher revision rates choose more successful prostheses, would this alone reduce their revision rate? QUESTIONS/PURPOSES: This study used Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) data for patients receiving primary THA for a diagnosis of osteoarthritis to answer the following questions: (1) Will the difference in revision rates among surgeons change or disappear when only procedures performed with the best prostheses or prostheses that have been identified as having higher revision rates are considered? (2) Is the benefit associated with using the best-performing prostheses different among surgeons with different revision rates? (3) Do the reasons for revision differ between surgeons with higher rates of revision compared with surgeons with lower rates of revision? METHODS: All primary THA procedures performed and recorded in the AOANJRR for osteoarthritis from September 1, 1999, to December 31, 2022, were considered for inclusion. Each THA prosthesis used was categorized per the AOANJRR as superior-performing, middle-performing, or identified as having a higher rate of revision by the AOANJRR benchmarking process. Surgeons who had performed at least 50 procedures and had a recorded 2-year cumulative percent revision (CPR) were included. After applying these restrictions, the study consisted of 302,066 procedures performed by 476 known surgeons. For the primary outcome measure of all-cause revision, we examined the variation in all-cause revision rates across individual surgeons when different classes of devices were used to assess whether differences between surgeons persisted when accounting for prosthesis selection. For the purposes of descriptively comparing reasons for revision between surgeons with higher-than-average or lower-than-average risk of revision, surgeons were classified into quartiles and outcomes compared when these surgeons used the same class of prosthesis. RESULTS: The difference in rates of revision among surgeons remained even after accounting for the effects of the prosthesis used. For any given surgeon, identified prostheses were associated with higher revision rates compared with both superior-performing prostheses (HR 1.73 [95% CI 1.57 to 1.92]; p < 0.01) and medium-performing prostheses (HR 1.31 [95% CI 1.20 to 1.43]; p < 0.01). All surgeons demonstrated a lower revision rate when using a superior-performing prosthesis, but the difference was greatest for surgeons with the highest rates of revision. Surgeons with the lowest rates of revision had a 19-year CPR of 3.9% (95% CI 3.0% to 5.0%) when using a superior-performing prosthesis compared with 5.4% (95% CI 4.0% to 7.3%) for procedures in which an identified prosthesis was used. Surgeons with the highest rates of revision had a 19-year CPR of 10.9% (95% CI 8.6% to 13.8%) when using a superior-performing prosthesis, and this increased to 20.4% (95% CI 18.0% to 23.1%) for procedures in which an identified prosthesis was used. The reasons for revision differ between surgeons, with causes of revision likely preventable and not related to the prosthesis choice being apparent for surgeons with high revision rates. CONCLUSION: The choice of implant and the surgeon performing the index procedure both affected the risk of revision as well as the reasons for revision. Surgeons could improve the survivorship of the arthroplasties they perform by choosing implants identified by registries as having lower revision rates. Acceptance of the fact that surgeons have different revision rates is needed, and detailed analysis is required to explain why surgeons with high revision rates have increased rates of likely preventable revisions, and outside of prosthesis choice, how revision rates can be lowered. The influence of training, fellowship completion, ongoing education, patient selection, indications for surgery, and factors underlying prosthesis decision-making should be assessed. The surgeon performing THA is an important confounder that should be considered in future registry analyses. LEVEL OF EVIDENCE: Level III, therapeutic study.

A Phase 1b/2 Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. PATIENTS AND METHODS: Multicenter Phase 1b/2 randomized clinical trial in patients with metastatic PDAC, untreated (Cohort A) or previously received gemcitabine-based chemotherapy (Cohort B) (NCT03611556). During escalation, patients received oleclumab 1500 or 3000 mg, durvalumab 1500 mg, and gemcitabine plus nab-paclitaxel (GnP) (Cohort A; n=14) or modified FOLFOX (Cohort B; n=11). During expansion, Cohort A patients (n=170) were randomized to: GnP (Arm A1), oleclumab (recommended Phase 2 dose; RP2D) with GnP (Arm A2), or oleclumab (RP2D) with durvalumab plus GnP (Arm A3). Primary objectives were safety (escalation) and objective response rate (ORR) (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During escalation, 1/11 patients from Cohort B (oleclumab 3000 mg) experienced two dose-limiting toxicities. Oleclumab RP2D was 3000 mg. During expansion, Grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. ORR was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs A3; p=0.650). PFS (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.47, 1.11) and OS (HR=0.75; 95% CI: 0.50, 1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. CONCLUSIONS: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

Outpatient Hysteroscopy: (Green-top Guideline no. 59).

All gynaecology departments should provide a dedicated outpatient hysteroscopy service to aid care of women and people with abnormal uterine bleeding, reproductive problems, and insertion/retrieval of intrauterine devices. [Grade A] Written information should be provided to the woman prior to their appointment. This should include details about the procedure, the benefits and risks, advice regarding pre-operative analgesia, as well as alternative options for care and contact details for the hysteroscopy unit. [Good Practice Point] Women should be made aware of other settings and modes of anaesthesia for hysteroscopy (e.g. under general or regional anaesthesia or intravenous sedation). [GPP] The woman should be advised that if they find the procedure too painful or distressing at any point, they must alert the clinical team who will stop the procedure immediately. The clinical team should alert the hysteroscopist if the woman appears to be in too much pain or is experiencing a vasovagal episode and therefore unable to voice the concerns so that the procedure can be stopped. [GPP] Women should be advised to take standard doses of oral non-steroidal anti-inflammatory agents (NSAIDs) one hour before their scheduled appointment. Vaginoscopy should be the standard technique for outpatient hysteroscopy unless the use of a vaginal speculum is required (e.g. for administering local cervical anaesthesia or dilating the cervix). [Grade A] When performing operative hysteroscopy, the smallest diameter hysteroscope should be used, with consideration given to the use of hysteroscopes with expandable outer working channels because they are associated with less pain. [Grade B] Mechanical hysteroscopic tissue removal systems should be preferred over miniature bipolar electrodes to remove endometrial polyps. [Grade A] Local anaesthesia should not be routinely administered prior to outpatient hysteroscopy where a vaginoscopic approach is used. It should be considered where use of a vaginal speculum is planned e.g. for cervical dilatation if anticipated, due to either cervical stenosis and/or the utilisation of larger-diameter hysteroscopes (≥5mm outer diameter). [Grade A] Saline should be instilled at the lowest possible pressure to achieve a satisfactory view. [Grade A] Conscious sedation should not be routinely used in outpatient hysteroscopic procedures. [Grade B].

Cyclin F-EXO1 axis controls cell cycle-dependent execution of double-strand break repair.

Ubiquitination is a crucial posttranslational modification required for the proper repair of DNA double-strand breaks (DSBs) induced by ionizing radiation (IR). DSBs are mainly repaired through homologous recombination (HR) when template DNA is present and nonhomologous end joining (NHEJ) in its absence. In addition, microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA) provide backup DSBs repair pathways. However, the mechanisms controlling their use remain poorly understood. By using a high-resolution CRISPR screen of the ubiquitin system after IR, we systematically uncover genes required for cell survival and elucidate a critical role of the E3 ubiquitin ligase SCFcyclin F in cell cycle-dependent DSB repair. We show that SCFcyclin F-mediated EXO1 degradation prevents DNA end resection in mitosis, allowing MMEJ to take place. Moreover, we identify a conserved cyclin F recognition motif, distinct from the one used by other cyclins, with broad implications in cyclin specificity for cell cycle control.

Predictors of distant metastatic recurrence in head and neck cutaneous squamous cell carcinoma with lymph node metastases treated with curative intent: A multicenter study.

BACKGROUND: We aimed to identify predictors of distant metastatic recurrence (DMR) in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases treated with curative intent. METHODS: Predictors of DMR were identified using Cox regression in a multicenter study of 1151 patients. RESULTS: The 5-year risk of DMR was 9.6%. On multivariate analysis, immunosuppression (HR 2.93; 95% CI: 1.70-5.05; p < 0.001), nodal size >6 cm [versus ≤3 cm (HR 2.77; 95% CI: 1.09-7.03; p = 0.032)], ≥5 nodal metastases [versus 1-2 (HR 2.79; 95% CI: 1.63-4.78; p < 0.001)], and bilateral disease (HR 3.11; 95% CI: 1.40-6.90; p = 0.005) predicted DMR. A DMR risk score was developed that stratified risk from 6.6% (no risk factors) to 100% (≥3 risk factors) (p < 0.001). CONCLUSIONS: The risk of DMR in nodal metastatic HNcSCC increases with immunosuppression, nodal size >6 cm, ≥5 nodal metastases, and bilateral disease. A simple DMR risk score estimated prior to treatment may be clinically useful.

Sex differences in patellar facet shape among healthy and osteoarthritic cohorts.

OBJECTIVE: Patellofemoral osteoarthritis (OA) may be more common in females than males. Reasons for this are not fully understood, but sex differences in patellar morphology may help explain this phenomenon. We quantified differences in patellar morphology between males and females in healthy and patellofemoral OA populations. DESIGN: A total of 97 (50F, 47M) healthy and 67 (40F, 27M) OA knees were scanned via computed tomography. OA individuals were on a waitlist for total knee replacement. Patella 3D models were segmented and 2D measurements were recorded: patellar width and height, lateral and medial facet width, and surface area. Medial and lateral facet surface topography was mapped using 81 points to describe 3D articular surface shape. Sex and group differences were assessed using Procrustes analysis of variance (ANOVA). Data were ordinated using Principal Component Analysis. RESULTS: Differences in patellar 2D measurements between healthy and OA individuals were smaller than were differences between males and females from healthy and OA groups. Sex and healthy/OA differences were most pronounced for medial facet shape, which featured a posteriorly-curving facet and taller, narrower facet shape in males compared to females. Lateral facet shape variance was higher in OA cohorts compared to healthy groups. CONCLUSIONS: Medial and lateral facet shapes showed different patterning of variation by sex and healthy/OA status. Lateral facet shape may be of interest in future models of OA risk in the patellofemoral joint, here showing increased magnitudes of variance associated with increased severity of disease (patellofemoral Kellgren and Lawrence score).

Correction to "ß-Phase Crystallinity, Printability, and Piezoelectric Characteristics of Polyvinylidene Fluoride (PVDF)/Poly(methyl methacrylate) (PMMA)/Cyclopentyl-polyhedral Oligomeric Silsesquioxane (Cp-POSS) Melt-Compounded Blends".

[This corrects the article DOI: 10.1021/acsapm.4c00468.].

Is There a Difference in Abdominal Wall Muscle Strength, Endurance, and Motor Control Following Bilateral DIEP and TRAM Flaps for Breast Reconstruction?

Background: Abdominal donor site complications in bilateral pedicled transverse rectus abdominis muscle (TRAM) have been a concern when compared with bilateral deep inferior epigastric perforator (DIEP) flap breast reconstruction. This study aimed to assess the strength, endurance, and motor control in patients undergoing DIEP and TRAM flaps. Methods: A prospective, cohort study was performed at a single institution including patients who underwent pedicled TRAM and DIEP flap reconstruction after mastectomy from August 2017 to August 2018. Patients underwent pre- and postoperative testing involving rectus abdominis, prone plank, side bridge, and trunk flexor tests. Descriptive analyses and multivariate linear regressions were performed. Results: The final analysis included a total of 9 patients, 4 of whom underwent TRAM flap reconstruction while 5 underwent DIEP flap reconstruction. The tests were not statistically significant between the TRAM versus DIEP groups, including rectus abdominis mean time decrease (0.25 vs 0.60 sec, P = .51), prone plank time increase (1.38 vs 1.38 sec, P = .51), right side bridge time increase (7.54 sec vs 32.15 sec, P = 1.00), left side bridge time increase (2.14 vs 44.5 sec, P = .37), and trunk flexor time decrease (4.68 vs 1.68 sec, P = .44). Overall complications were similar between the 2 groups. Conclusions: No significant difference in abdominal donor site morbidity was found when comparing the 2 groups. This article provides a point of conversation with patients when discussing available reconstruction options.

Prognostic potential of CUL3 ligase with differential roles in luminal A and basal type breast cancer tumors.

Breast cancer is a prevalent and significant cause of mortality in women, and manifests as six molecular subtypes. Its further histologic classification into non-invasive ductal or lobular carcinoma (DCIS) and invasive carcinoma (ILC or IDC) underscores its heterogeneity. The ubiquitin-proteasome system plays a crucial role in breast cancer, with inhibitors targeting the 26S proteasome showing promise in clinical treatment. The Cullin-RING ubiquitin ligases, including CUL3, have direct links to breast cancer. This study focuses on CUL3 as a potential biomarker, leveraging high-throughput sequencing, gene expression profiling, experimental and data analysis tools. Through comprehensive analysis using databases like GEPIA2 and UALCAN, as well as TCGA datasets, CUL3's expression and its association with prognostic values were assessed. Additionally, the impact of CUL3 overexpression was explored in MCF-7 and MDA-MB-231 breast cancer cell lines, revealing distinct differences in molecular and phenotypic characteristics. We further profiled its expression and localization in breast cancer tissues identifying prominent differences between luminal A and TNBC tumors. Conclusively, CUL3 was found to be associated with cell cycle progression, and DNA damage response, exhibiting diverse roles depending on the tumor's molecular type. It exhibits a tendency to act as an oncogene in triple-negative tumors and as a tumor suppressor in luminal A types, suggesting a potential significance in breast cancer progression and therapeutic directions.

Shape modelling reveals age-related knee bony shape changes in asymptomatic knees.

Osteoarthritis (OA) causes bony shape changes within the knee. Furthermore, the risk of developing OA increases with age. However, age alone does not cause OA. It is therefore important to understand the healthy age-related trajectories of knee shape before attributing these changes to OA. The aim of this study was to determine the association between bony knee shape and age using statistical-shape modelling (SSM). 96 participants received a CT scan of their knee. Three-dimensional models were created using manual segmentation. Separate SSM's for the distal femur and proximal tibia were created. Linear regression models were used to assess the association between age and femoral and tibial shape. Fourteen modes of the femoral and tibial SSM's captured 68% and 73% shape variation, respectively. Only femoral mode 3 and tibial mode 7 were associated with age. Increasing age was related to larger femoral bone volume and deepening of the femoral trochlear groove. Furthermore, increased age was associated with medial tibial plateau expansion. Aspects of bony femoral and tibial shape were significantly associated with aging, including femoral and tibial bone size, femoral trochlear groove, and medial tibial plateau area. Changes in knee morphology occur as a normal process of aging without osteoarthritis development. This may be a response to mechanical loading over time. Further research investigating the effect of these changes on loading in the knee may provide valuable information for knee health in older age.

A circumpolar study unveils a positive non-linear effect of temperature on arctic arthropod availability that may reduce the risk of warming-induced trophic mismatch for breeding shorebirds.

Seasonally abundant arthropods are a crucial food source for many migratory birds that breed in the Arctic. In cold environments, the growth and emergence of arthropods are particularly tied to temperature. Thus, the phenology of arthropods is anticipated to undergo a rapid change in response to a warming climate, potentially leading to a trophic mismatch between migratory insectivorous birds and their prey. Using data from 19 sites spanning a wide temperature gradient from the Subarctic to the High Arctic, we investigated the effects of temperature on the phenology and biomass of arthropods available to shorebirds during their short breeding season at high latitudes. We hypothesized that prolonged exposure to warmer summer temperatures would generate earlier peaks in arthropod biomass, as well as higher peak and seasonal biomass. Across the temperature gradient encompassed by our study sites (>10°C in average summer temperatures), we found a 3-day shift in average peak date for every increment of 80 cumulative thawing degree-days. Interestingly, we found a linear relationship between temperature and arthropod biomass only below temperature thresholds. Higher temperatures were associated with higher peak and seasonal biomass below 106 and 177 cumulative thawing degree-days, respectively, between June 5 and July 15. Beyond these thresholds, no relationship was observed between temperature and arthropod biomass. Our results suggest that prolonged exposure to elevated temperatures can positively influence prey availability for some arctic birds. This positive effect could, in part, stem from changes in arthropod assemblages and may reduce the risk of trophic mismatch.

Verification of a simplified aneurysm dimensionless flow parameter to predict intracranial aneurysm rupture status.

OBJECTIVES: Aneurysm number (An) is a novel prediction tool utilizing parameters of pulsatility index (PI) and aneurysm geometry. An has been shown to have the potential to differentiate intracranial aneurysm (IA) rupture status. The objective of this study is to investigate the feasibility and accuracy of An for IA rupture status prediction using Australian based clinical data. METHODS: A retrospective study was conducted across three tertiary referral hospitals between November 2017 and November 2020 and all saccular IAs with known rupture status were included. Two sets of An values were calculated based on two sets of PI values previously reported in the literature. RESULTS: Five hundred and four IA cases were included in this study. The results demonstrated no significant difference between ruptured and unruptured status when using An ≥1 as the discriminator. Further analysis showed no strong correlation between An and IA subtypes. The area under the curve (AUC) indicated poor performance in predicting rupture status (AUC1 = 0.55 and AUC2 = 0.56). CONCLUSIONS: This study does not support An ≥1 as a reliable parameter to predict the rupture status of IAs based on a retrospective cohort. Although the concept of An is supported by hemodynamic aneurysm theory, further research is needed before it can be applied in the clinical setting. ADVANCES IN KNOWLEDGE: This study demonstrates that the novel prediction tool, An, proposed in 2020 is not reliable and that further research of this hemodynamic model is needed before it can be incorporated into the prediction of IA rupture status.

The Clinical and Radiological Outcomes of the Multimodal Use of the Woven EndoBridge Device: A Large Multicenter Study.

BACKGROUND: The Woven EndoBridge (WEB) is a device used for intrasaccular flow diversion, designed for the elimination of wide-necked bifurcation aneurysms from the circulation. In this study, we aim to assess the safety and efficacy of the WEB and its uses in treating aneurysms of different morphologies and locations. METHODS: In a retrospective analysis, we compiled a comprehensive dataset from patients treated with the WEB device across three major Australian neurovascular centers from May 2017 to September 2023. The case series encompassed a spectrum of aneurysm types, including wide-necked bifurcation, sidewall, and irregularly shaped aneurysms, as well as cases previously managed with alternative therapeutic strategies. This study additionally encompasses cases where aneurysms were managed using the WEB device in combination with supplementary endovascular devices. RESULTS: The study included 169 aneurysms in 161 patients. The rate of satisfactory aneurysm occlusion was 85.6%, with 86.7% of patients maintaining good functional status at their most recent follow-up. The procedure exhibited a low mortality rate of 0.6% and a thromboembolic complication rate of 7.1% (n = 12/161). There were no instances of postoperative re-rupture and the procedure-related hemorrhage rate was low (1.2%, n = 2/169), aligning with the literature regarding the safety and efficacy of the WEB device. CONCLUSIONS: Our multicenter trial reinforces the WEB device's role as an effective and safe modality for intracranial aneurysm management, supporting its expanded application beyond wide-necked bifurcation aneurysms. Further prospective studies are required to delineate its evolving role fully.

Surgical evacuation with intraoperative ultrasound (SEE U): A randomised controlled trial.

OBJECTIVES: To test whether intraoperative ultrasound can reduce the incidence of early and late complications following surgical removal of products of conception. DESIGN: This was a prospective, multicentre, randomised, open clinical trial to assess feasibility. It was performed in two University Teaching hospitals in the West Midlands, England. The population consisted of women aged 16 years or over who were referred for surgical management of miscarriage. Patients were randomised to surgical management of miscarriage with either continuous intraoperative ultrasound or without intraoperative ultrasound. Process outcomes included the proportion of eligible women screened and proportion of eligible women randomised, attrition rates, evaluation of outcome measurement tools and acceptability. The primary clinical outcome was a composite outcome of unsuccessful procedure or a complication. RESULTS: Fifty-nine women requiring surgical management of miscarriage were randomised. The conversion rate for entry into the trial was 59/79(75 %; 95 %CI = 64-84 %). The composite clinical outcome was attained in 5/27(19 %) patients who had surgery without ultrasound and 7/28(25 %) patients who had surgery with ultrasound (RR = 0.74;95 %CI = 0.26, 2.10). When we excluded the patients that could not attend their hysteroscopy appointment, due to COVID-19 pandemic, 5/27(19 %) of patients who had surgery without ultrasound and 5/25(20 %) of patients who had surgery with ultrasound attained the composite clinical outcome (RR = 0.93;95 %CI = 0.30, 2.90). CONCLUSIONS: This multicentre pilot study showed that a large RCT comparing surgical management of miscarriage with and without intraoperative ultrasound is feasible.

Middle-schoolers' reading and lexical-semantic processing depth in response to digital and print media: An N400 study.

We report the first use of ERP measures to identify text engagement differences when reading digitally or in print. Depth of semantic encoding is key for reading comprehension, and we predicted that deeper reading of expository texts would facilitate stronger associations with subsequently-presented related words, resulting in enhanced N400 responses to unrelated probe words and a graded attenuation of the N400 to related and moderately related words. In contrast, shallow reading would produce weaker associations between probe words and text passages, resulting in enhanced N400 responses to both moderately related and unrelated words, and an attenuated response to related words. Behavioral research has shown deeper semantic encoding of text from paper than from a screen. Hence, we predicted that the N400 would index deeper reading of text passages that were presented in print, and shallower reading of texts presented digitally. Middle-school students (n = 59) read passages in digital and print formats and high-density EEG was recorded while participants completed single-word semantic judgment tasks after each passage. Following digital text presentation, the N400 response pattern to moderately-related words indicated shallow reading, tracking with responses to words that were unrelated to the text. Following print reading, the N400 responses to moderately-related words patterned instead with responses to related words, interpreted as an index of deeper reading. These findings provide evidence of differences in brain responses to texts presented in print and digital media, including deeper semantic encoding for print than digital texts.

Barriers to Implementing Registered Nurse-Driven Clinical Decision Support for Antibiotic Stewardship: Retrospective Case Study.

BACKGROUND: Up to 50% of antibiotic prescriptions for upper respiratory infections (URIs) are inappropriate. Clinical decision support (CDS) systems to mitigate unnecessary antibiotic prescriptions have been implemented into electronic health records, but their use by providers has been limited. OBJECTIVE: As a delegation protocol, we adapted a validated electronic health record-integrated clinical prediction rule (iCPR) CDS-based intervention for registered nurses (RNs), consisting of triage to identify patients with low-acuity URI followed by CDS-guided RN visits. It was implemented in February 2022 as a randomized controlled stepped-wedge trial in 43 primary and urgent care practices within 4 academic health systems in New York, Wisconsin, and Utah. While issues were pragmatically addressed as they arose, a systematic assessment of the barriers to implementation is needed to better understand and address these barriers. METHODS: We performed a retrospective case study, collecting quantitative and qualitative data regarding clinical workflows and triage-template use from expert interviews, study surveys, routine check-ins with practice personnel, and chart reviews over the first year of implementation of the iCPR intervention. Guided by the updated CFIR (Consolidated Framework for Implementation Research), we characterized the initial barriers to implementing a URI iCPR intervention for RNs in ambulatory care. CFIR constructs were coded as missing, neutral, weak, or strong implementation factors. RESULTS: Barriers were identified within all implementation domains. The strongest barriers were found in the outer setting, with those factors trickling down to impact the inner setting. Local conditions driven by COVID-19 served as one of the strongest barriers, impacting attitudes among practice staff and ultimately contributing to a work infrastructure characterized by staff changes, RN shortages and turnover, and competing responsibilities. Policies and laws regarding scope of practice of RNs varied by state and institutional application of those laws, with some allowing more clinical autonomy for RNs. This necessitated different study procedures at each study site to meet practice requirements, increasing innovation complexity. Similarly, institutional policies led to varying levels of compatibility with existing triage, rooming, and documentation workflows. These workflow conflicts were compounded by limited available resources, as well as an implementation climate of optional participation, few participation incentives, and thus low relative priority compared to other clinical duties. CONCLUSIONS: Both between and within health care systems, significant variability existed in workflows for patient intake and triage. Even in a relatively straightforward clinical workflow, workflow and cultural differences appreciably impacted intervention adoption. Takeaways from this study can be applied to other RN delegation protocol implementations of new and innovative CDS tools within existing workflows to support integration and improve uptake. When implementing a system-wide clinical care intervention, considerations must be made for variability in culture and workflows at the state, health system, practice, and individual levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04255303; https://clinicaltrials.gov/ct2/show/NCT04255303.

ß-Phase Crystallinity, Printability, and Piezoelectric Characteristics of Polyvinylidene Fluoride (PVDF)/Poly(methyl methacrylate) (PMMA)/Cyclopentyl-Polyhedral Oligomeric Silsesquioxane (Cp-POSS) Melt-Compounded Blends.

Poly(vinylidene fluoride) (PVDF) is a semicrystalline polymer that exhibits unique piezoelectric characteristics along with good chemical resistance and high thermal stability. Layer-based material extrusion (MEX) 3D printing of PVDF is desired to create complex structures with piezoelectric properties; however, the melt processing of PVDF typically directs the formation of the α crystalline allomorph, which does not contribute to the piezoelectric response. In this work, PVDF was compounded with poly(methyl methacrylate) (PMMA) and cyclopentyl-polyhedral oligomeric silsesquioxane (Cp-POSS) nanostructured additives in binary and ternary blends to improve MEX printability while maintaining piezoelectric performance. Overall crystallinity and ß phase content were evaluated and quantified using a combination of attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC). Enhancement of MEX printability was measured by quantifying the interlayer adhesion and warpage of printed parts. All blends studied contained a significant percentage of ß allomorph, but it could be detected by ATR-FTIR only after the removal of a thin surface layer. Inclusion of 1% Cp-POSS and up to 10% PMMA in blends with PVDF improved interlayer adhesion (2.3-3.6x) and lowered warpage of MEX printed parts compared to neat PVDF. The blend of 1% Cp-POSS/1% PMMA/PVDF was demonstrated to significantly improve the quality of MEX printed parts while showing similar piezoelectric performance to that of neat PVDF (average piezoelectric coefficient 24 pC/N). MEX printing of PVDF blends directly into usable parts with significant piezoelectric performance while reducing the challenges of printing the semicrystalline polymer opens the potential for application in a number of high value sectors.

Health-associated changes of the fecal microbiota in dairy heifer calves during the pre-weaning period.

Introduction: Neonatal calf diarrhea is a multifactorial condition that occurs in early life when calves are particularly susceptible to enteric infection and dysbiosis of the gut microbiome. Good calf health is dependent on successful passive transfer of immunity from the dam through colostrum. There are limited studies on the developing gut microbiota from birth to weaning in calves. Methodology: Therefore, the objective of this study was to examine the effect of immune status and diarrheal incidence on the development of the fecal microbiota in Jersey (n = 22) and Holstein (n = 29) heifer calves throughout the pre-weaning period. Calves were hand-fed a colostrum volume equivalent to 8.5% of their birthweight, from either the calf's dam (n = 28) or re-heated mixed colostrum (≤2 cows, ≤1d; n = 23) within 2 h of birth. All calves were clinically assessed using a modified Wisconsin-Madison calf health scoring system and rectal temperature at day (d) 0, d7, d21, or disease manifestation (DM) and weaning (d83). Weights were recorded at d0, d21, and d83. Calf blood samples were collected at d7 for the determination of calf serum IgG (sIgG). Fecal samples were obtained at d7, d21/DM [mean d22 (SE 0.70)], and at weaning for 16S rRNA amplicon sequencing of the fecal microbiota. Data were processed in R using DADA2; taxonomy was assigned using the SILVA database and further analyzed using Phyloseq and MaAsLin 2. Results and discussion: Significant amplicon sequence variants (ASVs) and calf performance data underwent a Spearman rank-order correlation test. There was no effect (p > 0.05) of colostrum source or calf breed on serum total protein. An effect of calf breed (p < 0.05) was observed on sIgG concentrations such that Holstein calves had 6.49 (SE 2.99) mg/ml higher sIgG than Jersey calves. Colostrum source and calf breed had no effect (p > 0.05) on health status or the alpha diversity of the fecal microbiota. There was a relationship between health status and time interaction (p < 0.001), whereby alpha diversity increased with time; however, diarrheic calves had reduced microbial diversity at DM. No difference (p > 0.05) in beta diversity of the microbiota was detected at d7 or d83. At the genus level, 33 ASVs were associated (adj.p < 0.05) with health status over the pre-weaning period.