Teprotumumab for Thyroid Eye Disease-related Strabismus.

PURPOSE: To assess and quantify teprotumumab's effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility. METHODS: We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab. RESULTS: Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation (p < 0.001), without significant change in mean horizontal deviation (p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye (p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion. CONCLUSIONS: Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.

Pharmacist-Led Diabetes Control Intervention and Health Outcomes in Hispanic Patients With Diabetes.

Importance: Among patients with type 2 diabetes (T2D), Hispanic individuals are more likely than non-Hispanic White individuals to develop diabetes-related complications. Objective: To examine the association of a pharmacist-led intervention (UCMyRx) with hemoglobin A1c (HbA1c) and systolic blood pressure (SBP) among Hispanic patients with T2D. Design, Setting, and Participants: This quality improvement study used electronic health record data and a difference-in-differences study design to evaluate the association of UCMyRx exposure with changes in HbA1c concentration and SBP among Hispanic patients with T2D, relative to usual care, at University of California, Los Angeles primary care clinics between February and April of 2023. The study population included patients with an International Classification of Diseases, Ninth Revision/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of T2D, self-reporting Hispanic ethnicity, age 18 years or older, with 1 or more visits with a UCMyRx pharmacist (treatment) or 2 or more visits, 2 or more years apart, during the study window (comparison). Additionally, patients had to have the following observations during the study window (March 2, 2013-December 31, 2018): (1) a HbA1c 8% or higher, anywhere between 365 days before and 14 days after the index date (date of the first UCMyRx visit or a randomly generated index date) and a follow-up HbA1c measure within 120 to 365 days after the index date (n = 396) and/or (2) a SBP 140 mm Hg or higher between 365 days before and 14 days after the index date, and a follow-up SBP measure within 120 to 450 days after the index date (n = 795). Exposure: Pharmacists review laboratory results/vital signs, perform medication reconciliation, and develop personally tailored interventions to address adherence barriers and increase guideline-concordant care. Main Outcomes and Measures: Pre- to post-index date changes in HbA1c and SBP. Results: Of the 931 unique patients with T2D analyzed, the mean (SD) age was 64 (14.1) years, and 552 (59.3%) were female. In adjusted analyses, having 1 or more UCMyRx visits was associated with a reduction in HbA1c concentration (ß = -0.46%; 95% CI, -0.84% to -0.07%) but no change in SBP (ß = -1.71 mm Hg; 95% CI, -4.00 to 0.58 mm Hg). Conclusions and Relevance: In this quality improvement study of UCMyRx among Hispanic patients with T2D, a negative association was observed between UCMyRx exposure and HbA1c concentration but not SBP. Pharmacist-led intervention may be a strategy for improving outcomes among Hispanic patients with T2D.

Knowledge user survey and Delphi process to inform development of a new risk of bias tool to assess systematic reviews with network meta-analysis (RoB NMA tool).

BACKGROUND: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee recommended that the RoB NMA tool to be used in combination with the Risk of Bias in Systematic reviews (ROBIS) tool (i.e. because it was designed to assess biases only) or other similar quality appraisal tools (eg, A MeaSurement Tool to Assess systematic Reviews 2 [AMSTAR 2]) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed and results were presented, including the way in which the evidence was assembled and interpreted. OBJECTIVES: Conduct (a) a Delphi process to determine expert opinion on an item's inclusion and (b) a knowledge user survey to widen its impact. DESIGN: Cross-sectional survey and Delphi process. METHODS: Delphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users' views and preferences about the importance, utility and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks. RESULTS: 22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2. Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organisation produced NMAs, and 78% showed high interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assess both bias in individual NMA results and authors' conclusions. Response bias in our sample is a major limitation as knowledge users working in high-income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines. CONCLUSIONS: This Delphi process and knowledge user survey informs the development of the RoB NMA tool.

Perceptions of clinical care and research among African-American patients with lymphoma.

Across lymphoma subtypes, African Americans experience disparities in clinical trial enrollment and outcomes. Understanding the needs of this population can aid addressing these disparities. Semi-structured interviews were conducted with 14 self-identified Black/African-American lymphoma patients to determine their perceptions and attitudes about aspects of treatment and research. Constant-comparative methods identified themes including trust in medical staff, lack of diagnosis information, interest in research, research priorities, and potentially unaddressed emotional needs. Patients trusted their doctors and desired more diagnosis information. Participants often did not consider the emotions surrounding their diagnoses and concentrated on positive attitudes during treatment. Most participants were interested in clinical trials to help future lymphoma patients. Participants suggested a range of future research topics emphasizing lymphoma etiology. Building on trusting doctor-patient relationships, expanding clinical trials information, addressing emotional needs, and aligning research objectives with patient concerns are potential strategies for increasing clinical trial enrollment among Black lymphoma patients.

Toxicity after adjuvant therapy for stage III uterine cancer.

OBJECTIVE: The optimal adjuvant therapy for stage III endometrial cancer is unknown. Studies have suggested that combination therapy with chemotherapy and radiation is associated with improved survival. We examined early and late-term toxicities associated with chemotherapy (CT), external beam radiotherapy (RT), or combination chemoradiotherapy for stage III uterine cancer. METHODS: The SEER-Medicare database was used to identify women age ≥ 65 years with stage III uterine cancer who received adjuvant CT, RT, or chemoradiotherapy from 2000 to 2015. The associations between therapy and early and late-term toxicities identified with billing claims, hospitalizations and emergency department visits were examined using multivariable regression models. RESULTS: A total of 2185 patients were identified including 574 (26.3%) who received CT, 636 (29.1%) who received RT, and 975 (44.6%) who received chemoradiotherapy. The proportion of patients receiving chemoradiotherapy or CT increased over time. During the first 6 and 12 months of adjuvant therapy, RT was associated with a lower risk of early-term toxicity compared to chemoradiotherapy (aRR = 0.59, 95%CI 0.49-0.70 and aRR = 0.76, 95%CI 0.67-0.86, respectively) while CT shared a similar risk of early toxicities as chemoradiotherapy. CT and RT shared a similar risk of late-term toxicities compared to chemoradiotherapy. CT and RT alone were associated with a higher hazard for overall mortality than chemoradiotherapy (aHR = 1.27, 95% CI 1.10-1.47 and aHR = 1.25, 95% CI 1.08-1.44, respectively). CONCLUSION: Chemoradiotherapy is associated with lower mortality compared to single modality therapy and has a similar risk of early and late term toxicities compared to CT, though higher risk of early toxicities compared to RT.

Priorities for Rural Lymphoma Survivors: A Qualitative Study.

BACKGROUND: We gathered rural patient perspectives on lymphoma care and unmet needs throughout the treatment course to better understand their attitudes toward treatment and their barriers to participating in clinical research studies. PATIENTS AND METHODS: We conducted 12 individual semi-structured telephone interviews in the spring of 2018 with lymphoma survivors from rural counties in Georgia. Patients were identified by a residential address in counties classified as rural according to the Rural-Urban Commuting Areas codes. Participants were recruited from regional patient education conferences and from current research participants at a university research hospital in Georgia. The interviews were recorded and transcribed verbatim. Thematic analysis and MAXQDA, version 18.0.8, were used to facilitate a constant comparative coding process during theme development. RESULTS: The greatest barrier to care was the travel distance. The participants described difficulty navigating between local clinics and larger cancer centers. The lack of communication between the local and specialized clinics complicated the process, and participants had difficulty contacting or seeking advice from the team at the larger cancer centers. Seeking treatment from specialized clinics farther away introduced additional barriers. Most participants agreed that the use of technology was important for improved communication. Participants described lymphoma etiology, subtype-specific studies, alternative therapies, and quality of life as key research priorities. CONCLUSION: These findings suggest that targeted research and interventions are necessary to address the specific needs of rural patients with and survivors of lymphoma. To address the disparity in health outcomes within rural populations, healthcare professionals and investigators can use these data to engage rural patients in treatment decision-making and research planning.

Patient and caregiver perceptions of lymphoma care and research opportunities: A qualitative study.

BACKGROUND: Although the number of lymphoma survivors has increased, the needs and research priorities of survivors and their caregivers rarely are examined and addressed. Determining the needs and priorities for this population requires an assessment of the attitudes and experiences of patients and caregivers. The authors conducted a qualitative study with lymphoma survivors and their caregivers to determine care needs and research priorities. METHODS: In the first phase, 2 semistructured focus groups were conducted with 15 lymphoma survivors and their caregivers. In phase 2, a total of 19 individual semistructured telephone interviews were conducted with lymphoma survivors and their caregivers. In both phases, participants discussed cancer experiences and research priorities. All interviews were transcribed. MAXQDA software (version 18.0.8) was used for coding and identifying themes. RESULTS: The majority of participants felt disconnected from their clinical care team due to a lack of communication. Focus group participants noted a lack of information regarding diagnoses, treatment, research, and survivorship care. Participants coped with fear through strong social support and fostering relationships with their clinical care teams. Some caregivers felt completely ignored by clinicians. Participants expressed interest in research, but had difficulty finding relevant studies. Several interviewees desired holistic and survivorship-oriented research and more studies regarding quality of life and mental health. CONCLUSIONS: The results of the current study identified unmet needs in clinical care and patient-oriented research, including needs for a focus on quality of life after treatment, communication between patients and the scientific community, and emotional well-being. Health care professionals can use these data to provide care delivery, supportive services, and research that meets the needs of lymphoma survivors and their caregivers.

Recurrence rates for patients with early-stage breast cancer treated with IOERT at a community hospital per the ASTRO consensus statement for APBI.

PURPOSE: To report the recurrence rates after single-fraction intraoperative electron radiotherapy (IOERT) in patients with early-stage breast cancer treated on a single institution prospective Phase I/II protocol at a community hospital. Results were retrospectively analyzed according to suitability criteria from the updated American Society for Radiation Oncology (ASTRO) consensus statement for accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: Patients over 40 years with early-stage invasive or in situ breast cancer (<2.5 cm and node negative) were enrolled. IOERT 2100 cGy was delivered during breast conservation surgery, and patients were followed up for a median of 3 years (0.8-6.5 years) to determine toxicity and recurrence rates. RESULTS: Single-fraction IOERT was performed in 215 cases (6 bilateral treatments, 196 patients) with 13 patients receiving whole-breast radiation (WBR) after IOERT for adverse pathologic features. Of 202 cases of IOERT without WBR, 89 patients experienced an ipsilateral breast tumor recurrence (IBTR) giving a cumulative incidence of 3.96%. When the ASTRO APBI suitability criteria were applied, the IBTR rate was significantly lower for suitable patients vs. cautionary or unsuitable patients (1.6% vs. 3.4% vs. 21.0%, p = 0.0002). 3-year progression-free survival after IOERT alone was 93.4%. For patients who received standard WBR (4500-5040 cGy) after IOERT, no Grade 3 or 4 toxicities (acute or late) occurred and all patients are disease-free. CONCLUSIONS: Single-fraction IOERT results in a low rate of IBTR when strictly adhering to ASTRO criteria for APBI suitability. Standard dose WBR for unfavorable pathologic results after 2100 cGy IOERT is well tolerated.

Mechanical diffraction reveals the role of passive dynamics in a slithering snake.

Limbless animals like snakes inhabit most terrestrial environments, generating thrust to overcome drag on the elongate body via contacts with heterogeneities. The complex body postures of some snakes and the unknown physics of most terrestrial materials frustrates understanding of strategies for effective locomotion. As a result, little is known about how limbless animals contend with unplanned obstacle contacts. We studied a desert snake, Chionactis occipitalis, which uses a stereotyped head-to-tail traveling wave to move quickly on homogeneous sand. In laboratory experiments, we challenged snakes to move across a uniform substrate and through a regular array of force-sensitive posts. The snakes were reoriented by the array in a manner reminiscent of the matter-wave diffraction of subatomic particles. Force patterns indicated the animals did not change their self-deformation pattern to avoid or grab the posts. A model using open-loop control incorporating previously described snake muscle activation patterns and body-buckling dynamics reproduced the observed patterns, suggesting a similar control strategy may be used by the animals. Our results reveal how passive dynamics can benefit limbless locomotors by allowing robust transit in heterogeneous environments with minimal sensing.

Corrigendum: In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.

This corrects the article DOI: 10.1038/nbt.3836.

In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.

In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.

Collagen/chitosan film containing biotinylated glycol chitosan nanoparticles for localized drug delivery.

The objective of this study was to design a drug delivery system consisting of biotinylated cholesterol-modified glycol chitosan (Bio-CHGC) nanoparticles and fish collagen/chitosan (Col/Ch) film for localized chemotherapy. Bio-CHGC was synthesized, and then its self-assembled nanoparticles were prepared by probe sonication. Doxorubicin (DOX)-loaded Bio-CHGC (DBC) nanoparticles prepared by dialysis had spherical shape, and their sizes were in the range of 330-397 nm. Col/Ch/DBC nanoparticle films were fabricated by freeze-drying. SEM showed that the DBC nanoparticles were uniformly distributed into the films, and the films retained their structural integrity. A higher degradation and swelling rate of the drug films led to a higher diffusion rate of the nanoparticles from the films, resulting in an increase in the drug release from nanoparticles. The release of DOX from the films or Bio-CHGC nanoparticles was sensitive to the pH value of the release medium. In addition, the DOX release ratio of the drug films was lower than that of the nanoparticles alone, suggesting that the drug films had a double-sustained effect on the drug release. MTT assay implied that the DBC nanoparticle film showed a higher inhibitory ratio than the film containing nanoparticles without biotin, indicating that biotin moieties in the nanoparticles played an important role in exerting a cytotoxic effect. These data demonstrate that Col/Ch/DBC nanoparticle film has the potential to be used as a localized delivery system for hydrophobic antitumor drugs.

Robust hippocampal responsivity during retrieval of consolidated associative memory.

A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories.

Choline in infant formula and adult nutritionals by ion chromatography and suppressed conductivity: First Action 2012.20.

Single-laboratory validation (SLV) data from a method for the determination of choline in infant formula and adult nutritionals by ion chromatography (IC) and suppressed conductivity were generated and presented to the Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Expert Review Panel (ERP) at the AOAC Annual Meeting held in Las Vegas, NV, during September 30 to October 3, 2012. The ERP reviewed the data and concluded that the data met the standard method performance requirements (SMPRs) established and approved the method as AOAC Official First Action. At the ERP's request, a second, full SLV was performed on 17 SPIFAN matrixes that included fortified and placebo products. Prior to IC analysis, microwave-assisted acid hydrolysis was used to digest and release bound choline from powder and ready-to-feed (RTF) infant formula and adult nutritional samples. Following hydrolysis, separation of choline from common cations was achieved on a Thermo Scientific Dionex IonPac CS19 column followed by suppressed conductivity detection. Total choline was measured and reported as the choline ion in mg/100 g reconstituted material or RTF as-is. The system was calibrated over the analytical range specified in the SMPR (2-250 mg/100 g). Recoveries of spiked samples at 50 and 100% of the fortified choline amounts ranged from 93.1 to 100.7% with RSDs < or = 6.7% for product containing < 2 mg/100 g and < or = 4.1% for product containing 2-100 mg/100 g. Accuracy for the National Institute of Standards and Technology Standard Reference Material 1849a was determined over a 6-day interval and found to be 10.2 +/- 0.2 mg/100 g calculated as the reconstituted powder with an RSD of 1.8%. The LOD was determined to be 0.009, and the LOQ 0.012 mg/100 g, well below the SMPR requirements of 0.7 and 2 mg/100 g, respectively. Repeatability RSDs over the range of the assay (2-200 mg/100 g) ranged from 1.0 to 5.93%

Laser ablative patterning of copoly(imide siloxane)s generating superhydrophobic surfaces.

Low surface energy copoly(imide siloxane)s were generated via condensation polymerization reactions. The generated materials were characterized spectroscopically, thermally, mechanically, and via contact angle goniometry. The decrease in tensile modulus and opaque appearance of copoly(imide siloxane) films indicated phase segregation in the bulk. Preferential surface partitioning of the siloxane moieties was verified by X-ray photoelectron spectroscopy (XPS) and increased advancing water contact angle values (theta(A)). Pristine copoly(imide siloxane) surfaces typically exhibited theta(A) values of 111 degrees and sliding angles from 27 degrees to >60 degrees. The surface properties of these copoly(imide siloxane) films were further altered using laser ablation patterning (frequency-tripled Nd:YAG laser, 355 nm). Laser-etched square pillar arrays (25 microm pillars with 25 microm interspaces) changed theta(A) by up to 64 degrees. Theta(A) values approaching 175 degrees and sliding angles from 1 degree to 15 degrees were observed. ATR-IR spectroscopy and XPS indicated polymer chain scission reactions occurred as a result of laser ablation. Initial particle adhesion studies revealed that the copoly(imide siloxane)s outperformed the corresponding homopolyimides and that laser ablation patterning further enhanced this result.

Dominance and context effects on activation of alternative homophone meanings.

Two eyetracking-during-listening experiments showed frequency and context effects on fixation probability for pictures representing multiple meanings of homophones. Participants heard either an imperative sentence instructing them to look at a homophone referent (Experiment 1) or a declarative sentence that was either neutral or biased toward the homophone's subordinate meaning (Experiment 2). At homophone onset in both experiments, the participants viewed four pictures: (1) a referent of one homophone meaning, (2) a shape competitor for a nonpictured homophone meaning, and (3) two unrelated filler objects. In Experiment 1, meaning dominance affected looks to both the homophone referent and the shape competitor. In Experiment 2, as compared with neutral contexts, subordinate-biased contexts lowered the fixation probability for shape competitors of dominant meanings, but shape competitors still attracted more looks than would be expected by chance. We discuss the consistencies and discrepancies of these findings with the selective access and reordered access theories of lexical ambiguity resolution.