Techniques for Implementing Continuous Glucose Monitoring in Primary Care: Key CGM Updates and Highlights from the ADA 2024 Conference [Podcast].

This podcast discusses innovations, advancements, and discoveries in continuous glucose monitoring that were presented at the American Diabetes Association 84th Scientific Sessions held in Orlando, Florida, June 2024. Specifically, the author will discuss sessions focused on (1) Equity and access to new technologies; (2) The role of the interdisciplinary team in technology onboarding in primary care; (3) New technologies for glucose monitoring and sensing; (4) New technologies for continuous glucose monitoring (CGM); and (5) CGM implementation in primary care.

What Free Flaps Are Surgeons Using for Palatal Fistula Repair in Patients with Cleft Palate? A Systematic Review.

OBJECTIVE: Recalcitrant palatal fistulas in patients with cleft palate history sometimes require free flap reconstruction. This study reviews the literature on described flaps and outcomes. DESIGN: A systematic review was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. SETTING: All study designs were included. Non-English articles were excluded. PATIENTS AND PARTICIPANTS: Patients with a history of cleft palate who underwent free flap reconstruction for a oronasal fistula. INTERVENTIONS: Free tissue transfer for a palatal fistula repair. MAIN OUTCOMEE MEASURES: Information regarding defect and flap characteristics were reviewed. Surgical outcomes such as flap loss rates, rates of recurrent fistula formation, and speech outcomes were also obtained. RESULTS: Our search returned 894 articles, of which 23 were included. All studies were retrospective case series and reports. A total of 65 patients were described with an average age of 19.3 (range 3-55) years and a median fistula size of 8.00 cm2 (range 2.54 cm2 - 24 cm2). The most common flap was the radial forearm flap (n = 37). Nine patients (13.8%) had recurrent fistula formation with surgical revision successful in all cases in which the patient returned to the operating room. There were two partial flap losses and no total flap losses. Speech outcomes showed improvement in 27 patients across 10 studies. CONCLUSIONS: Palatal fistula repair with free tissue transfer is safe with an acceptable risk profile and low flap loss rate. Early recurrence due to partial flap necrosis and dehiscence are successfully managed with flap readvancement.

Association of Changes in A1C Following Continuous Glucose Monitoring Acquisition in People with Sub-Optimally Treated Type 2 Diabetes Taking GLP-1 RA Therapy.

INTRODUCTION: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and continuous glucose monitoring (CGM) improve glycemia in patients with type 2 diabetes (T2D). However, it is unknown whether adding CGM to GLP-1 RA therapy further improves A1c. We evaluated changes in A1c levels 6 months after initiation of FreeStyle Libre (FSL) in adults with sub-optimally controlled T2D already on GLP-1 RA therapy. METHODS: This retrospective, observational study used Optum's de-identified Market Clarity Data, a linked electronic health record-claims database to assess changes in A1c after FSL acquisition. Inclusion criteria were T2D diagnosis, ≥ 18 years, baseline A1c ≥ 8%, with the first FSL acquisition between 2018 and 2022. Patients were required to be on GLP-1 RA prior to FSL with at least one GLP-1 RA prescription within 90 days of FSL acquisition. GLP-1 RA initiation was defined as the earliest GLP-1 RA prescription from 2017 onwards. Paired changes in A1c were assessed at 6 months after initial FSL acquisition. RESULTS: The study cohort included 1454 adults with T2D (age 55 ± 10 years, 52% male, 38% with intensive insulin therapy, median 471 days from GLP-1 RA initiation to FSL, and baseline A1c 9.8 ± 1.5%). After FSL acquisition, patients experienced an A1c decrease of 1.5 ± 1.9% (p < 0.001). Patients with a baseline A1c > 10% had the largest reduction (n = 497, - 2.7 ± 2.2%, p < 0.001). Significant improvements were observed in subgroups based on insulin therapy and GLP-1 RA formulation. Those initiating GLP-1 RA therapy > 24 months before FSL acquisition also showed improvements in A1c (n = 478; - 1.3 ± 1.7%, p < 0.001). CONCLUSIONS: In a large, real-world study of adults with T2D, those on prior GLP-1 RA therapy experienced significant A1c improvements after acquiring FSL, irrespective of GLP-1 RA duration, GLP-1 RA formulation, or insulin therapy type. These findings support the use of FSL in adults with T2D treated with GLP-1 RA.

The sugar cube: Network control and emergence in stereoediting reactions.

Stereochemical editing strategies have recently enabled the transformation of readily accessible substrates into rare and valuable products. Typically, site selectivity is achieved by minimizing kinetic complexity by using protecting groups to suppress reactivity at undesired sites (substrate control) or by using catalysts with tailored shapes to drive reactivity at the desired site (catalyst control). We propose "network control," a contrasting paradigm that exploits hidden interactions between rate constants to greatly amplify modest intrinsic biases and enable precise multisite editing. When network control is applied to the photochemical isomerization of hexoses, six of the eight possible diastereomers can be selectively obtained. The amplification effect can be viewed as a mesoscale phenomenon between the limiting regimes of kinetic control in simple chemical systems and metabolic regulation in complex biological systems.

Making treatment guideline recommendations in chronic kidney disease and type 2 diabetes more accessible to primary care providers in the United States.

Clinical practice guidelines for the management of chronic kidney disease (CKD) associated with type 2 diabetes (T2D) are designed to assist healthcare professionals with clinical decision making by providing recommendations on the screening, detection, management, and treatment of these conditions. However, primary care practitioners (PCPs) may have clinical inertia when it comes to routinely enacting CKD and T2D guideline recommendations in their clinical practices. Guideline developers have published a range of resources with the aim of facilitating easier access to guideline recommendations to support efficient and consistent implementation into clinical practice of PCPs. Challenges remain in providing strategies to reduce inertia in the application of guideline recommendations in primary care. In this review, we explore reasons behind the low level of awareness and poor uptake of published evidence-based care approaches to the optimal management of patients with T2D and CKD. Finally, we present suggestions on strategies to improve the implementation of guideline-directed recommendations in primary care.

Clinical practice guidelines for managing chronic kidney disease (CKD) for people who also have type 2 diabetes (T2D) provide healthcare providers with recommendations on how to identify, diagnose, and treat CKD. Although treatments cannot cure CKD, they can help to reduce the risk of CKD getting worse. The recommendations are based on results of clinical trials that tested how safe and how well a medication works among many people with CKD and T2D. If these clinical trials show that the medicine is beneficial for people with CKD and T2D, then it may be included in guideline recommendations. Most people living with T2D and early-stage CKD are treated by their primary care practitioner (PCP). If PCPs are not fully aware of guideline recommendations, then their patients may lose the opportunity to receive medications that can benefit them. PCPs have said that barriers to implementing guideline recommendations in their clinical practices include too many guidelines and that the guidelines are difficult to understand and use in their offices. Guideline developers have thought of ways to make the guidelines easier to access and use. This includes putting the guidelines onto mobile apps, providing online resources, making versions more relevant to PCPs, and combining multiple guidelines. These approaches are helpful, but more work is needed. This review article talks about the reasons why PCPs are not always aware of the most up-to-date guideline recommendations for CKD and T2D, how guideline developers have found different ways of sharing the guideline recommendations, and what more can be done.

Expert Panel Recommendations for a Standardized Ambulatory Glucose Profile Report for Connected Insulin Pens.

Background: Connected insulin pens capture data on insulin dosing/timing and can integrate with continuous glucose monitoring (CGM) devices with essential insulin and glucose metrics combined into a single platform. Standardization of connected insulin pen reports is desirable to enhance clinical utility with a single report. Methods: An international expert panel was convened to develop a standardized connected insulin pen report incorporating insulin and glucose metrics into a single report containing clinically useful information. An extensive literature review and identification of examples of current connected insulin pen reports were performed serving as the basis for creation of a draft of a standardized connected insulin pen report. The expert panel participated in three virtual standardization meetings and online surveys. Results: The Ambulatory Glucose Profile (AGP) Report: Connected Insulin Pen brings all clinically relevant CGM-derived glucose and connected insulin pen metrics into a single simplified two-page report. The first page contains the time in ranges bar, summary of key insulin and glucose metrics, the AGP curve, and detailed basal (long-acting) insulin assessment. The second page contains the bolus (mealtime and correction) insulin assessment periods with information on meal timing, insulin-to-carbohydrate ratio, average bolus insulin dose, and number of days with bolus doses recorded. The report's second page contains daily glucose profiles with an overlay of the timing and amount of basal and bolus insulin administered. Conclusion: The AGP Report: Connected Insulin Pen is a standardized clinically useful report that should be considered by companies developing connected pen technology as part of their system reporting/output.

Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies.

A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/apoptosis assay showed that apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was ∼0.19 cm3 for 50 mg/kg versus ∼2.39 cm3 in case of untreated mice and tumor weight was ∼71.6 mg for 50 mg/kg versus ∼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.

Dynamic sampling in autonomous process optimization.

Autonomous process optimization (APO) is a technology that has recently found utility in a multitude of process optimization challenges. In contrast to most APO examples in microflow reactor systems, we recently presented a system capable of optimization in high-throughput batch reactor systems. The drawback of APO in a high-throughput batch reactor system is the reliance on reaction sampling at a predetermined static timepoint rather than a dynamic endpoint. Static timepoint sampling can lead to the inconsistent capture of the process performance under each process parameter permutation. This is important because critical process behaviors such as rate acceleration accompanied by decomposition could be missed entirely. To address this drawback, we implemented a dynamic reaction endpoint determination strategy to capture the product purity once the process stream stabilized. We accomplished this through the incorporation of a real-time plateau detection algorithm into the APO workflow to measure and report the product purity at the dynamically determined reaction endpoint. We then applied this strategy to the autonomous optimization of a photobromination reaction towards the synthesis of a pharmaceutically relevant intermediate. In doing so, we not only uncovered process conditions to access the desired monohalogenation product in 85 UPLC area % purity with minimal decomposition risk, but also measured the effect of each parameter on the process performance. Our results highlight the advantage of incorporating dynamic sampling in APO workflows to drive optimization toward a stable and high-performing process.

Initiating GLP-1 Therapy in Combination with FreeStyle Libre Provides Greater Benefit Compared with GLP-1 Therapy Alone.

Background and Aim: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in hemoglobin A1c (HbA1c) between people acquiring GLP-1 with FSL (GLP-1+FSL) versus GLP-1 without FSL (GLP-1). Methods: This real-world study used Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database, and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018 and 2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c, and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at 6 months. Results: The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n = 478; GLP-1, n = 24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5 ± 11.8 and 53.5 ± 11.3 years, HbA1c 10.25 ± 1.68% and 10.22 ± 1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared with the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, P < 0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, P < 0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), nonintensive insulin (-2.50% vs. -1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (-2.73% vs. -1.92%) and dulaglutide (-2.45% vs. -1.71%) GLP-1 RA, all P < 0.001. Conclusions: Adults with suboptimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared with those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Influence of Exposure to a Wet Atmosphere on the UV-Sensing Characteristics of ZnO Nanorod Arrays.

Zinc oxide is a promising material for the creation of various types of sensors, in particular UV detectors. In this work, arrays of ordered nanorods were grown by chemical vapor deposition. The effect of environmental humidity on the sensing properties of zinc oxide nanorod arrays was investigated, and a prototype UV sensor using indium as an ohmic contact was developed. UV photoresponses were measured for the samples stored in dry and wet atmospheres. The increase in sensitivity and response of the ZnO nanorod arrays was observed after prolonged exposure to a wet atmosphere. A model was proposed to explain this effect. This is due to the formation of hydroxyl groups on the surface of zinc oxide nanorods, which is confirmed by FTIR spectroscopy data. For the first time, it has been shown that after storage in a wet atmosphere, the sensory properties of the structure remain stable regardless of the ambient humidity.

Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial.

Background: RYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in the RYR1 gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-RM. Methods: Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021. Findings: S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination. Interpretation: S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM. Funding: NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part II. Age-associated alterations in serotonin receptor binding profiles within medullary nuclei supporting cardiorespiratory homeostasis.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls-a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death. The prevalence and percentage of nuclei with low 5-HT1A and 5-HT2A/C binding in SIDS were twice that of controls. The percentage of nuclei with low 5-HT2A/C binding was greater in older SIDS infants. In >80% of older SIDS infants, low 5-HT2A/C binding characterized the hypoglossal nucleus, vagal dorsal nucleus, nucleus of solitary tract, and nuclei of the olivocerebellar subnetwork (important for blood pressure regulation). Together, our findings from SIDS infants and from animal models of serotonergic dysfunction suggest that some SIDS cases represent a serotonopathy. We present new hypotheses, yet to be tested, about how defects within serotonergic subnetworks may lead to SIDS.

Revisiting Breast Reduction Insurance Coverage: How the Schnur Scale Discriminates against Women Based on Body Habitus.

BACKGROUND: The Schnur scale used body surface area (BSA) to determine the amount of breast tissue resection in reduction mammaplasty, resulting in a greater requirement of breast weight removal in patients with larger BSA. The authors aimed to demonstrate BSA variance among women with similar mastectomy weights and the range of mastectomy weights among women with comparable BSAs. METHODS: A retrospective chart review of patients who underwent mastectomy from October of 2021 to June of 2022 was performed. Patients were included if they underwent skin-sparing or nipple-sparing mastectomy with a minimum specimen weight of 700 g. Patient's BSA, body mass index (BMI), mastectomy weight, and Schnur weight requirement (SWR) were collected. RESULTS: A total of 130 patients (194 breasts) were included. There was significant variance in mean BSA, BMI, SWR, and SWR-to-mastectomy weight ratio among women with similar mastectomy weights. BSA varied by as much as 0.82 units, BMI varied by as much as 32 kg/m 2 , and SWR varied by as much as 1365 g within the same mastectomy weight group. There was also significant variance in mastectomy weights among women with comparable BSA, especially in BSA groups greater than 2.20, with the greatest range in mastectomy weights being 1684 g. CONCLUSIONS: Analysis of mastectomy patients showed no predictable relationship between BSA and breast weight. There was significant variance in the BSA of patients with similar breast weights, and conversely in breast weights of patients with comparable BSA. Therefore, strict adherence to the Schnur weight requirement can prevent patients with macromastia from receiving breast reductions.

Total Synthesis of (+)-Discorhabdin V.

The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon-nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon-nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds.

Nearly complete structure of bacteriophage DT57C reveals architecture of head-to-tail interface and lateral tail fibers.

The T5 family of viruses are tailed bacteriophages characterized by a long non-contractile tail. The bacteriophage DT57C is closely related to the paradigmal T5 phage, though it recognizes a different receptor (BtuB) and features highly divergent lateral tail fibers (LTF). Considerable portions of T5-like phages remain structurally uncharacterized. Here, we present the structure of DT57C determined by cryo-EM, and an atomic model of the virus, which was further explored using all-atom molecular dynamics simulations. The structure revealed a unique way of LTF attachment assisted by a dodecameric collar protein LtfC, and an unusual composition of the phage neck constructed of three protein rings. The tape measure protein (TMP) is organized within the tail tube in a three-stranded parallel α-helical coiled coil which makes direct contact with the genomic DNA. The presence of the C-terminal fragment of the TMP that remains within the tail tip suggests that the tail tip complex returns to its original state after DNA ejection. Our results provide a complete atomic structure of a T5-like phage, provide insights into the process of DNA ejection as well as a structural basis for the design of engineered phages and future mechanistic studies.

Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study.

PURPOSE: The aim of this study was to assess the long-term safety and efficacy of perfluorohexyloctane (PFHO) ophthalmic drop (formerly NOV03) for treatment of dry eye disease (DED). METHODS: KALAHARI was a phase 3, multicenter, single-arm, open-label extension study in patients aged 18 years or older with DED associated with Meibomian gland dysfunction who completed the randomized, double-masked, hypotonic saline-controlled GOBI study. Patients instilled 1 drop of PFHO (MIEBO, Bausch + Lomb) 4 times daily in both eyes for 52 weeks. Safety assessments included adverse events, best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, and dilated fundoscopy. Efficacy end points included change from GOBI study baseline in total corneal fluorescein staining and eye dryness score (0-100 visual analog scale). RESULTS: Overall, 208 patients from GOBI (PFHO [n = 97]; saline [n = 111]) were rolled over into KALAHARI. Twenty-nine patients (13.9%) had ≥1 ocular adverse event, with most being mild or moderate in severity; the most common ocular adverse events were vitreous detachment (1.9%), allergic conjunctivitis (1.4%), blurred vision (1.4%), and increased lacrimation (1.4%). Other safety end points were unremarkable. For patients continuing PFHO from GOBI, improvements in total corneal fluorescein staining and visual analog scale dryness scores observed in GOBI were maintained throughout KALAHARI. Patients treated with saline in GOBI and switched to PFHO in KALAHARI showed improvements in total corneal fluorescein staining and visual analog scale scores by week 4 that were maintained for the rest of the study. CONCLUSIONS: PFHO was safe and well tolerated and maintained efficacy for improving signs and symptoms of DED in this year-long study of patients with DED associated with Meibomian gland dysfunction.

A review of the first anti-evaporative prescription treatment for dry eye disease: perfluorohexyloctane ophthalmic solution.

Dry eye disease (DED) is one of the most common ocular surface disorders. All DED involves an imbalance between tear production and evaporation. Most cases of DED are driven by excessive evaporation, which is often associated with meibomian gland dysfunction (MGD). In evaporative DED, a deficient tear film lipid layer is believed to lead to increased tear evaporation, inflammation, and ocular surface damage. Most prescription treatments for DED address signs and symptoms by targeting tear production and/or inflammation, but they do not address excessive evaporation. Perfluorohexyloctane (PFHO) ophthalmic solution (MIEBO™; Bausch + Lomb) is a water-free, single-ingredient, preservative-free prescription eye drop that directly targets tear evaporation and is approved by the FDA to treat the signs and symptoms of DED. Results from preclinical studies indicate that PFHO has a high oxygen carrying capacity, may reduce friction on blinking, and spreads quickly over the tear film surface to form a monolayer that inhibits evaporation. These effects can lead to stabilization of the tear film to promote ocular surface healing. Further, PFHO was detected in tears for at least 6 hours in a rabbit pharmacokinetic study, and results indicate that it may improve lipid layer thickness and quality. In 2 pivotal phase 3 trials in patients with DED and clinical signs of MGD (GOBI [NCT04139798] and MOJAVE [NCT04567329]), treatment with PFHO consistently met primary efficacy end points related to DED signs and symptoms (total corneal fluorescein staining and eye dryness, respectively) and was well tolerated. Compared with use of hypotonic saline solution, instillation of PFHO led to significant improvements in signs and symptoms in as early as 2 weeks. In a long-term, open-label safety extension study, efficacy of PFHO was sustained over 12 months, and the safety profile was consistent with those of previous studies. Clinical trial results indicate that treatment with PFHO effectively and consistently reduces the signs and symptoms of DED.

The transcription factor EBF1 non-cell-autonomously regulates cardiac growth and differentiation.

Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly expressed in non-myocytes and potently regulates heart development. Ebf1-deficient hearts display myocardial hypercellularity and reduced cardiomyocyte size, ventricular conduction system hypoplasia, and conduction system disease. Growth abnormalities in Ebf1 knockout hearts are observed as early as embryonic day 13.5. Transcriptional profiling of Ebf1-deficient embryonic cardiac non-myocytes demonstrates dysregulation of Polycomb repressive complex 2 targets, and ATAC-Seq reveals altered chromatin accessibility near many of these same genes. Gene set enrichment analysis of differentially expressed genes in cardiomyocytes isolated from E13.5 hearts of wild-type and mutant mice reveals significant enrichment of MYC targets and, consistent with this finding, we observe increased abundance of MYC in mutant hearts. EBF1-deficient non-myocytes, but not wild-type non-myocytes, are sufficient to induce excessive accumulation of MYC in co-cultured wild-type cardiomyocytes. Finally, we demonstrate that BMP signaling induces Ebf1 expression in embryonic heart cultures and controls a gene program enriched in EBF1 targets. These data reveal a previously unreported non-cell-autonomous pathway controlling cardiac growth and differentiation.

Lymphatic Mapping with Contrast-enhanced Ultrasound for Lymphaticovenous Anastomosis Surgery: How We Do It.

Lymphaticovenous anastomosis (LVA) surgery is an effective surgery for the treatment of lymphedema in the extremities. Indocyanine green lymphography is the reference standard for visualizing lymphatics for LVA surgery, but it has several limitations; most notably, superficial dermal congestion can mask deeper lymphatic vessels. To overcome the limitations, we add contrast-enhanced ultrasound (CEUS) lymphography. We have previously reported that CEUS lymphography can identify lymphatic vessels for LVA surgery that indocyanine green lymphography does not. Here, we describe how we perform CEUS lymphography, including workflow, technique, and documentation. Before informed consent, the patient must be screened for possible adverse reactions to microbubbles. The procedure involves multiple intradermal injections of the microbubble agent at various sites along the extremity. After each injection, imaging for microbubble uptake by lymphatic vessels is performed using an ultrasound scanner with contrast-specific software. We use sulfur hexafluoride lipid-type A microspheres (Lumason/SonoVue; Bracco Suisse SA), but we are investigating the performance of other Food & Drug Administration-approved microbubble agents for CEUS lymphography. Having a systematic approach to marking the skin can mitigate the hindrance of marking over ultrasound coupling gel. Another benefit of CEUS lymphography is the rapid identification of neighboring veins compatible in size and location for anastomosis. We hold regular scheduled multidisciplinary meetings for coordination of care, discussion of outcomes, quality assurance, and ongoing innovation.

Breast Implant-Associated Anaplastic Large Cell Lymphoma Awareness: An Analysis of the Responses to an Institutional Campaign and Global Recall.

BACKGROUND: We performed an assessment of patient response rates and clinical outcomes to the global recall for textured breast implants and to our institution's letters informing them of their risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). METHODS: A retrospective review of patients who had textured implants placed at our institution was completed. Outcome measures included patient response rates to either the global recall or our institution's letters, rate of textured implant removal, and type of subsequent revision surgery. RESULTS: A total of 1176 patients with textured implants were reviewed for this study. In total, 374 patients (31.8%) reached out to discuss their risk of BIA-ALCL, and 297 (25.3%) eventually presented to the clinic. One hundred twenty eight patients (34.2%) responded after the letter but before the US Food and Drug Administration (FDA) ban of macrotextured BIOCELL implants, 186 (49.7%) after the FDA ban, and 48 (12.8%) after the manufacturer's multichannel campaign. One hundred eighteen patients with textured implants (11.6%) proceeded with surgery. Most underwent exchange with smooth implants (76 patients [64.4%]) after textured implant removal. CONCLUSIONS: A significant portion of patients (31.8%) responded to our letters, the FDA ban, and the manufacturer's campaign. Despite the low incidence of BIA-ALCL and the ongoing recommendation for observation in the setting of no symptoms, 11.6% of our patients still elected to proceed with implant removal. Exchange to smooth implants was the most popular surgical option at 64.4%.