Help Me Help You: How to Request a Letter of Recommendation.

Letters of recommendation (LORs) are an essential component of a career in medicine. The process for obtaining certain letters, particularly those associated with scheduled periods of professional transition, often is governed by established institutional or specialty norms. The process of requesting LORs in more common scenarios-local or national awards, committee assignments, and leadership positions-many times is less clearly defined, however. Despite the important role that LORs play in professional development, the published literature on how to solicit a recommendation is limited, creating challenges for both those requesting LORs ("applicants") and the letter writers. This perspective piece offers insight on how to best identify and communicate with a potential writer. These suggestions are derived from the limited relevant literature and from the authors' experience both with requesting letters themselves and writing letters as leaders in undergraduate and graduate medical education. The goal is to reduce ambiguity for applicants and ensure that writers receive the information necessary to provide an informed and effective recommendation.

Twelve tips for developing simulation-based mastery learning clinical skills checklists.

Simulation-based mastery learning is a powerful educational paradigm that leads to high levels of performance through a combination of strict standards, deliberate practice, formative feedback, and rigorous assessment. Successful mastery learning curricula often require well-designed checklists that produce reliable data that contribute to valid decisions. The following twelve tips are intended to help educators create defensible and effective clinical skills checklists for use in mastery learning curricula. These tips focus on defining the scope of a checklist using established principles of curriculum development, crafting the checklist based on a literature review and expert input, revising and testing the checklist, and recruiting judges to set a minimum passing standard. While this article has a particular focus on mastery learning, with the exception of the tips related to standard setting, the general principles discussed apply to the development of any clinical skills checklist.

A clinical pharmacokinetic drug-drug interaction study between dextromethorphan and emvododstat, a potent anti-SARS-CoV-2 dihydroorotate dehydrogenase inhibitor.

PURPOSE: A therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2, coronavirus disease 2019, COVID-19) management. Emvododstat (PTC299; 4-chlorophenyl 6-chloro-1-[4-methoxyphenyl]-1,3, 4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by inhibition of dihydroorotate dehydrogenase to reduce the severity of SARS-CoV-2 infections This drug interaction study was performed to determine if emvododstat was an inhibitor of CYP2D6. METHODS: Potential drug-drug interactions between emvododstat and a CYP2D6 probe substrate (dextromethorphan) were investigated by measuring plasma dextromethorphan and metabolite (dextrorphan) concentrations before and after emvododstat administration. On day 1, 18 healthy subjects received an oral dose of 30 mg dextromethorphan followed by a 4-day washout period. On day 5, subjects received an oral dose of 250 mg emvododstat with food. Two hours later, 30 mg dextromethorphan was administered. RESULTS: When given with emvododstat, plasma dextromethorphan concentrations increased substantially, while metabolite levels (dextrorphan) remained essentially the same. Maximum plasma dextromethorphan concentration (Cmax) increased from 2006 to 5847 pg/mL. Dextromethorphan exposure (AUC) increased from 18,829 to 157,400 h·pg/mL for AUC0-last and from 21,585 to 362,107 h·pg/mL for AUC0-inf following administration of emvododstat. When dextromethorphan parameters were compared before and after emvododstat, least squares mean ratios (90% confidence interval) were found to be 2.9 (2.2, 3.8), 8.4 (6.1, 11.5), and 14.9 (10.0, 22.1) for Cmax, AUC0-last, and AUC0-inf, respectively. CONCLUSION: Emvododstat appears to be a strong CYP2D6 inhibitor. No drug-related treatment emergent adverse effects (TEAEs) were considered to be severe or serious. TRIAL REGISTRATION: EudraCT 2021-004626-29, 11 May 2021.

Absorption, distribution, metabolism and excretion of 14C-vatiquinone in rats, dogs, and human subjects.

Vatiquinone is a potent inhibitor of 15-lipoxygenase and is in clinical development for the treatment of mitochondrial diseases and other disorders characterised by high levels of oxidative stress and dysregulation of energy metabolism.In rats, 14C-vatiquinone-derived radioactivity was quickly and widely distributed throughout the body and cleared from most tissues by 24 h post-dose following a single oral dose of 14C-vatiquinone.Following oral administration, 94% of dose was recovered within seven days in rats, approximately 61% of dose was recovered within seven days in dogs and approximately 93% of dose was recovered within nine days in human subjects (IND 119220). Faecal excretion was the major route (>56% dose) in all species; urinary excretion was minimal in rats and dogs (<3% dose) but was higher in humans (∼ 22% dose).Following oral administration, vatiquinone was the dominant circulating component in rats and dogs but was minor in human subjects. There were no plasma metabolites that were more than 10% of total drug related exposures in all species.Following oral administration, vatiquinone was not detectable in urine but was the most prominent component in faeces in rats, dogs, and humans.

Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents.

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.

Autoantibodies to red blood cell surface Glycophorin A impact the activation poise of circulating leukocytes.

BACKGROUND: Both M and N alleles encode antigens on Glycophorin A (GPA), a red blood cell (RBC) surface sialoglycoprotein. Interaction between RBC GPA and leukocyte surface lectins may downregulate their activation. The current study investigates if RBC autoantibodies against GPA, such as auto-anti-M/N, prime an activated phenotype in peripheral blood leukocytes. METHODS: Leukocyte activation was assessed in whole blood from patients with auto-anti-GPA (anti-M/N) and compared to those with allo-anti-M/N and healthy subjects. Control samples from healthy subjects with no antibodies incubated in vitro with either anti-GPA or anti-Rh were analyzed for neutrophil and monocyte surface activation marker expression, reactive oxygen species (ROS) content, and formation of aggregates with RBCs. Samples incubated with an IgG1 isotype antibody served as controls. RESULTS: Ex vivo, neutrophil CD66b and monocyte CD63 surface expression was increased in patients with auto-anti-M/N compared to those with allo anti-M/N (p = .1757; p = .0698) and to healthy subjects (p = .0186; p = .013). In vitro, neutrophil CD66b and monocyte CD63 surface expression was increased following incubation with anti-GPA compared to anti-Rh (p = .0003; p = .0328) and isotype control (p = .000; p = .0062). Intracellular ROS content increased in both neutrophils and monocytes incubated with anti-GPA compared to anti-Rh (p = .0012; p = .0693) and isotype control (p = .001; p = .0021). Percentage of neutrophil-RBC aggregates was decreased when incubated with anti-GPA compared to isotype control (p < .01). CONCLUSIONS: Neutrophils and monocytes in peripheral blood exposed to an antibody directed against GPA on RBC surfaces, such as M or N antigens, may be primed towards an activated phenotype.

Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.

Ca2+ signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca2+ store, and dysregulation of ER Ca2+ signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca2+-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. These results, together with the previously described role of CCDC47 in Ca2+ signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.

Simulation-based mastery learning compared to standard education for discussing diagnostic uncertainty with patients in the emergency department: a randomized controlled trial.

BACKGROUND: Diagnostic uncertainty occurs frequently in emergency medical care, with more than one-third of patients leaving the emergency department (ED) without a clear diagnosis. Despite this frequency, ED providers are not adequately trained on how to discuss diagnostic uncertainty with these patients, who often leave the ED confused and concerned. To address this training need, we developed the Uncertainty Communication Education Module (UCEM) to teach physicians how to discuss diagnostic uncertainty. The purpose of the study is to evaluate the effectiveness of the UCEM in improving physician communications. METHODS: The trial is a multicenter, two-arm randomized controlled trial designed to teach communication skills using simulation-based mastery learning (SBML). Resident emergency physicians from two training programs will be randomly assigned to immediate or delayed receipt of the two-part UCEM intervention after completing a baseline standardized patient encounter. The two UCEM components are: 1) a web-based interactive module, and 2) a smart-phone-based game. Both formats teach and reinforce communication skills for patient cases involving diagnostic uncertainty. Following baseline testing, participants in the immediate intervention arm will complete a remote deliberate practice session via a video platform and subsequently return for a second study visit to assess if they have achieved mastery. Participants in the delayed intervention arm will receive access to UCEM and remote deliberate practice after the second study visit. The primary outcome of interest is the proportion of residents in the immediate intervention arm who achieve mastery at the second study visit. DISCUSSION: Patients' understanding of the care they received has implications for care quality, safety, and patient satisfaction, especially when they are discharged without a definitive diagnosis. Developing a patient-centered diagnostic uncertainty communication strategy will improve safety of acute care discharges. Although use of SBML is a resource intensive educational approach, this trial has been deliberately designed to have a low-resource, scalable intervention that would allow for widespread dissemination and uptake. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (NCT04021771). Registration date: July 16, 2019.

The effect of a pharmacist-led multidisciplinary transitions-of-care pilot for patients at high risk of readmission.

OBJECTIVES: To evaluate the feasibility and effect of a pharmacist-led transitions-of-care (TOC) pilot targeted to patients at high risk of readmission on process measures, hospital readmissions, and emergency department (ED) visits. SETTING: Academic medical center in Colorado. PRACTICE DESCRIPTION: Pharmacists enrolled patients identified as high risk for readmission in a TOC pilot from July 2014 to July 2015. The pilot included medication reconciliation, medication counseling, case management or social work evaluation, a postdischarge telephone call, and an expedited primary care follow-up appointment. PRACTICE INNOVATION: Implementation and evaluation of the pharmacist-led TOC pilot program with risk score embedded into the electronic health record. EVALUATION: Comparison of TOC-related process measures and clinical outcomes between pilot patients and randomly matched control patients included readmissions or ED visits at 30 and 90 days. RESULTS: We enrolled 34 pilot patients and randomly matched them to 34 control patients. The intervention took an average of 57.1 minutes for pharmacists to deliver. More pilot patients had a case management or social work note compared with control patients (88% vs. 59%; P = 0.006 [statistically significant]). Readmission rates in pilot versus nonpilot patients, respectively, were 18% versus 24% (P = 0.547) at 30 days and 27% versus 39% (P = 0.296) at 90 days. The composite outcome of a readmission or ED visit in pilot versus nonpilot patients was 24% versus 30% (P = 0.580) at 30 days and 36% versus 49% (P = 0.319) at 90 days. CONCLUSION: A pharmacist-led TOC pilot demonstrates potential for reducing hospital readmissions. The intervention was time intensive and led to creation of a TOC pharmacist role to implement medication-related transitional care.

Adductor Canal Block With Bupivacaine Liposome Versus Ropivacaine Pain Ball for Pain Control in Total Knee Arthroplasty: A Retrospective Cohort Study.

BACKGROUND: Appropriate postoperative pain control following total knee arthroplasty is important in patient recovery. Adductor canal block (ACB) is a novel method to deliver anesthesia. There are currently no studies using bupivacaine liposome with ACB while also taking into account cost. OBJECTIVE: To compare the efficacy and cost of using bupivacaine liposome to ropivacaine pain ball (RPB) for postsurgical pain control in total knee replacement surgery. The primary efficacy endpoint is mean pain score. Secondary endpoints include opioid and nonopioid pain medication consumption and cost per patient case. METHODS: This was a retrospective, matched cohort study with data collected from electronic medical records from February 2013 to June 2014. Mean pain score was measured by the 11-point Visual Analogue Scale over a 72-hour period. Cost analysis was also done looking at medication, direct, indirect, and total cost per patient case. RESULTS: Mean pain score over the 72 hours was 3.24 in the bupivacaine liposome group compared with 3.83 in the RPB group (P < 0.001). Lower mean pain scores were found in the bupivacaine liposome group during the first 36-hour interval postsurgery (3.1 vs 4.0, respectively, P < 0.001). Mean total cost was $20,919.53 with bupivacaine liposome versus $22,574.17 with RPB (P = 0.03). CONCLUSION: Liposomal bupivacaine demonstrated statistically significant impact in pain control in the first 36 hours, but by the end of the 72-hour interval, it was comparable to RPB in postoperative pain management. Using bupivacaine liposome did provide direct and total cost savings compared with RPB.

RNA-binding protein Sam68 controls synapse number and local ß-actin mRNA metabolism in dendrites.

Proper synaptic function requires the spatial and temporal compartmentalization of RNA metabolism via transacting RNA-binding proteins (RBPs). Loss of RBP activity leads to abnormal posttranscriptional regulation and results in diverse neurological disorders with underlying deficits in synaptic morphology and transmission. Functional loss of the 68-kDa RBP Src associated in mitosis (Sam68) is associated with the pathogenesis of the neurological disorder fragile X tremor/ataxia syndrome. Sam68 binds to the mRNA of ß-actin (actb), an integral cytoskeletal component of dendritic spines. We show that Sam68 knockdown or disruption of the binding between Sam68 and its actb mRNA cargo in primary hippocampal cultures decreases the amount of actb mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Consistent with these observations, we find that Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished levels of synaptic actb protein, suggesting that Sam68 promotes the translation of actb mRNA at synapses in vivo. Moreover, genetic knockout of Sam68 or acute knockdown in vivo results in fewer excitatory synapses in the hippocampal formation as assessed morphologically and functionally. Therefore, we propose that Sam68 regulates synapse number in a cell-autonomous manner through control of postsynaptic actb mRNA metabolism. Our research identifies a role for Sam68 in synaptodendritic posttranscriptional regulation of actb and may provide insight into the pathophysiology of fragile X tremor/ataxia syndrome.

Genomic responses in mouse models poorly mimic human inflammatory diseases.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders.

Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthesis, protein degradation must be carefully balanced for optimal proteostasis, as deviations resulting in excess or insufficient abundance of key synaptic factors produce pathologies. As such, mutations in components of the proteasomal or translational machinery, including RBPs, have been linked to the pathogenesis of neurological disorders such as Fragile X Syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS), and Autism Spectrum Disorders (ASD). In this review, we summarize recent scientific findings, highlight ongoing questions, and link basic molecular mechanisms to the pathogenesis of common neuropsychiatric disorders.

Morbidity and survival probability in burn patients in modern burn care.

OBJECTIVE: Characterizing burn sizes that are associated with an increased risk of mortality and morbidity is critical because it would allow identifying patients who might derive the greatest benefit from individualized, experimental, or innovative therapies. Although scores have been established to predict mortality, few data addressing other outcomes exist. The objective of this study was to determine burn sizes that are associated with increased mortality and morbidity after burn. DESIGN AND PATIENTS: Burn patients were prospectively enrolled as part of the multicenter prospective cohort study, Inflammation and the Host Response to Injury Glue Grant, with the following inclusion criteria: 0-99 years old, admission within 96 hours after injury, and more than 20% total body surface area burns requiring at least one surgical intervention. SETTING: Six major burn centers in North America. MEASUREMENTS AND MAIN RESULTS: Burn size cutoff values were determined for mortality, burn wound infection (at least two infections), sepsis (as defined by American Burn Association sepsis criteria), pneumonia, acute respiratory distress syndrome, and multiple organ failure (Denver 2 score>3) for both children (<16 yr) and adults (16-65 yr). Five hundred seventy-three patients were enrolled, of which 226 patients were children. Twenty-three patients were older than 65 years and were excluded from the cutoff analysis. In children, the cutoff burn size for mortality, sepsis, infection, and multiple organ failure was approximately 60% total body surface area burned. In adults, the cutoff for these outcomes was lower, at approximately 40% total body surface area burned. CONCLUSIONS: In the modern burn care setting, adults with over 40% total body surface area burned and children with over 60% total body surface area burned are at high risk for morbidity and mortality, even in highly specialized centers.

Benchmarking outcomes in the critically injured burn patient.

OBJECTIVE: To determine and compare outcomes with accepted benchmarks in burn care at 6 academic burn centers. BACKGROUND: Since the 1960s, US morbidity and mortality rates have declined tremendously for burn patients, likely related to improvements in surgical and critical care treatment. We describe the baseline patient characteristics and well-defined outcomes for major burn injuries. METHODS: We followed 300 adults and 241 children from 2003 to 2009 through hospitalization, using standard operating procedures developed at study onset. We created an extensive database on patient and injury characteristics, anatomic and physiological derangement, clinical treatment, and outcomes. These data were compared with existing benchmarks in burn care. RESULTS: Study patients were critically injured, as demonstrated by mean % total body surface area (TBSA) (41.2 ± 18.3 for adults and 57.8 ± 18.2 for children) and presence of inhalation injury in 38% of the adults and 54.8% of the children. Mortality in adults was 14.1% for those younger than 55 years and 38.5% for those aged 55 years and older. Mortality in patients younger than 17 years was 7.9%. Overall, the multiple organ failure rate was 27%. When controlling for age and % TBSA, presence of inhalation injury continues to be significant. CONCLUSIONS: This study provides the current benchmark for major burn patients. Mortality rates, notwithstanding significant % TBSA and presence of inhalation injury, have significantly declined compared with previous benchmarks. Modern day surgical and medically intensive management has markedly improved to the point where we can expect patients younger than 55 years with severe burn injuries and inhalation injury to survive these devastating conditions.

Running biomechanical and isokinetic strength differences in masters runners with and without Achilles tendinopathy.

Masters runners are an increasing proportion of the running community. The most significant musculoskeletal changes in runners occur after the age of 50 in addition to changes in injury rates and types, the most common being Achilles tendinopathy (AT). Previous evidence has suggested similarities between risk factors for AT and age-related changes that are focused at the hip and the ankle during the propulsive stage of running. The purpose of this study was to investigate biomechanical and peak torque association to AT in masters runners. Thirty-two masters runners over age 50 with AT (60.31 ± 8.37, n = 16) and without (59.94 ± 4.95 n = 16) were included. 3D motion capture and force plates were used to assess running biomechanics. A motor-driven dynamometer was used to assess isokinetic peak torque production. No significant differences in running biomechanics were found between masters runners with and without AT. Hip peak isokinetic torque production was found to be significantly less in masters runners with AT, but no significant differences in ankle plantarflexion peak isokinetic torque production were found. Masters runners with AT may be able to adapt their running biomechanics and muscular torque production during submaximal running efforts.

Masters runners with Achilles tendinopathy do not demonstrate differences in peak hip extension moments during the stance phase of running during submaximal efforts compared to healthy masters runners.Masters runners with Achilles tendinopathy do not demonstrate differences in peak ankle plantarflexion moments during the stance phase of running during submaximal efforts compared to healthy masters runners.Masters runners with Achilles tendinopathy do not demonstrate differences in peak ankle plantarflexion concentric or eccentric isokinetic torque compared to healthy masters runners.Masters runners with Achilles tendinopathy demonstrate differences in peak hip extension concentric and eccentric isokinetic torque compared to healthy masters runners.

Changes in Basal and Bolus Insulin Requirements with Tirzepatide as an Adjunctive Therapy in Adults with Type 1 Diabetes Using Tandem Control-IQ.

INTRODUCTION: This study was aimed at investigating changes in insulin requirements and glycemic outcomes in adults with type 1 diabetes (T1D) using Control IQ (Tandem Diabetes) automated insulin delivery system (AID) over 8 months of tirzepatide treatment. METHODS: In this single-center, observational study, we collected demographic, A1c, weight, sensor glucose, and insulin dose data for adults with T1D who were using AID and initiated tirzepatide adjunct therapy for clinical indications (n = 11, median age 37, 64% female and mean body mass index of 39.6 kg/m2). Data were compared from baseline and over 8 months. RESULTS: Within 2 months of tirzepatide treatment, there were significant reductions in total daily insulin [median (IQR) 73.9 (47.6-95.8) to 51.7 (46.7-66.8) units/day, p < 0.001], basal insulin [47 (28.2-51.8) to 32.4 (25.5-46.3) units/day, p < 0.001], and bolus insulin [31.4 (19.9-38.3) to 17.9 (14.9-22.2) units/day, p < 0.001] requirements. Insulin dose reduction from 2 to 8 months was modest. The frequency of user-initiated boluses did not differ throughout the study. Despite reductions in total insulin requirement, time in range (70-180 mg/dl) increased by 7%, A1c reduced by 0.5%, weight reduced by 9%, without increase in time below 70 mg/dl. CONCLUSIONS: This pilot study provides clinical guidance on insulin titration for adults with T1D who may initiate tirzepatide therapy. Based on the findings of this study, we recommend reducing 25% of total daily insulin dose at tirzepatide initiation in adults with T1D using AID with baseline A1c of less than 7.5%. Higher doses of tirzepatide were associated with greater weight loss, however, the reduction in insulin requirement was minimal.

Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity.

BACKGROUND: Once weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) have been shown to improve glycemic outcomes and cause significant weight loss. However, 9% to 27% of individuals have little or no response to these drugs. In this article, we investigated the efficacy of GLP-1 RA therapy among adults with type 1 diabetes and obesity likely related to genetic mutations compared with obesity likely unrelated to genetic mutations. METHODS: In this retrospective study, we compared body weight and glycated hemoglobin (HbA1c) change with the use of GLP-1 RA therapy (including a dual agonist, Tirzepatide) over six months among adults with type 1 diabetes and obesity likely (n = 11, median age 39.5 years with a median BMI of 43.0 kg/m2) versus unlikely related to genetic mutation(s) (n = 15, median age 45.8 years with a median BMI of 38.7 kg/m2). RESULTS: Six months of GLP-1 RA treatment resulted in a numerically lower reduction of weight (-5.75 ± 9.46 kg vs -8.65 ± 9.36 kg, P = .44) and HbA1c (-0.28 ± 0.96% vs -0.43 ± 0.57%, P = .64) among individuals with obesity likely versus unlikely related to a genetic mutation(s), respectively. Fewer individuals with genetic obesity met goal weight loss ≥5% or HbA1c decrease ≥0.4% than did individuals with obesity unlikely related to a genetic cause (36.4% vs 80.0%, P = .04). CONCLUSIONS: The weight loss and glycemic lowering effects of GLP-1 RA therapy may be decreased in people with type 1 diabetes and obesity likely related to genetic causes. Further research is needed to understand GLP-1 RA mechanisms via energy regulating genes.