Search

AIMS: There is limited evidence to support the efficacy of sacral neuromodulation (SNM) for older adults with overactive bladder (OAB). This study aims to report outcomes following SNM among nursing home (NH) residents, a vulnerable population with high rates of frailty and comorbidity. METHODS: This is a retrospective cohort study of long-stay NH residents who underwent a trial of percutaneous nerve evaluation (PNE) or Stage 1 permanent lead placement (Stage 1) between 2014 and 2016. Residents were identified using the Minimum Data Set linked to Medicare claims. The primary outcome of this study was successful progression from trial to implant. Rates of 1-year device explant/revisions were also investigated. RESULTS: Trial of SNM was observed in 1089 residents (mean age: 77.9 years). PNE was performed in 66.9% of residents and 33.2% underwent Stage 1. Of Stage 1 procedures, 23.8% were performed with simultaneous device implant (single-stage). Overall, 53.1% of PNEs and 72.4% of Stage 1 progressed to device implant, which was associated with Stage 1 procedure versus PNE (adjusted relative risk [aRR]: 1.34; 95% confidence interval [95% CI]: 1.21-1.49) and female versus male sex (aRR: 1.26; 95% CI: 1.09-1.46). One-year explant/revision was observed in 9.3% of residents (6.3% for PNE, 10.5% for Stage 1, 20.3% single-stage). Single stage procedure versus PNE was significantly associated with device explant/revision (aRR: 3.4; 95% CI: 1.9-6.2). CONCLUSIONS: In this large cohort of NH residents, outcomes following SNM were similar to previous reports of younger healthier cohorts. Surgeons managing older patients with OAB should use caution when selecting patients for single stage SNM procedures.

Introduction: Ultrasound-guided nerve blocks are fast becoming a core part of opioid- sparing, multimodal, acute pain management in the emergency department (ED) setting. The ultrasound-guided erector spinae plane block (ESPB) has been shown to be effective in treating a variety of musculoskeletal and neuropathic painful conditions in the ED. Case Series: Here we report the effective use of the ESPB for pain control in four patients who presented with acute abdominal pain related to biliary obstruction in a resource-limited setting. Conclusion: The ESPB may be helpful in treating abdominal pain related to biliary obstruction, which is a novel indication for this well-established technique. This application is particularly relevant in resource-limited settings with significant delay in definitive surgical management. Further research is needed prior to widespread adoption.

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

Heating and cooling demand for space conditioning and refrigeration accounts for around a fifth of global final energy consumption. Climate change, urbanisation, and economic development have tripled electricity demand for cooling alone since the 1990s, with the majority coming from the use of inefficient cooling equipment, which burdens electricity grids, especially during the peak hours. It is imperative to address the energy required to provide cooling. The Kigali Amendment to the Montreal Protocol addresses these needs by setting ambitious global targets to phase down refrigerants with high global warming potential, while improving energy efficiency. Integrating energy efficiency and the refrigerant transition will contribute to economic security, well-being, energy access and security, and sustainability among the G20 countries.

While physics is often promoted as being for everyone, its cultural narrative, i.e., what physicists do and who they are, has been and continues to be created by a dominant social group. As such, many students who come from marginalized backgrounds in physics are required to fit themselves into its narrow culture that does not reflect who they are and how they see the world. As physics educators, we have unconsciously internalized this narrow physics culture and need resources to help broaden our perceptions. To this end, we suggest some design principles for creating materials that help physics educators reflect on these issues and disrupt inequitable structures in their classrooms. We draw on the STEP UP project to exemplify how these design principles were implemented.

Introduction: Ultrasound-guided nerve blocks (UGNB) represent a procedural skill set that can be used to treat acute pain by physicians in the emergency department (ED). However, limited access to education and training represents a barrier to widespread adoption of this core skill set. The implementation of UGNBs within the ED can aid in resource allocation, particularly in limited-resource settings.Case Series: In this case series we discuss our experience using tele-ultrasound to train emergency physicians on the use of UGNBs within our international point-of-care ultrasound fellowship in Peru. We highlight the potential role UGNBs serve in management of acute pain when working in resource-limited, public safety-net hospitals in Peru.Conclusion: Tele-ultrasound may represent a strategy for teaching procedures such as UGNBs via remote guidance and supervision.

Introduction: Frostbite is a painful condition that requires rapid identification and wound care to optimize outcomes. The Posterior Tibial Nerve (PTN) block, however, has yet to be described in the literature for pain control of frostbite injuries on the plantar surfaces.Case Series: In this case series we discuss three patients who presented with bilateral frostbite on the plantar surfaces. Ultrasound-guided PTN blocks were performed on these patients and pain control was achieved in under 10 minutes, facilitating burn care. No patient experienced adverse effects. All patients had been scheduled for future debridement that was either not performed or performed using intravenous (IV) medications due to pain control issues.Conclusion: The ultrasound-guided PTN block facilitated proper wound debridement that was previously intolerable with oral and IV pain medications. This case series highlights the efficacy, safety, and accessibility of this block for frostbite pain control in the emergency department.   Additionally, it emphasizes the potential role of ultrasound-guided PTN blocks as part of a multi-modal pain control strategy in other clinical settings.

Introduction: Tetralogy of Fallot (TOF) is a congenital heart defect with characteristic features leading to unique physical exam and ultrasound findings. In settings where there is limited prenatal screening, TOF can present with cyanosis at any time from the neonatal period to adulthood depending on the degree of obstruction of the right ventricular outflow tract.Case Report: This case describes a pediatric patient who presented with undifferentiated dyspnea and cyanosis, for whom point-of-care ultrasound (POCUS) supported the diagnosis of TOF. We highlight the important role POCUS can play in a setting with limited access to formal echocardiography or consultative pediatric cardiology services.Conclusion: This report highlights the utility of POCUS as an inflection point in the diagnostic and management pathway of this patient, which is particularly important when working in a limited-resource or rural setting.

Objective: Insulin acts on the liver via changes in gene expression to maintain glucose and lipid homeostasis. This study aimed to the Forkhead box protein K1 (FOXK1) associated gene regulatory network as a transcriptional regulator of hepatic insulin action and to determine its role versus FoxO1 and possible actions of the insulin receptor at the DNA level. Methods: Genome-wide analysis of FoxK1 binding were studied by chromatin immunoprecipitation sequencing and compared to those for IR and FoxO1. These were validated by knockdown experiments and gene expression analysis. Results: Chromatin immunoprecipitation (ChIP) sequencing shows that FoxK1 binds to the proximal promoters and enhancers of over 4000 genes, and insulin enhances this interaction for about 75% of them. These include genes involved in cell cycle, senescence, steroid biosynthesis, autophagy, and metabolic regulation, including glucose metabolism and mitochondrial function and are enriched in a TGTTTAC consensus motif. Some of these genes are also bound by FoxO1. Comparing this FoxK1 ChIP-seq data to that of the insulin receptor (IR) reveals that FoxK1 may act as the transcription factor partner for some of the previously reported roles of IR in gene regulation, including for LARS1 and TIMM22, which are involved in rRNA processing and cell cycle. Conclusion: These data demonstrate that FoxK1 is an important regulator of gene expression in response to insulin in liver and may act in concert with FoxO1 and IR in regulation of genes in metabolism and other important biological pathways.

Background: Psoriatic arthritis (PsA), an immune-mediated chronic inflammatory skin and joint disease, affects approximately 0.27% of the adult population, and 20% of patients with psoriasis. Up to 10% of psoriasis patients are estimated for having undiagnosed PsA. Early diagnosis and treatment can prevent irreversible joint damage, disability and deformity. Questionnaires for screening to identify undiagnosed PsA patients require patient and physician involvement. Objective: To evaluate a proprietary machine learning tool (PredictAI™) developed for identification of undiagnosed PsA patients 1–4 years prior to the first time that they were suspected of having PsA (reference event). Methods: This retrospective study analyzed data of the adult population from Maccabi Healthcare Service between 2008 and 2020. We created 2 cohorts: The general adult population (“GP Cohort”) including patients with and without psoriasis and the Psoriasis cohort (“PsO Cohort”) including psoriasis patients only. Each cohort was divided into two non-overlapping train and test sets. The PredictAI™ model was trained and evaluated with 3 years of data predating the reference event by at least one year. Receiver operating characteristic (ROC) analysis was used to investigate the performance of the model, built using gradient boosted trees, at different specificity levels. Results: Overall, 2096 patients met the criteria for PsA. Undiagnosed PsA patients in the PsO cohort were identified with a specificity of 90% one and four years before the reference event, with a sensitivity of 51% and 38%, and a PPV of 36.1% and 29.6%, respectively. In the GP cohort and with a specificity of 99% and for the same time windows, the model achieved a sensitivity of 43% and 32% and a PPV of 10.6% and 8.1%, respectively. Conclusions: The presented machine learning tool may aid in the early identification of undiagnosed PsA patients, and thereby promote earlier intervention and improve patient outcomes.

Abstract Background The extent of the consequences of an episode of severe acute kidney injury (AKI) on long-term outcome of critically ill patients remain debated. We conducted a prospective follow-up of patients included in a large multicenter clinical trial of renal replacement therapy (RRT) initiation strategy during severe AKI (the Artificial Kidney Initiation in Kidney Injury, AKIKI) to investigate long-term survival, renal outcome and health related quality of life (HRQOL). We also assessed the influence of RRT initiation strategy on these outcomes. Results Follow-up of patients extended from 60 days to a median of 3.35 years [interquartile range (IQR), 1.89 to 4.09] after the end of initial study. Of the 619 patients included in the AKIKI trial, 316 survived after 60 days. The overall survival rate at 3 years from inclusion was 39.4% (95% CI 35.4 to 43.4). A total of 46 patients (on the 175 with available data on long-term kidney function) experienced worsening of renal function (WRF) at the time of follow-up [overall incidence of 26%, cumulative incidence at 4 years: 20.6% (CI 95% 13.0 to 28.3)]. Fifteen patients required chronic dialysis (5% of patients who survived after day 90). Among the 226 long-term survivors, 80 (35%) answered the EQ-5D questionnaire. The median index value reported was 0.67 (IQR 0.40 to 1.00) indicating a noticeable alteration of quality of life. Initiation strategy for RRT had no effect on any long-term outcome. Conclusion Severe AKI in critically ill patients was associated with a high proportion of death within the first 2 months but less so during long-term follow-up. A quarter of long-term survivors experienced a WRF and suffered from a noticeable impairment of quality of life. Renal replacement therapy initiation strategy was not associated with mortality outcome. Graphical Abstract

Introduction: Point-of-care ultrasound (POCUS) is accepted as an important tool for evaluatingpatients presenting to the emergency department (ED) with dyspnea1 and undifferentiated shock.2Identifying the etiology and type of shock is time-critical since treatments vary based on thisinformation. Clinicians typically rely on the history, exam, and diagnostics tests to identify theetiology of shock. In resource-limited settings where there is reduced access to timely laboratory anddiagnostic studies. The use of POCUS enables rapid classification and directed treatment of shock.Additionally, POCUS can aid in the diagnosis of rarer tropical diseases that can be important causesof shock in resource-limited settings.Case Report: We discuss a case of a pediatric patient who presented to an ED in Cusco, Peru, withacute dyspnea and shock. Point-of-care ultrasound was used to expedite the diagnosis of a rupturedpulmonary hydatid cyst, guide proper management of septic and anaphylactic shock, and expeditedefinitive surgical intervention.Conclusion: In resource-limited settings where there is reduced access to timely laboratory anddiagnostic studies, the use of POCUS enables rapid classification and directed treatment of shock.

Purpose: Radiation therapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces invasive and in situ recurrences. Whereas landmark studies suggest that a tumor bed boost improves local control for invasive breast cancer, the benefit in DCIS remains less certain. We evaluated outcomes of patients with DCIS treated with or without a boost. Methods and Materials: The study cohort comprised patients with DCIS who underwent BCS at our institution from 2004 to 2018. Clinicopathologic features, treatment parameters, and outcomes were ascertained from medical records. Patient and tumor characteristics were evaluated relative to outcomes using univariable and multivariable Cox models. Recurrence-free survival (RFS) estimates were generated using the Kaplan-Meier method. Results: We identified 1675 patients who underwent BCS for DCIS (median age, 56 years; interquartile range, 49-64 years). Boost RT was used in 1146 cases (68%) and hormone therapy in 536 (32%). At a median follow-up of 4.2 years (interquartile range, 1.4-7.0 years), we observed 61 locoregional recurrence events (56 local, 5 regional) and 21 deaths. Univariable logistic regression demonstrated that boost RT was more common among younger patients (P < .001) with positive or close margins (P < .001) and with larger tumors (P < .001) of higher grade (P = .025). The 10-year RFS rate was 88.8% among those receiving a boost and 84.3% among those without a boost (P = .3), and neither univariable nor multivariable analyses revealed an association between boost RT and locoregional recurrence. Conclusions: Among patients with DCIS who underwent BCS, use of a tumor bed boost was not associated with locoregional recurrence or RFS. Despite a preponderance of adverse features among the boost cohort, outcomes were similar to those of patients not receiving a boost, suggesting that a boost may mitigate risk of recurrence among patients with high-risk features. Ongoing studies will elucidate the extent to which a tumor bed boost influences disease control rates.

Point-of-care ultrasound (POCUS) enables physicians to make critical diagnosis and treatment decisions at the bedside. However, access to and expertise with this technology remain limited in Peru. Establishing longitudinal POCUS educational curriculums in remote, low-resource settings can be challenging due to geographical distances, encumbering the ability to provide ongoing hands-on support. Previously described educational interventions have focused on training individual users on clinical applications of POCUS, rather than training physicians how to teach POCUS, thereby limiting scalability and sustainable impact. We therefore describe our experiences establishing the first ultrasound fellowship curriculum in Peru, which incorporates tele-ultrasonography to circumvent traditional geographical barriers.

Ebstein’s anomaly is a congenital heart defect that when left untreated can lead to unique physical exam and ultrasound findings. This case describes a patient who presented with dyspnea and was found to have cyanosis, clubbing, and dilation of right-sided chambers on point-of-care ultrasound. The series of images highlights findings in late-stage Ebstein’s anomaly and serves as a springboard for the discussion of the pathophysiology, diagnosis, and treatment of this rare congenital heart disease.

Abstract Background Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient’s prognosis. Patients and methods This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy. Results One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not. Conclusions In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration. Trial registration: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis.

Introduction: Ultrasound-guided nerve blocks are fast becoming a core part of opioid-sparing, multimodal, acute pain management in the emergency department (ED) setting. The ultrasound-guided erector spinae plane block (ESPB) has been shown to be effective in treating a variety of musculoskeletal and neuropathic painful conditions in the ED. Case Series: Here we report the effective use of the ESPB for pain control in four patients who presented with acute abdominal pain related to biliary obstruction in a resource-limited setting. Conclusion: The ESPB may be helpful in treating abdominal pain related to biliary obstruction, which is a novel indication for this well-established technique. This application is particularly relevant in resource-limited settings with significant delay in definitive surgical management. Further research is needed prior to widespread adoption.

Single injection, ultrasound-guided nerve blocks have drastically changed the multimodal approach to pain management of the acutely injured patient in the emergency department (ED). Ultrasound-guided femoral nerve blocks in the ED have become standard aspects of multiple, hospital system pain management protocols, with early evidence demonstrating improved patient outcomes. Developing a multimodal pain management strategy can improve analgesia while reducing reliance on opioids in this era of opioid addiction.1 The single injection, ultrasound-guided erector spinae plane (ESP) block is a technique safely used for pain control for rib fractures that can be easily performed at the bedside and integrated into optimal emergency care. A more inferiorly located ultrasound-guided ESP block has been recently described in the anesthesia literature for perioperative pain control for various abdominal surgeries but has not yet been described for patients with acute appendicitis. Here we describe a single injection, lower ESP block performed by emergency physicians that successfully alleviated pain from acute appendicitis in an ED patient awaiting definitive surgical treatment. Along with allowing clinicians to actively manage pain without reliance on opioids, this novel ED technique may improve patient care outcomes.

In 2018, in response to the proposed elimination of physics at a predominately Hispanic and socioeconomically disadvantaged (SED) high school, the Northern California/Nevada chapter of the AAPT investigated school demographics and their effect on physics offerings in public high schools in our region. As access was a key issue, the focus was on public, non-charter high schools, which are free to students and do not require winning a lottery for attendance. As reported previously, the data revealed that the percentage of Hispanic students and the percentage of SED students at a high school are highly correlated (r[superscript 2]=0.60). Additionally, these factors could be used as predictors of a school's physics offerings. To determine if the disparities in course offerings extended through other Advanced Placement (AP) STEM classes, the data were further analyzed, revealing that as the popularity of an AP exam drops, so do the relative odds of it being offered, when comparing schools with different demographics. A Northern California public high school student is much more likely to get a strong selection of AP STEM classes if his/her school serves an affluent, non-Hispanic student majority rather than mostly poor, Hispanic students.

Abstract Background Trials comparing early and delayed strategies of renal replacement therapy in patients with severe acute kidney injury may have missed differences in survival as a result of mixing together patients at heterogeneous levels of risks. Our aim was to evaluate the heterogeneity of treatment effect on 60-day mortality from an early vs a delayed strategy across levels of risk for renal replacement therapy initiation under a delayed strategy. Methods We used data from the AKIKI, and IDEAL-ICU randomized controlled trials to develop a multivariable logistic regression model for renal replacement therapy initiation within 48 h after allocation to a delayed strategy. We then used an interaction with spline terms in a Cox model to estimate treatment effects across the predicted risks of RRT initiation. Results We analyzed data from 1107 patients (619 and 488 in the AKIKI and IDEAL-ICU trial respectively). In the pooled sample, we found evidence for heterogeneous treatment effects (P = 0.023). Patients at an intermediate-high risk of renal replacement therapy initiation within 48 h may have benefited from an early strategy (absolute risk difference, − 14%; 95% confidence interval, − 27% to − 1%). For other patients, we found no evidence of benefit from an early strategy of renal replacement therapy initiation but a trend for harm (absolute risk difference, 8%; 95% confidence interval, − 5% to 21% in patients at intermediate-low risk). Conclusions We have identified a clinically sound heterogeneity of treatment effect of an early vs a delayed strategy of renal replacement therapy initiation that may reflect varying degrees of kidney demand-capacity mismatch.

To assess whether a radiation therapy (RT) dose affects response in bulky tumors in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). Data from patients with r/r DLBCL treated with salvage- or palliative-intent RT (2008-2020) at a single institution were examined. Index lesion size ≥7.5 cm was defined as bulky. Equivalent doses in 2-Gy fractions (EQD2) were calculated to compare doses between conventional and hypofractionated (≥2.5 Gy/fraction) schemes. Objective response rates (ORRs) were compared using nonparametric Mann-Whitney U test or Kruskal-Wallis test with Dunn's multiple comparison corrections. Freedom from local progression (FFLP) was assessed using Kaplan-Meier and Cox proportional hazard regression analyses. One hundred eighty-three courses of 151 unique patients were included (salvage: 37% and palliative: 63%). Nonbulky and bulky tumors were irradiated in 109 (60%) and 74 (40%) courses, respectively. Median EQD2 was 33 Gy (IQR, 23-39 Gy) with hypofractionation in 84 (46%) cases. Of those with post-RT imaging (80%), the ORR was 59%, with a trend toward worsened ORR in bulky tumors (50% vs 65%, P =.077). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs >30 Gy: 27% vs 64%, P =.0073), whereas a lower EQD2 cutoff was sufficient for nonbulky tumors (≤20 Gy vs >20 Gy: 38% vs 75%, P =.0011). On multivariable regression analysis, bulky tumor size was associated with worsened FFLP (hazard ratio, 2.07; 95% CI, 1.16-3.68; P =.014), whereas high EQD2s >30 Gy were associated with better FFLP (hazard ratio, 0.48; 95% CI, 0.25-0.93; P =.031). Bulky tumors treated with EQD2s ≤30 Gy had the lowest median FFLP (4.0 months), whereas EQD2s >30 Gy had an unreached median FFLP (P =.0047). Bulky r/r DLBCL tumors were associated with less favorable tumor control outcomes in the salvage and palliative settings. RT regimens with higher EQD2s (>30 Gy) should be considered if durable local control of bulky tumors is desired. [ABSTRACT FROM AUTHOR]

Insulin and IGF-1 receptors (IR and IGF1R) are highly homologous and share similar signaling systems, but each has a unique physiological role, with IR primarily regulating metabolic homeostasis and IGF1R regulating mitogenic control and growth. Here, we show that replacement of a single amino acid at position 973, just distal to the NPEY motif in the intracellular juxtamembrane region, from leucine, which is highly conserved in IRs, to phenylalanine, the highly conserved homologous residue in IGF1Rs, resulted in decreased IRS-1/PI3K/Akt/mTORC1 signaling and increased Shc/Gab1/MAPK cell cycle signaling. As a result, cells expressing L973F-IR exhibited decreased insulin-induced glucose uptake, increased cell growth, and impaired receptor internalization. Mice with knockin of the L973F-IR showed similar alterations in signaling in vivo, and this led to decreased insulin sensitivity, a modest increase in growth, and decreased weight gain when mice were challenged with a high-fat diet. Thus, leucine-973 in the juxtamembrane region of the IR acts as a crucial residue differentiating IR signaling from IGF1R signaling.