Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

Comparison of short-term outcomes following robotic ventral hernia repair in patients with obesity: a review of 9742 patients from the Abdominal Core Health Quality Collaborative database.

Despite the paucity of evidence on robotic ventral hernia repair (RVHR) in patients with obesity, the robotic platform is being used more frequently in hernia surgery. The impact of obesity on RVHR outcomes has not been thoroughly studied. Obesity is considered a major risk factor for the development of recurrent ventral hernias and postoperative complications; however, we hypothesize that patients undergoing robotic repairs will have similar complication profiles despite their body mass index (BMI). We performed a retrospective analysis of patients aged 18-90 years who underwent RVHR between 2013 and 2023 using data from the Abdominal Core Health Quality Collaborative registry. Preoperative, intraoperative, and postoperative characteristics were compared in non-obese and obese groups, determined using a univariate and logistic regression analysis to compare short-term outcomes. The registry identified 9742 patients; 3666 were non-obese; 6076 were classified as obese (BMI > 30 kg/m2). There was an increased odds of surgical site occurrence in patients with obesity, mostly seroma formation; however, obesity was not a significant factor for a complication requiring a procedural intervention after RVHR. In contrast, the hernia-specific quality-of-life scores significantly improved following surgery for all patients, with those with obesity having more substantial improvement from baseline. Obesity does increase the risk of certain complications following RVHR in a BMI-dependent fashion; however, the odds of requiring a procedural intervention are not significantly increased by BMI. Patients with obesity have a significant improvement in their quality of life, and RVHR should be carefully considered in this population.

Cross-Sectional Melt Pool Geometry of Laser Scanned Tracks and Pads on Nickel Alloy 718 for the 2022 Additive Manufacturing Benchmark Challenges.

The Additive Manufacturing Benchmark Series (AM Bench) is a NIST-led organization that provides a continuing series of additive manufacturing benchmark measurements, challenge problems, and conferences with the primary goal of enabling modelers to test their simulations against rigorous, highly controlled additive manufacturing benchmark measurement data. To this end, single-track (1D) and pad (2D) scans on bare plate nickel alloy 718 were completed with thermography, cross-sectional grain orientation and local chemical composition maps, and cross-sectional melt pool size measurements. The laser power, scan speed, and laser spot size were varied for single tracks, and the scan direction was varied for pads. This article focuses on the cross-sectional melt pool size measurements and presents the predictions from challenge problems. Single-track depth correlated with volumetric energy density while width did not (within the studied parameters). The melt pool size for pad scans was greater than single tracks due to heat buildup. Pad scan melt pool depth was reduced when the laser scan direction and gas flow direction were parallel. The melt pool size in pad scans showed little to no trend against position within the pads. Uncertainty budgets for cross-sectional melt pool size from optical micrographs are provided for the purpose of model validation.

Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.

The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

The fasciola cinereum of the hippocampal tail as an interventional target in epilepsy.

Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.

Risk of revision total knee arthroplasty for patients with prior bariatric surgery or class III obesity.

BACKGROUND: Bariatric surgery (BS) is indicated for select class III obesity patients undergoing total knee arthroplasty (TKA) to reduce obesity-related complications. This study assessed the effect of BS on TKA revision rates compared to the general population and class III obesity patients without a history of BS. METHODS: A national database identified patients who had primary TKA. They were divided into two groups: those with BS prior to TKA and those without. Patients without BS formed two control groups, a matched general population, and a matched class III obese cohort. The BS group was matched with controls based on age, Charlson Comorbidity Index (CCI), gender, and diabetes mellitus. Revision rates were analyzed using Kaplan-Meier survival analysis and hazard ratios (HR), calculated using Cox proportional hazard modeling. RESULTS: 14,292 BS patients were compared to 57,006 matched general population controls, and 19,504 BS patients were compared to 77,846 matched class III obesity control patients. BS patients had a higher risk of 5-year all-cause revision (HR: 1.13; P = 0.014) and revision due to periprosthetic fracture (HR: 1.39; P < 0.001) compared to the general population. Compared to class III obesity controls, BS patients had a lower risk of 5-year revision due to prosthetic joint infection (HR: 0.77; P = 0.001), with no difference in all-cause revision (P = 0.362). CONCLUSION: BS does not reduce all-cause TKA revision risk compared to the general or matched class III obesity population. However, it lowers the risk of revision due to prosthetic joint infection when compared to patients with class III obesity. LEVEL OF EVIDENCE: IV.

Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

The effects of inhaled corticosteroids on healthy airways.

BACKGROUND: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. OBJECTIVES: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. METHODS: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. RESULTS: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. CONCLUSIONS: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

Tumor Necrosis Factor Receptor-2 Signals Clear-Cell Renal Carcinoma Proliferation via Phosphorylated 4E Binding Protein-1 and Mitochondrial Gene Translation.

Clear-cell renal cell carcinoma (ccRCC), a tubular epithelial malignancy, secretes tumor necrosis factor (TNF), which signals ccRCC cells in an autocrine manner via two cell surface receptors, TNFR1 and TNFR2, to activate shared and distinct signaling pathways. Selective ligation of TNFR2 drives cell cycle entry of malignant cells via a signaling pathway involving epithelial tyrosine kinase, vascular endothelial cell growth factor receptor type 2, phosphatidylinositol-3-kinase, Akt, pSer727-Stat3, and mammalian target of rapamycin. In this study, phosphorylated 4E binding protein-1 (4EBP1) serine 65 (pSer65-4EBP1) was identified as a downstream target of this TNFR2 signaling pathway. pSer65-4EBP1 expression was significantly elevated relative to total 4EBP1 in ccRCC tissue compared with that in normal kidneys, with signal intensity increasing with malignant grade. Selective ligation of TNFR2 with the TNFR2-specific mutein increased pSer65-4EBP1 expression in organ cultures that co-localized with internalized TNFR2 in mitochondria and increased expression of mitochondrially encoded COX (cytochrome c oxidase subunit) Cox1, as well as nuclear-encoded Cox4/5b subunits. Pharmacologic inhibition of mammalian target of rapamycin reduced both TNFR2-specific mutein-mediated phosphorylation of 4EBP1 and cell cycle activation in tumor cells while increasing cell death. These results signify the importance of pSer65-4EBP1 in mediating TNFR2-driven cell-cycle entry in tumor cells in ccRCC and implicate a novel relationship between the TNFR2/pSer65-4EBP1/COX axis and mitochondrial function.

AIDS but not asymptomatic HIV is associated with lower 2-10-year implant survivorship following total knee arthroplasty.

INTRODUCTION: Prior studies have demonstrated HIV does not increase the risk of 2-year complications following TKA; however, the literature is sparse regarding the impact of HIV and AIDS on long-term implant survivorship. The purpose of this study was to compare the 10-year cumulative incidence and risk of revision TKA in patients with and without asymptomatic HIV, and with and without AIDS. METHODS: Patients with HIV who underwent elective TKA were identified using a national database and divided into subgroups of asymptomatic HIV (AHIV) and acquired immunodeficiency syndrome (AIDS). These patients with HIV were propensity matched based on age, sex, and Charlson Comorbidity Index (CCI) to a control group of elective TKA patients without HIV in a 1:2 ratio. Patients were also compared to an unmatched control group. RESULTS: The 10-year risk for all-cause revision TKA was higher in the HIV group compared to unmatched controls (HR 1.40, 95% CI 1.02-1.93, p = 0.038) but not matched controls (HR 1.13, 95% CI 0.77-1.63, p = 0.594). When compared to both control groups (unmatched; matched), the AIDS group had a higher risk of 10-year all-cause revision (HR 2.74, 95% CI 1.51-4.99, p < 0.001; HR 2.19, 95% CI 1.17-4.11, p = 0.014), dislocation/instability (HR 4.89, 95% CI 1.54-15.51, p = 0.007; HR 3.86, 95% CI 1.12-13.34, p = 0.033), and periprosthetic fracture [PPF] (HR 0.67, 95% CI 0.16-2.74, p = 0.002; HR 3.82, 95% CI 1.08-13.45, p = 0.037). However, patients with AIDS were not at increased risk of PJI or mechanical loosening compared to unmatched controls or matched controls. DISCUSSION: This study expands on current literature by following a nationwide cohort of HIV/AIDS patients for 10 years after TKA. Although a diagnosis of asymptomatic HIV was not associated with increased risk of 10-year revision rates following TKA, a diagnosis of AIDS was. Surgeons should ensure patients' serum CD4 level is sufficient, ideally in the normal range of 500-1500 cells per mm3, before undergoing TKA.

Survival following lung volume reduction procedures: results from the UK Lung Volume Reduction (UKLVR) registry.

INTRODUCTION: Lung volume reduction surgery (LVRS) and endobronchial valve (EBV) placement can produce substantial benefits in appropriately selected people with emphysema. The UK Lung Volume Reduction (UKLVR) registry is a national multicentre observational study set up to support quality standards and assess outcomes from LVR procedures at specialist centres across the UK. METHODS: Data were analysed for all patients undergoing an LVR procedure (LVRS/EBV) who were recruited into the study at participating centres between January 2017 and June 2022, including; disease severity and risk assessment, compliance with guidelines for selection, procedural complications and survival to February 2023. RESULTS: Data on 541 patients from 14 participating centres were analysed. Baseline disease severity was similar in patients who had surgery n=244 (44.9%), or EBV placement n=219 (40.9%), for example, forced expiratory volume in 1 s (FEV1) 32.1 (12.1)% vs 31.2 (11.6)%. 89% of cases had discussion at a multidisciplinary meeting recorded. Median (IQR) length of stay postprocedure for LVRS and EBVs was 12 (13) vs 4 (4) days(p=0.01). Increasing age, male gender and lower FEV1%predicted were associated with mortality risk, but survival did not differ between the two procedures, with 50 (10.8%) deaths during follow-up in the LVRS group vs 45 (9.7%) following EBVs (adjusted HR 1.10 (95% CI 0.72 to 1.67) p=0.661) CONCLUSION: Based on data entered in the UKLVR registry, LVRS and EBV procedures for emphysema are being performed in people with similar disease severity and long-term survival is similar in both groups.

No Difference in Revision Rates up to 10 years Following Total Hip Arthroplasty in Patients Who Had Prior Bariatric Surgery When Compared to Patients Who Had Class III Obesity: A Propensity Matched Analysis.

BACKGROUND: There is no clear research showcasing bariatric surgery's (BS's) impact on long-term surgical complications following total hip arthroplasty (THA). Therefore, this study compared the 10-year cumulative incidence and risk of revision following THA in patients who underwent BS when compared to the general population and class III obesity patients who did not undergo BS. METHODS: Patients who underwent elective THA from 2010 to 2021 were identified using an all-payer claims database. Patients who underwent BS prior to THA were separately matched to a control of the general population and those who had class III obesity (body mass index ≥40) by age, sex, Charlson Comorbidity Index, and diabetes using a 1:4 ratio. Kaplan-Meier analyses generated 10-year cumulative incidence rates, and a Cox proportional hazard ratio (HR) model generated HRs and 95% confidence intervals (CIs). RESULTS: When compared to the general control, patients who have a history of BS had an elevated 10-year risk of all-cause revision (HR 1.31, 95% CI: 1.16 to 1.47, P < .001), prosthetic joint infection (HR: 1.62, CI: 1.30 to 2.04; P < .001), mechanical loosening (HR: 1.20, CI: 1.01 to 1.44; P = .040), and dislocation/instability (HR: 1.35, CI: 1.09 to 1.68; P = .007). There was no difference in the 10-year risk of all-cause revision or other indications for revision in the BS cohort compared to the matched class III obesity cohort (P = .142). CONCLUSIONS: Those who underwent BS before THA had comparable 10-year revision rates when compared to those who had class III obesity and higher rates compared to the general population. This suggests BS may not reduce the 10-year surgical risks associated with obesity when compared to a class III obese surgical population.

SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.

Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.

Outcomes of High-Grade Immune Checkpoint Inhibitor Hepatitis in Hospitalized and Nonhospitalized Patients.

BACKGROUND & AIMS: Guidelines recommend hospitalization for severe immune checkpoint inhibitor (ICI) hepatitis. We compared patient outcomes in the inpatient versus outpatient settings. METHODS: We conducted a multicenter, retrospective cohort study of 294 ICI-treated patients who developed grade 3-4 ICI hepatitis. The primary outcome was time to alanine aminotransferase (ALT) normalization (≤40); secondary outcomes included time to ALT ≤100 U/L and time to death. To account for confounding by indication, inverse probability of treatment weighting was applied to perform Cox regression. A sensitivity analysis was performed excluding patients with grade 4 hepatitis. RESULTS: One hundred and sixty-six patients (56.5%) were hospitalized for a median of 6 (interquartile range, 3-11) days. On inverse probability of treatment weighting Cox regression, hospitalization was not associated with time to ALT normalization (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.86-1.43; P = .436) or time to ALT ≤100 U/L (HR, 1.11; 95% CI, 0.86-1.43; P = .420). In the sensitivity analysis limited to patients with grade 3 hepatitis, hospitalization was also not associated with time to ALT normalization (HR, 1.11; 95% CI, 0.83-1.50; P = .474) or time to ALT ≤100 U/L (HR, 1.19; 95% CI, 0.90-1.58; P = .225). In a subgroup analysis of 152 patients with melanoma, hospitalization was not associated with reduced risk of all-cause death (HR, 0.93; 95% CI, 0.53-1.64; P = .798). Notably, despite their Common Terminology Criteria for Adverse Events classification of high-grade hepatitis, 94% of patients had "mild" liver injury based on International Drug-Induced Liver Injury Criteria. CONCLUSIONS: Hospitalization of patients with high-grade ICI hepatitis was not associated with faster hepatitis resolution and did not affect mortality. Routine hospitalization may not be necessary in all patients with high-grade ICI hepatitis and Common Terminology Criteria for Adverse Events criteria may overestimate severity of liver injury.

ß-Actin G342D as a Cause of NK Cell Deficiency Impairing Lytic Synapse Termination.

NK cell deficiency (NKD) occurs when an individual's major clinical immunodeficiency derives from abnormal NK cells and is associated with several genetic etiologies. Three categories of ß-actin-related diseases with over 60 ACTB (ß-actin) variants have previously been identified, none with a distinct NK cell phenotype. An individual with mild developmental delay, macrothrombocytopenia, and susceptibility to infections, molluscum contagiosum virus, and EBV-associated lymphoma had functional NKD for over a decade. A de novo ACTB variant encoding G342D ß-actin was identified and was consistent with the individual's developmental and platelet phenotype. This novel variant also was found to have direct impact in NK cells because its expression in the human NK cell line YTS (YTS-NKD) caused increased cell spreading in lytic immune synapses created on activating surfaces. YTS-NKD cells were able to degranulate and perform cytotoxicity, but they demonstrated defective serial killing because of prolonged conjugation to the killed target cell and thus were effectively unable to terminate lytic synapses. G342D ß-actin results in a novel, to our knowledge, mechanism of functional NKD via increased synaptic spreading and defective lytic synapse termination with resulting impaired serial killing, leading to overall reductions in NK cell cytotoxicity.

The Changing Faces of Leadership in Surgery: Study on Presidents of Major Surgical Organizations.

INTRODUCTION: To gain an understanding of the changing faces of leadership in surgery, we examined trends in the demographics, additional degrees pursued, and scientific publication characteristics of the past presidents of three major surgery organizations. METHODS: We queried the BoardCertifiedDocs and Web of Science databases for the demographics, as well as the quantity and quality of publications, of the past presidents of the Association for Academic Surgery, Society of University Surgeons, and American College of Surgeons from 1970 to 2020. Data were analyzed by decade to identify any trends. RESULTS: We identified a total of 140 presidents from the organizations. The proportion of female presidents significantly increased from the 1990s to the 2010s (10% versus 33%, P < 0.05). The percentage of non-White presidents increased from the 1970s to the 2010s (3.33% versus 21.2%, P = 0.024). The percentage of presidents with additional degrees also increased from the 1970s to the 2010s (10.0% versus 48.8%, P = 0.039). During this same time period, the most common area of expertise of presidents shifted from cardiothoracic surgery to surgical oncology. The ratio of presidents' postinduction to preinduction publications was significantly increased among all three organizations in the 2010s compared to the 1970s (P < 0.05). Co-cluster analysis revealed a research topic change from the 1970s to the 2010s. CONCLUSIONS: The faces of surgical leadership have changed in terms of gender equality, racial diversity, surgical subspecialty, and additional degrees held. Such a transformation mirrors evolving diversity, equity, and inclusion initiatives, and it further highlights the adaptability of surgical leadership to the ever-changing landscape of surgery.

Incidental central pulmonary emboli in outpatients with deep vein thrombosis.

BACKGROUND: While it has been demonstrated that large asymptomatic pulmonary embolism (PE) can occur, many studies have assessed inpatients or patients with known risk factors for venous thromboembolism (such as malignancy). There are few data regarding incidental PE in outpatients with deep vein thrombosis (DVT) or assessing whether these emboli occur centrally or peripherally in the pulmonary arteries. AIMS: To determine the rates of incidental central and peripheral PE in outpatients with proximal and distal DVT. METHODS: This was a retrospective cross-sectional study of 120 patients attending our community imaging clinic between January 2015 and March 2020, with ultrasound-confirmed lower limb DVT, and subsequent computed tomography pulmonary angiogram (CTPA) within 24 h. Exclusion criteria were symptoms indicative of PE. Imaging reports were retrospectively reviewed to record the proximity of DVT and the location of any PE as either central (pulmonary trunk or main pulmonary arteries) or peripheral (lobar, segmental or subsegmental pulmonary arteries). RESULTS: Incidental PE occurred in 71 patients (59.2%), with a rate of 77.5% in proximal and 50.0% in distal DVT. Sixteen patients had central PE (13.3% of all patients with DVT; 22.5% of all patients with PE). Two patients (both with proximal DVT) had PE in the pulmonary trunk. CONCLUSIONS: Incidental PE occur frequently in outpatients with lower limb DVT, including the possibility of asymptomatic central emboli. Further studies with larger patient cohorts would be useful to assess the utility of baseline chest imaging in outpatients with DVT.

Randomized Trial of the Insulin-Only iLet Bionic Pancreas for the Treatment of Cystic Fibrosis- Related Diabetes.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis and adds significant morbidity and treatment burden. We evaluated the safety and efficacy of automated insulin delivery with the iLet bionic pancreas (BP) in adults with CFRD in a single-center, open-label, random-order, crossover trial. RESEARCH DESIGN AND METHODS: Twenty participants with CFRD were assigned in random order to 14 days each on the BP or their usual care (UC). No restrictions were placed on diet or activity. The primary outcome was the percent time sensor-measured glucose was in target range 70-180 mg/dL (time in range [TIR]) on days 3-14 of each arm, and key secondary outcomes included mean continuous glucose monitoring (CGM) glucose and the percent time sensor-measured glucose was in hypoglycemic range <54 mg/dL. RESULTS: TIR was significantly higher in the BP arm than the UC arm (75 ± 11% vs. 62 ± 22%, P = 0.001). Mean CGM glucose was lower in the BP arm than in the UC arm (150 ± 19 vs. 171 ± 45 mg/dL, P = 0.007). There was no significant difference in percent time with sensor-measured glucose <54 mg/dL (0.27% vs. 0.36%, P = 1.0), although self-reported symptomatic hypoglycemia episodes were higher during the BP arm than the UC arm (0.7 vs. 0.4 median episodes per day, P = 0.01). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either arm. CONCLUSIONS: Adults with CFRD had improved glucose control without an increase in CGM-measured hypoglycemia with the BP compared with their UC, suggesting that this may be an important therapeutic option for this patient population.