Egan, Aoife M.

Abstract Fibrosing mediastinitis is an infiltrative disease which may develop secondary to a variety of causes, including autoimmune, infectious, and malignant processes. Here, we present a case of fibrosing mediastinitis, with initial concerns for IgG4-related disease. A 36-year-old man presented to his primary provider with three months of intermittent dyspnea. CT chest was significant for a large, infiltrative mediastinal and left hilar mass with calcifications and involvement of the left upper and lower lobe bronchi, lingular bronchus, and left main pulmonary artery. Subsequent autoimmune and fungal studies were negative. The patient underwent bronchoscopy, with biopsy of a lymph node at station 11L showing increased IgG4 on immunostain (30 cells/hpf), though IgG immunostaining was not completed for comparison. Despite initial concerns for fibrosing mediastinitis, the patient was diagnosed with IgG4-related disease and initiated on rituximab and mycophenolate. Notably, the patient's serum IgG4 concentrations were consistently within normal limits before and after initiation of rituximab. The patient was referred to our clinic after lack of response to therapy on imaging. Laboratory evaluation redemonstrated a normal serum IgG4 concentration and fungal studies were consistent with previous histoplasma infection, suggesting fibrosing mediastinitis secondary to histoplasmosis. IgG4-related disease was determined to be unlikely considering repeatedly normal IgG4 levels and weakly positive IgG4 staining. Repeat CT chest demonstrated fibrosis of the left upper lobe; compression of the left atrial appendage; and occlusion and severe obstruction of the left superior pulmonary vein and left lower lobe pulmonary artery, respectively. VQ scan demonstrated significantly reduced perfusion of the left lung and the patient was referred for stenting of the affected vasculature. PET-CT revealed moderate FDG avidity of the left hilar nodes, concerning for ongoing active fibrosing mediastinitis, for which he was continued on rituximab. The indolent nature of fibrosing mediastinitis often leads to advanced disease at the time of presentation. Hilar structures are commonly involved, as in the case of this patient with a severe perfusion defect secondary to obstruction of the pulmonary vessels. A diagnosis of fibrosing mediastinitis merits careful investigation of the underlying cause. Fungal infections, specifically histoplasmosis in North America, are a leading cause of this condition. IgG4-related disease is also associated with fibrosing mediastinitis, and both conditions are driven by fibroinflammatory processes. However, it is important to note that IgG4 immunostaining is non-specific, and diagnosis of IgG4-related disease requires the meeting of rigorous criteria. Differentiation between these diagnoses is important given potential differences in management.

Abstract Introduction: Birt-Hogg-Dube (BHD) is a rare autosomal dominant genetic disorder caused by mutations in the FLCN tumor suppressor gene. Clinically, BHD is characterized by development of cutaneous fibrofolliculomas/trichodiscomas, renal tumors, and pulmonary cysts, the latter which can result in recurrent, spontaneous pneumothoraces. We present a case of BHD in which diagnosis was delayed given absence of dermatologic and renal manifestations. Case Report: A 66-year-old female never smoker with a past medical history of left-sided breast cancer treated with lumpectomy and chemoradiation and osteoporosis presented for evaluation of recurrent pneumothoraces. Her first pneumothoraces occurred in her 20s-30s and required doxycycline pleurodesis (right side) and video-assisted thoracoscopic pleurodesis (left side). The most recent pneumothorax was in her 50s and resolved with chest tube placement. She reported repeated episodes of pneumonia which prompted pulmonary re-evaluation. A non-contrast CT chest was obtained which demonstrated middle and lower lobe predominant irregular thin-walled cystic changes with paramediastinal involvement. Pulmonary function testing revealed mild hyperinflation but otherwise no evidence of obstruction, restriction, or diffusion limitations (FEV1 113% predicted, FEV1/FVC of 0.72 predicted, FVC 109% predicted, TLC 108% predicted, DLCO 90% predicted). Immunoglobulins and alpha-1 antitrypsin were obtained and normal. A lung biopsy was discussed for definitive diagnosis but never performed. Upon presentation to our clinic, she reported no symptoms such as cough, shortness of breath, pleuritic chest pain, fevers, arthralgias, myalgias, rashes, dry mouth, or dry eyes. A broad differential was considered and a connective tissue disease cascade, VEGF-D testing, and SPEP/UPEP were sent and negative/normal. Given the distribution of cysts on her CT, BHD was considered, and she was referred to clinical genetics for germline testing which identified a heterozygous FLCN variant (c.837dup, p.Glu280Argfs[asterisk]12) consistent with BHD. Discussion: BHD is a rare and underdiagnosed cause of cystic lung disease as it has a broad range of clinical manifestations. Recognizing the disease without either renal or dermatologic manifestations as in our patient can be challenging and requires a high degree of suspicion. Clues to the diagnosis include a family history of spontaneous pneumothorax, which can be highly predictive of BHD as it is the most common cause of hereditary pneumothorax. Definitive diagnosis of BHD depends on a combination of clinical features and germline testing for mutations in the FLCN gene.

Abstract Obstructive shock is rare, occurring in 2% of patients admitted to the intensive care unit (ICU) with shock. Understanding the unique pathophysiology of obstructive shock can aid in resuscitation efforts and significantly impact patient outcomes. Our goal is to expand the current understanding of possible shock etiologies and the treatment of obstructive shock. We present a case of an 88-year-old woman presenting to the ICU following an out-of-hospital cardiac arrest. Family found her unresponsive, called EMS, and started CPR. Upon EMS arrival, she had a pulse; the rhythm was identified as atrial fibrillation. She was cardioverted and transferred to the emergency room. Upon admission, she was intubated and sedated but hemodynamically stable. Shortly after arrival, she developed refractory shock requiring volume resuscitation and rapid titration of three vasoactive medications. She intermittently responded to volume but quickly developed recurrent shock following infusion completion. Bedside ultrasound showed collapse of the right atrium with a pericardial effusion and hyperechoic mobile mass within the pericardial space. Cardiology was called to the bedside for further evaluation of possible cardiac tamponade. There was lack of consensus regarding need for pericardiocentesis. Therefore, further chest imaging was ordered. CTA chest was negative for pulmonary emboli but showed a large hematoma in the anterior mediastinum with active bleeding. Formal echocardiogram confirmed a large extracardiac mass with extrinsic compression of the right atrium as well as a small-moderate circumferential pericardial effusion without obvious features of tamponade. She underwent an urgent IR angiogram with embolization of the internal mammary artery and placement of a 14F locking loop pigtail catheter into the anterior mediastinal hematoma felt to be contained within a known 3.5 cm benign cystic lesion. She experienced significant hemodynamic improvement following embolization and drain placement. The etiology of her presumed PEA arrest remained unclear, though it was concluded that the obstructive shock was due to the anterior mediastinal hematoma, a consequence of CPR. In this case we highlight the risk of arterial hemorrhage following resuscitation for cardiac arrest and the role it can play in the development of obstructive shock. There have been some documented cases of pericardial bleeding and the development of cardiac tamponade but limited case reports regarding arterial hemorrhage following CPR. Quickly identifying extracardiac compression allowed for appropriate and rapid IR embolization which led to clinical improvement in our patient.

Abstract Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. They are also associated with life-threatening immune-related adverse events (irAEs), including the rare, poorly understood, and potentially fatal triad of myasthenia gravis, myocarditis, and myositis(triple M syndrome). We aimed to describe the management, intensive care unit (ICU)utilization, and outcomes of patients with irAEs with a specific focus on triple M syndrome. Methods: We conducted a retrospective chart review of patients with irAEs admitted to three quaternary care hospitals between December 2018 and 2023. We aimed to collect data on demographics, cancer type, treatment, ICU resource utilization, and outcomes including mortality. Results: Over this 5-year period, 140 patients were admitted for irAEs. Forty-nine percent were male, median age was 73 (IQR 64-80) years, 7% were of African American or Asian descent, and 32%required ICU admission. Median ICU and hospital length of stay (LOS) were 1.5 (IQR 0.7-2.9)and 7.2 (IQR 4.1-13.4) days, respectively. Among ICU patients, 14/140 (10%) had myositis,22/140 (16%) myocarditis, and 9/140 (6.4%) myasthenia gravis. Triple-M syndrome was diagnosed in 7/140 (5%) patients, including 3 with metastatic melanoma, 2 with genitourinary malignancies, 1 with metastatic lung and 1 with colon cancer. Four had received pembrolizumab and 3 nivolumab. Median ICU and hospital LOS were 3 (IQR 1-6) and 10 (IQR 8-21) days in this group. Three patients required mechanical ventilation, one required tracheostomy, and one required vasopressor support. Triple-M management included corticosteroids, IVIG, pyridostigmine, mycophenolate mofetil, and rituximab. Patients with triple-M syndrome were significantly older than other patients with ICI toxicity (P <0.009) and had higher mortality (57%vs 25%, p = 0.07). Patients discharged from the ICU had a median survival of 67 (IQR 26-201)days. Conclusions: Patients with irAEs frequently require ICU level of support with significant morbidity and mortality, especially with triple M syndrome. Clinicians should always consider the possibility of triple-M syndrome in patients with multiple irAEs as symptoms can be subtle and easily overlooked. Corticosteroids remain the primary treatment of irAEs and can be combined with other immunosuppressive agents such as infliximab, anti-thymocyte globulin, or pyridostigmine. Unfortunately, mortality due to triple-M syndrome remains high underscoring the importance of early recognition and prompt multidisciplinary management of these toxicities.

Abstract Aims To investigate the cost‐effectiveness of early initiation of metformin and usual care for gestational diabetes mellitus (GDM). Methods Economic evaluation from a healthcare perspective, based on the EMERGE randomised controlled trial. In total, 535 women with GDM were randomised to placebo in addition to usual care or metformin in addition to usual care. Economic outcomes included incremental healthcare costs and quality adjusted life years ( QALYs ) and expected cost‐effectiveness at cost‐effectiveness threshold values of €20,000, €45,000 and €100,000 per QALY gained. Uncertainty was explored using parametric, non‐parametric, deterministic and probabilistic methods and heterogeneity using subgroup analysis. Results On average, relative to the placebo arm, the early metformin arm was associated with non‐statistically significant mean increases of €193.07 (95% CI : −€789.88, €1176.01; p = 0.700) and 0.002 QALYs (95% CI : −0.009, 0.013; p = 0.771). In terms of expected cost‐effectiveness at threshold values of €20,000, €45,000 and €100,000 per QALY gained, the probability of the early metformin arm being more cost‐effective was estimated at 0.423, 0.452 and 0.524. Exploratory subgroup analyses provided more favourable but not definitive evidence in favour of the early metformin arm for cohorts with previous GDM and previous caesarean section. Conclusions We do not find definitive evidence that early initiation of metformin in addition to usual care for GDM was more cost‐effective than usual care alone. The clinical and economic evidence may be considered equivocal, but worthy of further examination.

Abstract Metformin is well‐established as a treatment for type 2 diabetes in non‐pregnant individuals. The low cost, acceptability and broad tolerability of metformin have also made it an attractive option for research into the treatment of other conditions associated with insulin resistance. Despite almost 50 years of clinical experience with the use of metformin to treat diabetes in pregnancy, many questions remain regarding its precise effectiveness in different maternal subgroups, as well as potential short‐term and long‐term effects on the offspring. In this narrative review, we present the current evidence for the use of metformin during pregnancy in various maternal subgroups, including women living with overweight and obesity, women at risk of gestational diabetes, women diagnosed with gestational diabetes and women with pregestational diabetes, including type 2 diabetes. Our specific focus is on the impact of metformin on short‐term maternal, fetal and neonatal outcomes. We also consider the evidence for other emerging indications for metformin in pregnancy, such as the prevention and management of pre‐eclampsia. Plain Language Summary This article looks at research on how metformin use in pregnancy affects mothers and newborns in the short term. Doctors have prescribed metformin since the 1970s for the treatment of diabetes in pregnancy. Despite years of use, there are still questions about how safe and effective metformin is for mothers and their children. Metformin taken during pregnancy moves through the placenta into the foetus's bloodstream. The short‐term and long‐term effects of metformin on offspring need careful attention. The studies that have looked at the link between metformin use and birth defects have not found any strong link between taking metformin in pregnancy and birth defects, however close attention will continue to be paid in this area. Some large studies have examined the use of metformin in pregnant women who do not have diabetes, but who do live with overweight or obesity. The studies are difficult to compare. Some, but not all, of these studies have shown less weight gain for the mother if metformin is taken by these women during pregnancy. Other large studies have looked at whether metformin can prevent gestational diabetes. The results are mostly disappointing. They suggest that metformin does not stop gestational diabetes from developing. However, the participants in these studies were mostly from white backgrounds and metformin may help prevent gestational diabetes in women of different ethnic backgrounds. However, more research is needed. Metformin has been widely studied as an alternative to insulin for the treatment of gestational diabetes. Because different countries diagnose and treat GDM differently, this makes comparing study results difficult. Women with gestational diabetes seem to gain less weight during pregnancy if they use metformin rather than insulin. Using metformin instead of insulin may result in lower average birth weights for babies from these pregnancies. Also, the use of metformin may lead to fewer babies being born abnormally large. Similarly, large trials have examined the use of metformin in pregnant women who are living with type 2 diabetes. These studies show that metformin can lower a mother's insulin needs. It can also help control weight gain and reduce the risk of having a large baby. One study found that metformin use in women living with Type 2 diabetes might increase the risk of having smaller babies. This was especially true if the mother had high blood pressure or kidney disease. This finding requires further investigation. Metformin might help prevent pre‐eclampsia, but this is still unclear. Research is ongoing into a potential role for metformin in the treatment of pre‐eclampsia. In conclusion, metformin has been studied in many groups of pregnant women. Women with gestational diabetes or type 2 diabetes may see benefits like less weight gain and better blood sugar/glucose control. Current evidence suggests that metformin shouldn't be used if there are foetal growth issues. It is also not recommended for mothers with high blood pressure or kidney disease. Future studies might find specific groups of pregnant women who would benefit the most from metformin.

In this study, we propose a new mathematical model able to quantify C-peptide secretion and β-cell responsivity in response to a glucagon bolus in individuals without and with type 2 diabetes. We show that individuals with type 2 diabetes exhibit reduced β-cell responsivity to glucagon.

ImportanceUnderstanding the interplay between diabetes risk factors and diabetes development is important to develop individual, practice, and population-level prevention strategies.ObjectiveTo evaluate the progression from normal and impaired fasting glucose levels to diabetes among adults.Design, Setting, and ParticipantsThis retrospective community-based cohort study used data from the Rochester Epidemiology Project, in Olmsted County, Minnesota, on 44 992 individuals with at least 2 fasting plasma glucose (FPG) measurements from January 1, 2005, to December 31, 2017. People who met criteria for diabetes on or before their first FPG measurement were excluded. Data were electronically retrieved in December 2019 with analyses finalized in November 2024.ExposuresThe exposure was baseline FPG level, with covariates including the following measures that are consistently recorded in the electronic health record: body mass index (BMI), age, and sex.Main Outcomes and MeasuresThe cumulative probability of freedom from diabetes was estimated and presented graphically using a Kaplan-Meier curve. Multivariable Cox proportional hazards regression modeling was used to estimate the partial hazard ratios (HRs) for variables of interest. Diabetes was defined as an FPG level greater than 125 mg/dL.ResultsA total of 44 992 individuals (mean [SD] age at baseline, 43.7 [11.8] years; 26 025 women [57.8%]) were included. The baseline mean (SD) BMI was 28.9 (6.6). Over a median follow-up of 6.8 years (IQR, 3.6-9.7 years), 3879 individuals (8.6%) developed diabetes. The Kaplan-Meier 10-year cumulative risk of incident diabetes was 12.8% (95% CI, 12.4%-13.2%). All initial FPG levels outside a range of 80 to 94 mg/dL were associated with increased risk for diabetes (ie, FPG <70 mg/dL: HR, 3.49 [95% CI, 2.19-5.57]; FPG 120-125 mg/dL: HR, 12.47 [10.84-14.34]). Other independent risk factors were male sex (HR, 1.31 [95% CI, 1.22-1.40]), older age (≥60 years: HR, 1.97 [95% CI, 1.71-2.28]), and any abnormal category of BMI, including underweight (BMI <18.5: HR, 2.42 [95% CI, 1.77-3.29]; BMI ≥40: HR, 4.03 [95% CI, 3.56-4.56]). There was a significant additive association of variables, particularly FPG level and BMI. For instance, a woman aged 55 to 59 years with a BMI of 18.5 to 24.9 and an FPG level of 95 to 99 mg/dL had an estimated 10-year diabetes risk of 7.0%. However, an almost doubling of risk to 13.0% was observed if the BMI was 30.0 to 34.9, and risk more than doubled again to 28.0% if FPG level also increased to 105 to 109 mg/dL. A nomogram was generated to facilitate individual classification into one of four 10-year risk categories.Conclusions and RelevanceThis retrospective cohort study of 44 992 individuals suggests that FPG level, age, BMI, and male sex were all associated with development of diabetes, with significant interaction between these variables. These data contribute to understanding the clinical course of diabetes and highlight the substantial individual variation in diabetes risk according to commonly measured clinical variables. The findings facilitate lifestyle and pharmacologic interventions to treat those at highest risk of diabetes to reduce future morbidity and mortality. Further work is needed to validate this risk categorization tool for different populations.

Abstract Context Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear. Objective This work aimed to understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance. Methods A longitudinal, community-based observational study was conducted at a clinical research unit at an academic medical center. We studied 96 individuals without diabetes (age 55 ± 1 years; body mass index 27.7 ± 0.4) on 2 occasions, 3 years apart using an oral 75-g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Main outcome measures included glucose tolerance status (categorical variable) and then symmetrical percentage change in peak and 120-minute glucose (post oral glucose tolerance test) concentrations (continuous variables). Results A total of 32 individuals progressed from normal to impaired glucose tolerance (IGT) or from IGT to type 2 diabetes. The disposition index (DI) declined in the progressors (568 ± 98 vs 403 ± 65 10−4 dL/kg/min per μU/mL, baseline vs 3 years; P = .04). α-Cell suppression by glucose (δGSR/δglucose) did not change in the nonprogressors (1.5 ± 0.1 vs 1.3 ± 0.1 nmol/min/L; P = .37) but decreased (1.0 ± 0.2 vs 0.8 ± 0.2 nmol/min/L; P < .01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion. Conclusion These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.