Online supplemental material is available for this article. See also the editorial by Grant in this issue.

Nucleotide analog interference mapping (NAIM) is a powerful method for identifying RNA functional groups involved in protein-RNA interactions. We examined particles assembled on modified U1 small nuclear RNAs (snRNAs) in vitro and detected two categories of interferences. The first class affects the stability of two higher-order complexes and comprises changes in two adenosines, A65 and A70, in the loop region previously identified as the binding site for the U1 small nuclear ribonucleoprotein (snRNP)-specific U1A protein. Addition of an exocyclic amine to position 2 of A65 interferes strongly with protein binding, whereas removal or modification of the exocyclic amine at position 6 makes little difference. Modifications of A70 exhibit the opposite effects: Additions at position 2 are permitted, but modification of the exocyclic amine at position 6 significantly inhibits protein binding. These interactions, critical for U1A-U1 snRNA recognition in the context of in vitro snRNP assembly, are consistent with previous structural studies of the isolated protein with the RNA hairpin containing the U1A binding site. The second category of interferences affects all partially assembled U1-protein complexes by decreasing the stability of Sm core protein associations. Interestingly, most strong interferences occur at phosphates in the terminal stem-loop region of U1, rather than in the Sm binding site. These data argue that interactions with the phosphate backbone of the terminal stem loop are essential for the stable association of Sm core proteins with the U1 snRNA. We suggest that the stem loop of all Sm snRNAs may act as a clamp to hold the ring of Sm proteins in place.

An esophagopulmonary fistula (EPF) may occur in patients with esophageal carcinoma and result in pulmonary abscess formation. Lung abscesses may in turn cause pulmonary artery (PA) pseudoaneurysms and life-threatening hemoptysis. We report a 59-year-old man with past medical history of metastatic distal esophageal adenocarcinoma who presented with fever, cough, and massive hemoptysis. Imaging evaluation demonstrated an EPF, associated lung abscess, and PA pseudoaneurysms. The presented case illustrates that embolization of PA pseudoaneurysms to prevent bleeding, and endoscopic esophageal covered stent graft placement to divert esophageal contents from the abscess, may facilitate a favorable outcome.

PURPOSE:The purpose of this study is to assess the incremental effect of tissue plasminogen activator (t-PA) dose on pulmonary artery pressure (PAP) and bleeding during catheter directed thrombolysis (CDT) of submassive pulmonary embolism (PE). MATERIALS AND METHODS:Records of 46 consecutive patients (25 men, 21 women, mean age 55±14 y) who underwent CDT for submassive PE between September 2009 and February 2017 were retrospectively reviewed. Mean t-PA rate was 0.7±0.3 mg/h. PAP was measured at baseline and daily until CDT termination. Mixed-effects regression modeling was performed of repeated PAP measures in individual patients. Bleeding events were classified by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) and t-PA dose at onset. RESULTS:Mean t-PA dose was 43.0±30.0 mg over 61.9± 28.8 h. Mean systolic PAP decreased from 51.7±15.5 mmHg at baseline to 35.6±12.7 mmHg at CDT termination (p<0.001). Mixed-effects regression revealed a linear decrease in systolic PAP over time (β = -0.37 (SE = 0.05), p<0.001) with reduction in mean systolic PAP to 44.8±1.9 mmHg at 12 mg t-PA/20 h, 39.5±2.0 mmHg at 24 mg t-PA/40 h, and 34.9±2.1 mmHg at 36 mg/60 h. No severe, one moderate, and 8 mild bleeding events occurred; bleeding onset was more frequent at ≤24 mg t-PA (p <0.001). One patient expired from cardiopulmonary arrest after 16 h of CDT (15.4 mg t-PA); no additional intra-procedural fatalities occurred. CONCLUSION:Increased total t-PA dose and CDT duration were associated with greater PAP reduction without increased bleeding events.

Objective

To systematically evaluate the evidence for an association between physical activity of moderate intensity and risk of type 2 diabetes.

Research design and methods

We searched EMBASE and Medline through March 2006 and examined reference lists of retrieved articles. We excluded studies that did not assess physical activity of moderate intensity independent of activities of vigorous intensity (more than six times the resting metabolic rate). Information on study design, participant characteristics, assessment of physical activity, and outcomes and estimates of associations were extracted independently by two investigators. We calculated summary relative risks (RRs) using a random-effects model for the highest versus the lowest reported duration of activities.

Results

We identified 10 prospective cohort studies of physical activity of moderate intensity and type 2 diabetes, including a total of 301,221 participants and 9,367 incident cases. Five of these studies specifically investigated the role of walking. The summary RR of type 2 diabetes was 0.69 (95% CI 0.58-0.83) for regular participation in physical activity of moderate intensity as compared with being sedentary. Similarly, the RR was 0.70 (0.58-0.84) for regular walking (typically > or = 2.5 h/week brisk walking) as compared with almost no walking. The associations remained significant after adjustment for BMI. Similar associations were observed in men and women and in the U.S. and Europe.

Conclusions

These findings indicate that adherence to recommendations to participate in physical activities of moderate intensity such as brisk walking can substantially reduce the risk of type 2 diabetes.

Intrahepatic arterioportal fistulas may be complicated by portal hypertension. An associated portal venous aneurysm (PVA) may impinge upon adjacent structures or rupture. We present a 65-year-old man with an intrahepatic Intrahepatic arterioportal fistula and 6.4 × 5.8 cm right portal vein aneurysm extending within 0.4 cm of the hepatic margin, associated with pain concerning for impending rupture. The PVA was refractory to transarterial embolization due to recruitment of arterial collaterals. Therefore, it was additionally excluded from the portal vein with a 12 mm × 9.5 cm venous stent graft. Although endovascular therapy thrombosed the aneurysm and improved symptoms, it was complicated by a type 2 endoleak into the PVA.

Background

Aneurysms are rare anomalies of the portomesenteric venous system. Thrombotic complications of these lesions can lead to mesenteric venous ischemia and bowel infarction, potentially requiring surgical intervention. Herein we describe a case of mesenteric ischemia due to a large thrombosed portomesenteric aneurysm treated with endovascular techniques.

Case presentation

A 37-year-old previously healthy male who presented with abdominal pain to his local emergency department was found to have a thrombosed 12.0 × 5.1 cm portomesenteric venous aneurysm with evidence of mesenteric ischemia on CT. When conservative management with anticoagulation failed, transhepatic pharmacomechanical thrombolysis was initially performed. This was followed by TIPS placement with additional trans-TIPS thrombectomy to improve sluggish portal outflow and prevent re-thrombosis. The patient's symptoms and imaging findings of ischemia resolved after endovascular therapy. No surgical intervention was required, and the patient was discharged on enoxaparin before being transitioned to apixaban. The TIPS remained patent at 2-year follow-up, with no change in the size of the aneurysm or re-thrombosis noted. The patient's synthetic liver function was preserved with no evidence of hepatic encephalopathy during the follow-up period.

Conclusions

Endovascular therapies may be used to manage thrombotic complications of portomesenteric venous aneurysms, obviating the need for surgical intervention in selected patients.

Objectives

Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients.

Study design

In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures.

Results

A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only).

Conclusions

During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception.

Implications

In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.