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Abstract: MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88 L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88 WT) and MYD88 L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88 L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

Abstract A 33‐year‐old female presented with coryzal symptoms, facial swelling, severe haemorrhagic stomatitis, blistering oral mucositis, conjunctival injection and a sparse targetoid rash on the back and face, requiring admission to hospital. She had received the seasonal influenza vaccination 3 days prior to feeling unwell. Differential diagnosis included erythema multiforme major (EMM) secondary to the influenza vaccine or Mycoplasma pneumoniae‐induced rash and mucositis (MIRM). Oropharyngeal swabs were negative on PCR for cutaneous viruses and Mycoplasma pneumoniae (MP). A skin biopsy from a targetoid lesion on the body showed full thickness epidermal necrosis with epidermal–dermal clefting, numerous civatte bodies and a moderate perivascular infiltrate of lymphocytes and plasma cells in the papillary dermis. She was successfully treated with oral prednisolone and azithromycin. Following discharge from hospital, the paired serological testing for MP returned positive, confirming a diagnosis of MIRM. Our case highlights the difficulties in detecting MP as two diagnostic methods yielded different results, and so we advocate performing both MP PCR and serology to maximise the yield and speed of diagnosis. Secondly, our case highlights the clinical challenge in differentiating MIRM from EMM or Stevens–Johnson syndrome, particularly if there is a potential drug trigger (in our case the influenza vaccine), as all these conditions can feature a severe mucositis with often indistinguishable histological findings. Correct diagnosis of MIRM is important for appropriate and timely administration of anti‐MP antibiotic therapy to facilitate recovery and minimise complications.

Abstract Objective To characterize normative adult ranges for cochlear promontory thickness relevant to the development of subendosteal and transpromontory electrodes to rehabilitate various neurotologic disorders. Patients Adults (≥18 years). Intervention In vivo radiologic assessment using a 192‐slice CT scanner (Force‐192; Siemens Healthcare) with ultrahigh‐resolution scan mode combined and iterative reconstruction. Main Outcome Measure Cochlear promontory thickness. Results Among 48 included patients (96 ears), the mean (SD) age was 56 (18) years (range 25–94) and included 25 (52%) women. Of that 12 patients (25%) had osteopenia (n = 6) or osteoporosis (n = 6). The mean (SD) body mass index was 28 (5) kg/m2. The mean (SD) promontory thickness for the 96 temporal bones under study was 1.22 (0.24) mm (range 0.55–1.85). There was not a statistically significant association between age and promontory thickness (correlation coefficient .08; p = .44). Promontory thickness was significantly greater for men than women (mean 1.28 vs. 1.17 mm; p = .03) and increased with increasing body mass index (correlation coefficient .30; p = .004). Last, promontory thickness was significantly less for patients with osteopenia or osteoporosis compared with those without these conditions (mean 1.09 vs. 1.27 mm; p = .002). Conclusions Cochlear promontory thickness can vary by almost 1.5 mm across patients and is significantly associated with patient sex, body mass index, and comorbid osteopenia/osteoporosis. Subendosteal and transpromontory electrode placement techniques must account for this degree of variability. Level of Evidence IV

Transcriptional enhancers are known to regulate transcript production. Here, the authors show that transcription factors that bind to enhancers also regulate polyadenylation site cleavage activity, thus changing expression of alternative 3’ UTRs.

Background: The 5-factor modified frailty index (mFI-5) has been shown to be a concise and effective tool for predicting adverse events following various spine procedures. However, there have been no studies assessing its utility in patients undergoing anterior lumbar interbody fusion (ALIF). Therefore, the aim of this study was to analyze the predictive capabilities of the mFI-5 for 30-day postoperative adverse events following elective ALIF. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried from 2010 through 2019 to identify patients who underwent elective ALIF using Current Procedural Terminology (CPT) codes in patients over the age of 50. The mFI-5 score was calculated using variables for hypertension, congestive heart failure, comorbid diabetes, chronic obstructive pulmonary disease, and partially or fully dependent functional status which were each assigned 1 point. Univariate analysis and multivariate logistic regression models were utilized to identify the associations between mFI-5 scores, and 30-day rates of overall complications, readmissions, reoperations, and mortality. Results: 11,711 patients were included (mFI-5=0: 4,026 patients, mFI-5=1: 5,392, mFI-5=2: 2,102, mFI-5=3+: 187. Multivariate logistic regression revealed that mFI-5 scores of 1 (OR: 2.2, CI: 1.2–4.2, p=0.02), 2 (OR: 3.6, CI: 1.8–7.3, p

Abstract Background BNO 1016 is an ethanolic extract of a mixture of five herbs that has been sold in different formulations for decades in the European market and more recently, in the United States market as an over-the-counter treatment for rhinosinusitis. Previous studies indicated activation of chloride secretion and increase in ciliary beat frequency by BNO 1016 but the functional consequences on mucociliary transport velocity and airway surface liquid homeostasis are unknown. This study intends to examine the effects of BNO 1016 on these properties in vitro. Results Human sinonasal epithelial cells were grown at an air-liquid interface, with addition of BNO 1016 basolaterally in each experiment. Polystyrene fluorescent microspheres were added to the apical surface of the culture, and distance traveled across the surface of the culture over a fixed time period was measured using live imaging. BNO 1016 concentrations of 50 μg/ml and 500 μg/ml were tested. Basolateral application of compound resulted in a non-dose-dependent increase in culture surface liquid height compared to controls at 30 min, and this effect persisted through the one-hour duration of the experiment (p

Background & Aims: Fontan-associated liver disease (FALD) has emerged as an important morbidity following surgical palliation of single ventricle congenital heart disease. In this study, non-invasive biomarkers that may be associated with severity of FALD were explored. Methods: A retrospective cohort of paediatric patients post-Fontan who underwent liver biopsy at a high volume at a paediatric congenital heart disease centre was reviewed. Results: Among 106 patients, 66% were male and 69% were Hispanic. The mean age was 14.4 ± 3.5 years, and biopsy was performed 10.8 ± 3.6 years post-Fontan. The mean BMI was 20.8 ± 5 kg/m2, with 27.4% meeting obesity criteria. Bridging fibrosis was observed in 35% of patients, and 10.4% of all patients had superimposed steatosis. Bridging fibrosis was associated with lower platelet counts (168.3 ± 58.4 vs. 203.9 ± 65.8 K/μl for congestive hepatic fibrosis score [CHFS] 0–2b, p = 0.009), higher bilirubin (1.7 ± 2.2 vs. 0.9 ± 0.7 mg/dl, p = 0.0090), higher aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] scores (APRI: 0.5 ± 0.3 vs. 0.4 ± 0.1, p

Background: Association of history of coronary artery bypass graft surgery (CABG) with clinical outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI) is unclear from current data. Methods: Using Nationwide Inpatient Sample (NIS) data from 2003 to 2014, adult patients hospitalized with principal diagnosis of STEMI were extracted. The cohort was divided into patients with a history of CABG and those without a history of CABG. The primary outcome measure was in-hospital mortality (IHM). Results: 2,710,375 STEMI patients were included in final analysis of which 110,066 had history of CABG. Patients with history of CABG had higher unadjusted (12.2% vs. 8.8%, P

Objective To evaluate whether frailty or age increases the risk of postoperative complications following cochlear implant (CI) surgery. Study Design Retrospective cohort study. Setting Tertiary academic center. Methods An evaluation of all adult patients undergoing cochlear implantation between 2006 and 2020 was performed. The 5-item Modified Frailty Index (mFI-5, comprising preoperative history of pulmonary disease, heart failure, hypertension, diabetes, and partially/totally dependent functional status) was calculated for all patients included in analysis in addition to demographic characteristics. The primary outcome was postoperative complications following CI within a 3-month period. Major complications included myocardial infarction, bleeding, and cerebrospinal fluid leak, among others. Predictors of postoperative complications were examined using multivariable logistic regression reporting odds ratios (ORs) and 95% CIs. Results There were 520 patients included for review with a median age of 68 (range, 18-94) years and a slight male predominance (n = 283, 54.4%). There were 340 patients (65.4%) who were robust (nonfrail) with an mFI of 0, while 180 (34.6%) had an mFI of ≥1. There were 20 patients who experienced a postoperative complication (3.85%). There was no statistically significant association between postoperative complications as a result of preoperative frailty (OR, 1.56; 95% CI, 0.98-2.48, P = .06) or age as a continuous variable (OR, 0.99; 95% CI, 0.97-1.02, P = .51). Conclusions CI is safe for elderly and frail patients and carries no additional risk of complications when compared to younger, healthier patients. While medical comorbidities should always be considered perioperatively, this study supports the notion that implantation is low risk in older, frail patients.

Abstract Background Recurrent respiratory papillomatosis is a chronic disease of viral origin affecting the larynx, trachea, and lower airways. Inverted papilloma, most commonly originating from the lateral nasal wall, is typically a single, expansile, locally aggressive tumor that remodels bone around the site of origin. Case presentation We report a case of histopathologically proven inverted papilloma occurring in a 50-year-old Caucasian man with recurrent respiratory papillomatosis affecting his nasal cavity, larynx, and trachea. This constitutes the first report of nasal involvement in recurrent respiratory papillomatosis. Viral in situ hybridization studies demonstrated evidence of human papillomavirus in both the septum and middle turbinate subsites. Repeat nasal excision with margin analysis is planned. Conclusions This report emphasizes the importance of considering a broad differential diagnosis in patients with papillomata, and obtaining comprehensive histopathologic evaluation of lesions in multiple subsites in order to rule out inverted papilloma or overt malignant transformation, particularly if high-risk human papillomavirus (HPV) subtypes are identified. Level of evidence 4

An intramural ventricular septal defect (IVSD) is a type of interventricular communication that can occur following biventricular repair of a conotruncal malformation. There have been no previous reports depicting the actual pathologic anatomy of this defect. We describe two cases of IVSDs with their clinical imaging and postmortem pathology.

There has been a conscious effort to address osteoporosis in the aging population. As bisphosphonate and intermittent parathyroid hormone (PTH) therapy become more widely prescribed to treat osteoporosis, it is important to understand their effects on other physiologic processes, particularly the impact on spinal fusion. Despite early animal model studies and more recent clinical studies, the impact of these medications on spinal fusion is not fully understood. Previous animal studies suggest that bisphosphonate therapy resulted in inhibition of fusion mass with impeded maturity and an unknown effect on biomechanical strength. Prior animal studies demonstrate an improved fusion rate and fusion mass microstructure with the use of intermittent PTH. The purpose of this study was to determine if bisphosphonates and intermittent PTH treatment have impact on human spinal fusion. A systematic review of the literature published between 1980 and 2015 was conducted using major electronic databases. Studies reporting outcomes of human subjects undergoing 1, 2, or 3-level spinal fusion while receiving bisphosphonates and/or intermittent PTH treatment were included. The results of relevant human studies were analyzed for consensus on the effects of these medications in regards to spinal fusion. There were nine human studies evaluating the impact of these medications on spinal fusion. Improved fusion rates were noted in patients receiving bisphosphonates compared to control groups, and greater fusion rates in patients receiving PTH compared to control groups. Prior studies involving animal models found an improved fusion rate and fusion mass microstructure with the use of intermittent PTH. No significant complications were demonstrated in any study included in the analysis. Bisphosphonate use in humans may not be a deterrent to spinal fusion. Intermittent parathyroid use has shown early promise to increase fusion mass in both animal and human studies but further studies are needed to support routine use.

Study DesignRetrospective analysis of a nationwide private insurance database. Chi-square analysis and linear regression models were utilized for outcome measures.PurposeThe purpose of this study was to investigate any relationship between lumbar degenerative disc disease, diabetes, obesity and smoking tobacco.Overview of LiteratureDiabetes, obesity, and smoking tobacco are comorbid conditions known to individually have effect on degenerative disc disease. Most studies have only been on a small populous scale. No study has yet to investigate the combination of these conditions within a large patient cohort nor have they reviewed the combination of these conditions on degenerative disc disease.MethodsA retrospective analysis of insurance billing codes within the nationwide Humana insurance database was performed, using PearlDiver software (PearlDiver, Inc., Fort Wayne, IN, USA), to identify trends among patients diagnosed with lumbar disc degenerative disease with and without the associated comorbidities of obesity, diabetes, and/or smoking tobacco. Patients billed for a comorbidity diagnosis on the same patient record as the lumbar disc degenerative disease diagnosis were compared over time to patients billed for lumbar disc degenerative disease without a comorbidity. There were no sources of funding for this manuscript and no conflicts of interest.ResultsThe total number and prevalence of patients (per 10,000) within the database diagnosed with lumbar disc degenerative disease increased by 241.4% and 130.3%, respectively. The subsets of patients within this population who were concurrently diagnosed with either obesity, diabetes, tobacco use, or a combination thereof, was significantly higher than patients diagnosed with lumbar disc degenerative disease alone (p

Abstract Objectives To present a rare case of traumatic facial neuroma involving the geniculate ganglion and review relevant literature. Patient Thirty-year-old man. Intervention Microsurgical resection via combined mastoid-middle fossa approach with great auricular nerve interpositional graft. Main Outcome Measures Patient demographics and pre- and postoperative facial nerve function. Results A 30-year-old man with a reported history of prior Bell's palsy developed progressive complete (House–Brackmann VI) right facial paralysis following blunt trauma. Imaging was strongly suggestive of a geniculate ganglion hemangioma. As the patient had no spontaneous improvement in his poor facial function over the course of 9 months, he underwent resection of the facial nerve lesion with great auricular nerve graft interposition via a combined mastoid-middle fossa approach. Histopathology demonstrated disorganized fascicles, with axonal clustering reminiscent of sprouting/regeneration following trauma. No cellular proliferation or vascular malformation was present. Conclusion Traumatic facial nerve neuromas can occur following temporal bone trauma and can closely mimic primary facial nerve tumors. Akin to the management of geniculate ganglion hemangioma and schwannoma, preoperative facial function largely dictates if and when surgery should be pursued.

Evidence is emerging that shows taste receptors serve functions outside of taste sensation of the tongue. Taste receptors have been found in tissue across the human body, including the gastrointestinal tract, bladder, brain, and airway. These extraoral taste receptors appear to be important in modulating the innate immune response through detection of pathogens. This review discusses taste receptor signaling, focusing on the G-protein–coupled receptors that detect bitter and sweet compounds in the upper airway epithelium. Emphasis is given to recent studies which link the physiology of sinonasal taste receptors to clinical manifestation of upper airway disease.

Background. Throughout the world, intrauterine contraceptive devices (IUDs) are a frequently used, reversible, popular contraceptive method. They are usually placed without major complications. Uterine perforation is a rarely observed complication. Migration of the IUD to the pelvic/abdominal cavity or adjacent structures can occur after perforation. We present 3 cases of uterine perforation, possibly due to scarred myometrium associated with a cesarean delivery. We describe 3 perforations with IUDs lodged in the bladder serosa, the posterior cul-de-sac, and tissue adjacent to the cardinal ligament and external iliac artery. Cases. Case 1. 26-year-old, Gravid 4, Para 2113, nonpregnant female with a history of a cesarean delivery underwent placement of an IUD one year after an elective pregnancy termination, presenting with abdominal pain requesting removal of the IUD. On speculum, although the IUD strings were visualized, the IUD could not be removed. Sonogram imaging identified an empty endometrial cavity with the IUD in posterior cul-de-sac. The IUD was removed via laparoscopy. Case 2. 34-year-old Gravida 5, Para 4004, at 27 weeks and 3 days gestation, female with history of two previous cesarean deliveries underwent a third cesarean after spontaneous rupture of membranes with comorbid chorioamnionitis. Reproductive history was significant for placement of an IUD that had not been removed or imaged during obstetrical sonograms. The clinical evaluation revealed that the IUD had been spontaneously expelled. On the fifth operative day, the patient is febrile with CT demonstrating the IUD penetrating the anterior surface of bladder. On cystoscopy the bladder mucosa was intact. The IUD was removed via laparotomy with repair of the bladder, serosa, and muscular layer. Case 3. 26-year-old, Gravid 4, P3013, nonpregnant female with three previous Cesarean deliveries had an IUD in place. However, with the IUD in situ, the patient conceived and had a spontaneous abortion. After the spontaneous abortion, she presented to clinic to have the IUD removed due to pain that was present since placement. Although the IUD strings were visualized, attempts to remove it were unsuccessful. Imaging identified the IUD outside the uterine cavity. Palpation with a blunt probe laparoscopically revealed a hard object within the adhesion band, close to the cardinal ligament. As per radiology evaluation, IUD was embedded 1cm from the external iliac artery on the right side outside the uterus in the adnexal region. A multidisciplinary procedure with gynecologic-oncologist was scheduled for removal due to the high risk of perioperative bleeding. Conclusion. Patients in whom uterine perforation and IUD migration are suspected should have appropriate evaluation that includes transvaginal or transabdominal ultrasound or radiographs to confirm the position of the IUD, regardless of whether they are asymptomatic or present with symptoms. It is particularly important in the presence of a scarred uterus that imaging is used to identify the location of a missing IUD. The uterine scar of a cesarean may facilitate migration of the IUD. Cross sectional imaging, such as CT or MRI scan, may be needed to rule out adjacent organ involvement before surgical removal.

Neil D Patel1, William D Fales1, Robert N Farrell1,21Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, MI, USA; 2Portage Fire Department, Portage, MI, USAObjective: The objective of this investigation was to determine if a photoionization detector (PID) could be used to detect the presence of a simulated harmful chemical on simulated casualties of a chemical release.Methods: A screening protocol, based on existing radiation screening protocols, was developed for the purposes of the investigation. Three simulated casualties were contaminated with a simulated chemical agent and two groups of emergency responders were involved in the trials. The success–failure ratio of the participants was used to judge the performance of the PID in this application.Results: A high success rate was observed when the screening protocol was properly adhered to (97.67%). Conversely, the success rate suffered when participants deviated from the protocol (86.31%). With one exception, all failures were noted to have been the result of a failure to correctly observe the established screening protocol.Conclusions: The results of this investigation indicate that the PID may be an effective screening tool for emergency responders. However, additional study is necessary to both confirm the effectiveness of the PID and refine the screening protocol if necessary.Keywords: prehospital, device, protocol, photoionization detectors

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12-15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects. Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days. Cell death was measured by MTT reduction assay. PROG and TMZ individually induced tumor cell death in a dose-dependent manner. PROG at high doses produced more cell death than TMZ alone. When combined, PROG enhanced the cell death-inducing effect of TMZ. In HDFs, PROG did not reduce viability even at the same high cytotoxic doses, but TMZ did so in a dose-dependent manner. In combination, PROG reduced TMZ toxicity in HDFs. PROG alone and in combination with TMZ suppressed the EGFR/PI3K/Akt/mTOR signaling pathway and MGMT expression in U87MG cells, thus suppressing cell proliferation. PROG and TMZ individually reduced cell migration in U87MG cells but did so more effectively in combination. PROG enhances the cytotoxic effects of TMZ in GBM cells and reduces its toxic side effects in healthy primary cells.

U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.

Background Conventional buprenorphine inductions require patients to abstain from full agonist opioids until they experience mild-to-moderate opioid withdrawal. We described a successful buprenorphine induction case in a pregnant patient using microdosing, which avoided withdrawal symptoms.

Two derivatives of the numeric rating scale (NRS) and visual analog scale (VAS), namely patient-reported percentage pain reduction (PRPPR) and calculated percentage pain reduction (CPPR), are commonly used when evaluating pain reduction. A small number of studies have attempted to assess the agreement between PRPPR and CPPR. However, they have been limited in their scope by a focus on specific types of pain, or by their focus on specific treatment modalities. As far as the authors of this article are aware, this is the first study to assess the agreement between PRPPR and CPPR in chronic pain patients, as well as the first to assess how the duration of treatment affects the correlations between PRPPR and CPPR. The aim of this retrospective analysis was to determine whether the duration of treatment affects CPPR and PRPPR, and the discrepancy and agreement between the two. Additionally, the study assessed whether individual treatment modalities, or the lack there of, impacted the discrepancy and correlation between PRPPR and CPPR. The mean PRPPR and CPPR for the entire patient population were 59.98 and 40.71, respectively. The mean discrepancy between the two parameters was 19.27. The agreement between PRPPR and CPPR, as measured by the concordance correlation coefficient, was 0.984 (95% C.I., 0.982–0.986).

Introduction Cerebrospinal‐venous fistulae (CSF‐VFs) represent a pathologic, low‐flow direct connection between the intrathecal space, usually at the level of a diverticular dilation of a nerve root sleeve, and the thoracolumbar venous system. They can cause CSF hypovolemia resulting in an often‐debilitating intracranial hypotension syndrome. Lateral decubitus CT or DSA myelography (CTM, DSM) are the gold‐standard modalities for diagnosing these entities. Their high spatial and temporal resolution allows visualization of the abnormal connection between the two spaces. Yet, the small size and low flow make CSF‐VFs radiographically subtle, and may not be consistently visualized even after a correctly‐performed CTM/DSM, requiring repeated invasive procedures to definitively establish or exclude their presence. Opacification of the renal excretory system 30‐60 minutes after lateral decubitus myelograms is thought to be a highly sensitive and specific indirect sign of the presence of a CSF‐VF 1,2, as this amount of time is considered insufficient to allow arachnoid reabsorption of contrast. Renal pelvises hyperdensity or its absence after a negative decubitus CTM/DSM can prompt further myelographic investigation or definitively rule out the presence of a CSF‐VF on the side of the examination, respectively. Methods We present three patients with severely symptomatic CSF‐VFs treated at our hospital between 2021 and 2023. All patients were females (range: 50‐60 years old). All three patients underwent bilateral diagnostic lateral decubitus DSM/CTM. Exams were performed at least 72 hours apart in order to allow complete clearance of intrathecal contrast. After each myelographic acquisition, patients remained in the lateral decubitus position until abdominal CT imaging was performed at 30 and 45 minutes to detect the presence of contrast in the renal collecting system. Results Patients 1 and 2, had a CSF‐VF between nerve root dural diverticula and the azygos system that was directly visualized on lateral decubitus CTM (patient 1: right T10‐T11, patient 2: left T8‐T9). Contrast was detectable in the renal pelvises after myelography was performed on the affected side, and not detectable after the contralateral investigation. One fistula was treated via CT‐guided targeted blood patch and fibrin glue injection and the other via endovascular Onyx embolization of the tributary Intercostal veins. Patient 3 had an extremely slow flow CSF‐VF at the right T11‐12 level that was identified only after 5 right‐sided decubitus myelograms with both modalities. The repeated exams were based on the presence of contrast in the renal pelvises after each right‐sided procedure and on the absence of renal opacification after the left‐sided myelograms. Eventually, a CSF‐VF was identified. Successful Onyx embolization of the foraminal veins of the R T11‐12 levels was performed. All three patients had complete resolution of symptoms. Conclusion Contrast presence in the renal excretory system after a lateral decubitus CTM/DSM is a potentially highly sensitive and specific indirect diagnostic sign that can establish or exclude the presence of a CSF‐VF on the examined side. It could be particularly helpful when the fistula is not initially detected, as it can prompt aggressive continuation of the myelographic work‐up. Similarly, it can exclude its presence on one side, sparing the patient invasive and low yield diagnostic procedures.

Introduction Extracorporeal membrane oxygenation (ECMO) is associated with gastrointestinal haemorrhage (GIH), which may result from coagulo­pathy, systemic inflammation, reduced gastric perfusion, and arteriovenous malformation from non-pulsatile blood flow. Data are limited regarding the burden of this complication in the United States. Material and methods We analysed the National Inpatient Sample (NIS) database for the years 2007 to 2011 to identify hospitalisations in which an ECMO procedure was performed. Hospitalizations complicated by GIH in this cohort were then identified by relevant codes. Results Between 2007 and 2011, ECMO hospitalisations increased from 1869 to 3799 (p < 0.01). The proportion of hospitalisations complicated by GIH increased from 2.12% in 2007 to 7.46% in 2011 (p < 0.01). Gastrointestinal haemorrhage was more common in men (56.7%) and in Caucasians (57.4%). Common comorbidities in this population were renal failure (71%), anaemia (55%), and hypertension (26%). All-cause inpatient mortality showed a numerical but nonsignificant increase from 56.7% to 61.9% (p = 0.49). The average cost of care per hospitalisation with GIH associated with ECMO use increased from $132,420 in 2007 to $215,673 in 2011 (p < 0.01). Conclusions Gastrointestinal haemorrhage during ECMO hospitalisations occurred in small but significantly increasing proportions. The inpatient mortality rate and costs associated with GIH were substantial and increased significantly during the study period.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

Extracellular vesicles (EVs) are small membrane-bound vesicles secreted into the extracellular space by all cell types. EVs transfer their cargo which includes nucleic acids, proteins, and lipids to facilitate cell-to-cell communication. As EVs are released and move from parent to recipient cell, EVs interact with the extracellular matrix (ECM) which acts as a physical scaffold for the organization and function of cells. Recent work has shown that EVs can modulate and act as regulators of the ECM. This review will first discuss EV biogenesis and the mechanism by which EVs are transported through the ECM. Additionally, we discuss how EVs contribute as structural components of the matrix and as components that aid in the degradation of the ECM. Lastly, the role of EVs in influencing recipient cells to remodel the ECM in both pathological and therapeutic contexts is examined.