Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma.

Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large-scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence-profiled 524 American Joint Committee on Cancer Stage I-III primary tumours. Our analysis of these data reveals recurrent driver mutations, mutually exclusive genetic interactions, where two genes were never or rarely co-mutated, and an absence of co-occurring genetic events. Further, we intersected copy number calls from our primary melanoma data with whole-genome CRISPR screening data to identify the transcription factor interferon regulatory factor 4 (IRF4) as a melanoma-associated dependency. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort.

Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 coding variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.

Inhibition of angiogenesis in the management of refractory gastrointestinal bleeding in patients with LVAD support.

BACKGROUND: Gastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF-LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD-associated GIAD bleeding, and now present follow-up data on patients treated with IV bevacizumab and/or low-dose oral pazopanib. METHODS: All consecutive adult patients with LVAD-associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3-59.8 months). RESULTS: Eleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference - 2.87, p = 0.002), blood transfusions (median difference - 20.9, p = 0.01), and endoscopies (median difference - 6.95, p = 0.007) in patients pre- and post-anti-angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference - 2.75, p = 0.014), blood transfusions (median difference - 24.5, p = 0.047), and number of endoscopies (median differences -6.88, p = 0.006). CONCLUSION: Anti-angiogenic therapy with IV bevacizumab and/or low-dose oral pazopanib appears to provide benefits in patients with LVAD-associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.

Executive summary of the 14th HHT international scientific conference.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin-ENG, activin like kinase 1 ACVRL1 aka ALK1, and SMAD4) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000. Expert clinicians and international scientists gathered in Cascais, Portugal from September 29th to October 2nd, 2022 to present the latest scientific research in the HHT field and novel treatment strategies for people living with HHT. During the largest HHT scientific conference yet, participants included 293 in person and 46 virtually. An impressive 209 abstracts were accepted to the meeting and 59 were selected for oral presentations. The remaining 150 abstracts were presented during judged poster sessions. This review article summarizes the basic and clinical abstracts selected as oral presentations with their new observations and discoveries as well as surrounding discussion and debate. Two discussion-based workshops were also held during the conference, each focusing on mechanisms and clinical perspectives in either AVM formation and progression or current and future therapies for HHT. Our hope is that this paper will represent the current progress and the remaining unanswered questions surrounding HHT, in order to serve as an update for those within the field and an invitation to those scientists and clinicians as yet outside of the field of HHT.

Digital Pulmonology Practice with Phonopulmography Leveraging Artificial Intelligence: Future Perspectives Using Dual Microwave Acoustic Sensing and Imaging.

Respiratory disorders, being one of the leading causes of disability worldwide, account for constant evolution in management technologies, resulting in the incorporation of artificial intelligence (AI) in the recording and analysis of lung sounds to aid diagnosis in clinical pulmonology practice. Although lung sound auscultation is a common clinical practice, its use in diagnosis is limited due to its high variability and subjectivity. We review the origin of lung sounds, various auscultation and processing methods over the years and their clinical applications to understand the potential for a lung sound auscultation and analysis device. Respiratory sounds result from the intra-pulmonary collision of molecules contained in the air, leading to turbulent flow and subsequent sound production. These sounds have been recorded via an electronic stethoscope and analyzed using back-propagation neural networks, wavelet transform models, Gaussian mixture models and recently with machine learning and deep learning models with possible use in asthma, COVID-19, asbestosis and interstitial lung disease. The purpose of this review was to summarize lung sound physiology, recording technologies and diagnostics methods using AI for digital pulmonology practice. Future research and development in recording and analyzing respiratory sounds in real time could revolutionize clinical practice for both the patients and the healthcare personnel.

Predictors of seroconversion after coronavirus disease 2019 vaccination.

BACKGROUND: Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks. OBJECTIVE: To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (< 0.4 U/mL) antibody response were assessed and summarized. RESULTS: A total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination. CONCLUSION: Vaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.

Intensive Care Unit and Hospital Outcomes of Patients Admitted with Blastomycosis: A 14-Year Retrospective Study.

INTRODUCTION: Blastomycosis is an uncommon; potentially life-threatening granulomatous fungal infection. The aim of this study is to report hospital and intensive care unit (ICU) outcomes of patients admitted with blastomycosis. METHODS: All patients admitted for treatment of blastomycosis at the Mayo Clinic-Rochester, Minnesota between 01/01/2006 and 09/30/2019 were included. Demographics, comorbidities, clinical presentation, ICU admission, and outcomes were reviewed. RESULTS: A total of 84 Patients were identified with 90 unique hospitalizations primarily for blastomycosis. The median age at diagnosis was 49 (IQR 28.1-65, range: 6-85) years and 56 (66.7%) were male. The most frequent comorbidities included hypertension (n = 28, 33.3%); immunosuppressed state (n = 25, 29.8%), and diabetes mellitus (n = 21, 25%). The lungs were the only organ involved in 56 (66.7%) cases and the infection was disseminated in 19 (22.6%) cases. A total of 29 patients (34.5%) underwent ICU admission due to complications of blastomycosis. ICU related events included mechanical ventilation (n = 20, 23.8%), acute respiratory distress syndrome (ARDS) (n = 13, 15.5%), tracheostomy (n = 9, 10.7%), renal replacement therapy (n = 8, 9.5%), and extracorporeal membrane oxygenation (ECMO) (n = 4, 4.8%). A total of 12 patients (14.3%) died in the hospital; all of whom had undergone ICU admission. In-hospital mortality was associated with renal replacement therapy (RRT) (P = 0.0255). CONCLUSION: Blastomycosis is a serious, potentially life-threatening infection that results in significant morbidity and mortality with a 34.5% ICU admission rate. RRT was associated with in-hospital mortality.

ICU and Hospital Outcomes in Patients with Hepatopulmonary Syndrome Undergoing Liver Transplantation.

PURPOSE: There are limited data regarding hospital and intensive care unit (ICU) outcomes in patients with hepatopulmonary syndrome (HPS) following liver transplantation (LT). METHODS: Data were retrospectively collected from consecutive HPS adult patients who underwent LT and were immediately admitted to the ICU at three transplant centers with shared management protocols, from 2002 to 2018. Demographic, clinical, surgical, laboratory, and outcome data were extracted. RESULTS: We identified 137 patients (74 male, 54%), with a median age at LT of 58 years (IQR: 52-63). One hundred and 31 (95.6%) patients were admitted to the ICU on invasive mechanical ventilation (MV). The median time on invasive MV in the ICU was 12 hours (IQR: 5-28) and 97 patients (74%) were extubated within 24 hours of ICU admission. The median highest positive end expiratory pressure and fraction of inspired oxygen (FiO2) were 7 (IQR: 5-8) and 0.6 (IQR: 0.5-0.7), respectively. 7 patients (5%) developed severe post-transplant hypoxemia. Of all patients, 42 (30.4%) required vasopressors and the median ICU and hospital length of stay (LOS) were 3 (IQR: 1-5) and 10 (IQR: 7-20) days, respectively. The in-hospital mortality rate was 3.6% (5/137). HPS severity was not associated with hospital mortality. CONCLUSION: Most HPS patients have short durations of MV, ICU, and hospital LOS post-LT. HPS severity does not impact hospital mortality.

Collateral damage and CRISPR genome editing.

The simplicity and the versatility of clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR-Cas) systems have enabled the genetic modification of virtually every organism and offer immense therapeutic potential for the treatment of human disease. Although these systems may function efficiently within eukaryotic cells, there remain concerns about the accuracy of Cas endonuclease effectors and their use for precise gene editing. Recently, two independent reports investigating the editing accuracy of the CRISPR-Cas9 system were published by separate groups at the Wellcome Sanger Institute; our study-Iyer and colleagues [1]-defined the landscape of off-target mutations, whereas the other by Kosicki and colleagues [2] detailed the existence of on-target, potentially deleterious deletions. Although both studies found evidence of large on-target CRISPR-induced deletions, they reached seemingly very different conclusions.

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) [mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p<0.0001)] and decreased the epistaxis severity score (ESS) by 3.4 (3.2-3.7) points [mean ESS 6.8 (6.6-7.1) versus 3.4 (3.2-3.7), P<0.0001] during the first year of treatment. Compared with 6 months pretreatment, RBC units transfused decreased by 82% [median of 6.0 (IQR 0.0-13.0) units versus 0 (IQR, 0.0-1.0) units, P<0.0001] and iron infusions decreased by 70% [median of 6.0 (1.0-18.0) infusions versus 1.0 (0.0-4.0) infusions, P<0.0001] during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective to manage chronic bleeding and anemia in HHT.

Outcomes among patients with COVID-19 and asthma: A systematic review and meta-analysis.

Background: It remains unclear if asthma is a risk factor associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19). Methods: We performed a comprehensive database search for studies published from January 1, 2019, to October 2, 2020. We included studies that evaluated outcomes among patients with COVID-19 and underlying asthma. Outcomes of interest included the need for hospitalization, length of hospitalization, intensive care unit (ICU) admission, and death. The meta-analysis was conducted by using random-effects methodology. Results: A total of 389 studies were identified through data base searches. After abstract and full-text screening, 16 observational studies with 92,275 patients were included in the analysis. Of the 16 studies, 15 were retrospective and 1 was a prospective cohort study. The average age was 39.6 years, with 48% female patients. Six of the studies included pediatric patients, and one of these studies only evaluated pediatric patients. One study only evaluated pregnant patients. Among patients with COVID-19, the presence of asthma was not associated with any significant increase in risk of hospitalization (odds ratio [OR] 1.46 [95% confidence interval {CI}, 0.29-7.28]), length of hospitalization (1.59 days [-0.55 to 3.74]), ICU admission (OR 1.65 [95% CI, 0.56-4.17]), or death (OR 0.73 [95% CI, 0.38-1.40]). The overall risk of bias of the included studies was high. Conclusion: Among the patients with COVID-19, asthma did not seem to significantly increase the risk of hospitalization, length of hospitalization, ICU admission, or death.

No unexpected CRISPR-Cas9 off-target activity revealed by trio sequencing of gene-edited mice.

CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole-genome sequencing (WGS) of gene-edited embryos or animals to search for de novo mutations (DNMs), which may represent candidate changes introduced by poor editing fidelity. Critically, these studies used strain-matched, but not pedigree-matched controls and thus were unable to reliably distinguish generational or colony-related differences from true DNMs. Here we used a trio design and whole genome sequenced 8 parents and 19 embryos, where 10 of the embryos were mutagenised with well-characterised gRNAs targeting the coat colour Tyrosinase (Tyr) locus. Detailed analyses of these whole genome data allowed us to conclude that if CRISPR mutagenesis were causing SNV or indel off-target mutations in treated embryos, then the number of these mutations is not statistically distinguishable from the background rate of DNMs occurring due to other processes.

Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia.

INTRODUCTION: Systemic bevacizumab is a novel targeted therapy for severe epistaxis and chronic gastrointestinal bleeding in hereditary haemorrhagic telangiectasia (HHT), but published data are very limited. AIM: We conducted a survey-based study to characterize current treatment practices and physician-reported safety and effectiveness of systemic bevacizumab for bleeding in (HHT). METHODS: A 27-item survey was sent to physician centre directors of 31 International HHT Centers of Excellence. RESULTS: Response rate was 84%. Approximately half of centres had treated >10 HHT patients with systemic bevacizumab for chronic bleeding for a total of 291 patients treated. All centres utilize a 5 mg/kg dose for induction treatment and most administer six doses (range, 4-8) every 2 weeks. However, maintenance regimens varied considerably between centres. Bevacizumab was highly effective, with 86% reporting significant (>50%) improvement in GI bleeding and/or epistaxis and haemoglobin rise in most patients treated with bevacizumab; 52% reported haemoglobin normalization in most patients. All centres reported adverse event rates <30% and two-thirds of centres reported adverse event rates <10%. Discontinuation for adverse events or inefficacy was rare. Bleeding severity thresholds for initiation of bevacizumab were highly variable, and it is typically administered by haematologists (76% of centres). Two-thirds of centres reported obtaining insurance approval for bevacizumab for most or all patients but 48% reported difficulty in obtaining coverage. CONCLUSION: Systemic bevacizumab is widely used to treat bleeding in HHT with excellent physician-reported effectiveness and safety. There is considerable variation in maintenance treatment practices and thresholds for initiation of bevacizumab among HHT centres.

Adherence to Global Initiative for Chronic Obstructive Lung Disease guidelines in the real world: current understanding, barriers, and solutions.

PURPOSE OF REVIEW: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides a comprehensive review and guidance for clinicians managing patients with chronic obstructive pulmonary disease (COPD). However, adherence to GOLD guidelines has been suboptimal over the years. The current review summarizes the current body of literature addressing the multitude of reasons for the lack of adherence to GOLD guidelines in clinical practice. RECENT FINDINGS: There continue to be several reasons for suboptimal adoption of GOLD guidelines in clinical practice. A primary and recurrent theme appears to be both delayed as well as missed diagnosis of COPD. There are several reasons for this including lack of awareness about current COPD guidelines, lack of availability as well as utilization of office spirometry and improper symptom assessment. Other issues include improper selection of proper pharmacotherapy options, misdiagnosis/mislabeling of COPD phenotypes, lack of smoking cessation counselling as well as enrollment in pulmonary rehabilitation. Potential solutions include adoption of clinical decision support systems, self-care models and careful phenotyping of COPD patients. SUMMARY: There are currently several barriers for the adoption of GOLD guidelines into routine clinical practice. These barriers are all amenable to systematic solutions that will increase adherence to current GOLD guidelines.

Best practice for CRISPR design using current tools and resources.

Users facing the task of designing gRNAs for a CRISPR-mutagenesis experiment are typically confronted with a large variety of possible tools and existing libraries. Here we examine the design principles for such resources, and suggest a best practice which allows a user to evaluate and effectively use any of the existing CRISPR design tools or genome-wide libraries.

Clinical Outcomes of Weight-Based Norepinephrine Dosing in Underweight and Morbidly Obese Patients: A Propensity-Matched Analysis.

BACKGROUND: Weight-based dosing strategy for norepinephrine in septic shock patients with extremes of body mass index has been lesser studied. METHODS: This historical study of adult septic shock patients was conducted from January 1, 2010, to December 31, 2015, at all intensive care units (ICUs) in Mayo Clinic, Rochester. Patients with documented body mass index were classified into underweight (body mass index <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), and morbidly obese (≥40 kg/m2) patients. Patients with repeat ICU admissions, ICU stay <1 day, and body mass index 25 to 39.9 kg/m2 were excluded. The primary outcome was in-hospital mortality, and secondary outcomes included cumulative norepinephrine exposure acute kidney injury, cardiac arrhythmias, and 1-year mortality. Two-tailed P < .05 was considered statistically significant. RESULTS: From 2010 to 2015, 2016 patients met inclusion-145, 1406, and 466 patients, respectively, in underweight, normal weight, and morbidly obese cohorts. Underweight patients used the highest peak dose and absolute exposure was greatest for morbidly obese patients. In-hospital mortality decreased with increasing log10 body mass index: 41.4% (underweight), 28.4% (normal weight), and 24.7% (morbidly obese), respectively (P < .001); however, this relationship was not noted at 1 year. Unadjusted log10 norepinephrine cumulative exposure (mg) was associated with higher in-hospital mortality, acute kidney injury, cardiac arrhythmias, and 1-year mortality. After adjustment for demographics, body mass index, comorbidity, and illness severity, log10 norepinephrine exposure was an independent predictor of in-hospital mortality (odds ratio 2.4 [95% confidence interval, 2.0-2.8]; P < .001) and 1-year mortality (odds ratio 1.7 [95% confidence interval, 1.5-2.0]; P < .001). In a propensity-matched analysis of 1140 patients, log10 norepinephrine was an independent predictor of in-hospital mortality (odds ratio 2.2 [95% confidence interval, 1.8-2.6]; P < .001). CONCLUSIONS: Morbidly obese patients had lower in-hospital mortality but had higher 1-year mortality compared to normal weight and underweight patients. Cumulative norepinephrine exposure was highest in morbidly obese patients. Total norepinephrine exposure was an independent mortality predictor in septic shock.

Newer Biological Agents in the Treatment of Severe Asthma: Real-World Results from a Tertiary Referral Center.

PURPOSE: To determine the efficacy of IL-5 inhibitory therapy in severe, refractory asthma in a real-world clinical setting from a tertiary referral center. METHODS: A retrospective chart review of patients with severe asthma treated with IL-5 biologic therapy for ≥ 6 months at Mayo Clinic in Rochester, Minnesota between January 1, 2013 and August 31, 2019. RESULTS: Over the study period, we identified 63 patients with a mean age of 54 who received an IL-5 inhibitor for ≥ 6 months. A total of 55 patients received mepolizumab, 2 received benralizumab, and 9 patients received both. Patients were followed up for a mean of 25 months. The mean number of months of oral prednisone use prior to biologic initiation was 64. There was a significant reduction in the median dose of prednisone in the 24 months after drug initiation (15 mg vs. 0 mg; p = < 0.0001). Similarly; there was a significant decline in the median number of asthma exacerbations in the 24 months before and after drug initiation (7 vs. 2; p = < 0.0001). The mean number of emergency room (ER) visits and hospitalizations decreased from 5.1 and 2.0 to 1.6 and 0.4 in the 24 months before and after therapy initiation (p < 0.0001 and p = 0.007, respectively) CONCLUSIONS: IL-5 inhibitory therapy is associated with significant and long-term sustained reductions in asthma exacerbation frequency, ER visits, hospitalizations, as well as oral steroid usage in a patient population with refractory steroid-dependent asthma referred to a tertiary referral center.

Pulmonary Arteriovenous Malformations in Non-hereditary Hemorrhagic Telangiectasia Patients: An 18-Year Retrospective Study.

PURPOSE: Pulmonary arteriovenous malformations (PAVMs) are most commonly associated with hereditary hemorrhagic telangiectasia (HHT). Patients with PAVMs can present with serious complications including stroke, transient ischemic attack (TIA), and brain abscess. PAVMs are rare in non-HHT patients and little is known about this patient population. The aim of this retrospective study is to better understand clinical presentation and outcomes of PAVMs occurring exclusively in non-HHT patients. METHODS: Non-HHT patients with PAVMs at the Mayo Clinic-Rochester between 01/01/2000 and 12/31/2018 were reviewed. Patients with Curacao score > 1 were excluded. Demographics, imaging characteristics, neurological complications, and follow-up imaging were analyzed. RESULTS: Seventy-seven patients with PAVMs were identified. The mean age at diagnosis was 48.2 ± 18.3 years with female preponderance (59.7%). The majority of PAVMs had lower lobe predominance (66.7%) and were simple and single in 75.3% and 89.6% of cases, respectively. Most patients were asymptomatic (46.8%) with dyspnea being the most common symptom (28.6%). Neurologic complications occurred in 19.5% of patients. The majority of PAVMs were idiopathic (61%). Thirty patients (39%) had one or more possible risk factors including previous thoracic surgery (23.4%), congenital heart disease (19.5%), and chest trauma (10.4%). Embolization was performed in 37 (48.1%) patients and only 4 (5.2%) underwent surgical resection. CONCLUSIONS: Non-HHT PAVMs occur more commonly in females, are most commonly simple and single, and have lower lobe predominance and a high rate of neurologic complications. Potential predisposing risk factors were identified in about 40% of the cases. Clinicians should be aware of the risk of PAVM development in patients with history of chest trauma, congenital heart disease, lung infection/abscess, and thoracic surgery.