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.

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.

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.

COVID-19 in patients with B cell immune deficiency.

This article aims to describe the clinical manifestations and management of COVID-19 in patients with primary and secondary B cell deficient states. We describe the epidemiologic and clinical features as well as unique management paradigm including isolation precautions with COVID-19. We then focus upon primary and secondary preventive approaches including vaccination and pre- as well as post-exposure prophylaxis. Further, we elaborate upon the important disease specific risk factors in these patients and the need to conduct prospective clinical trials to develop individualized management strategies in this population.

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.

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.

Neuropilin-1 deficiency in vascular smooth muscle cells is associated with hereditary hemorrhagic telangiectasia arteriovenous malformations.

Patients with hereditary hemorrhagic telangiectasia (HHT) have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent studies have shown that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with a decrease in SMCs, and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung arteriovenous fistulas (AVFs) with enlarged liver vessels. Evaluation of the retina vessels at P5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO versus WT mice, there was a significant decrease in Tgfb1, Eng, and Alk1 expression and phosphorylated SMAD1/5/8 (pSMAD1/5/8), with an increase in apoptosis. TGF-ß1-stimulated aortic SMCs from Nrp1SM22KO versus WT mice have decreased pSMAD1/5/8 and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In summary, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, and pSMAD1/5/8 signaling and reduced cell death associated with AVM formation.

The Evolving Clinical Practice of Chronic Cough.

Chronic cough, defined as a cough lasting for greater than 8 weeks, accounts for a substantial number of primary care and specialist consultations in the United States. Although cough can arise from a myriad number of serious respiratory diseases, attention has traditionally focused on diagnosing and treating gastroesophageal reflux, upper airway cough syndrome, and eosinophilic airway inflammation (asthma and nonasthmatic eosinophilic bronchitis) in patients with normal chest imaging. The newly described paradigm and entity of cough hypersensitivity syndrome (CHS) becomes useful when the etiology of cough remains elusive or when the cough remains refractory despite appropriate therapy for underlying causes. We present an update on the evolving understanding of refractory chronic cough and/or unexplained chronic cough as manifestations of laryngeal hypersensitivity and CHS. This includes a focus on understanding the pathophysiology underlying current and novel therapeutics for CHS, while also ensuring that common causes of chronic cough continue to be evaluated and treated in a systematic multidisciplinary manner.

Early thoracentesis correlated with survival benefit in patients with spontaneous bacterial empyema.

BACKGROUND: Spontaneous bacterial empyema (SBEM) is a rare complication of hepatic hydrothorax characterized by hydrothorax infection in the absence of pneumonia. AIMS AND METHODS: We conducted this study to compare clinical outcomes in SBEM patients who underwent early thoracentesis (ET) (≤ 24 h from presentation) versus those who underwent delayed thoracentesis (DT). All patients diagnosed with SBEM at Mayo Clinic Rochester, Minnesota from January 1st 1999 to December 31st 2020 were reviewed. Demographics, pleural fluid studies, laboratory results and clinical outcomes were analyzed. RESULTS: A total of 54 SBEM patients (27 ET and 27 DT) were identified with 38 (70.4%) of patients presenting with right-sided effusions. Both groups had similar baseline characteristics. The rate of ICU admission was significantly higher in the DT group (15 (55.6%) vs. 7 (25.9%) patients, P = 0.027). Patients with DT had similar rate of AKI (11 (40.7%) vs. 6 (22.2%) patients, P = 0.074). In-hospital mortality (11 (40.7%) vs. 2 (7.4%) patients, P = 0.004), 3-month mortality (16 (59.3%) vs. 2 (7.4%) patients, P < 0.001) and 1-year mortality rate (21 (77.8%) vs. 6 (22.2%) patients, P < 0.001) were higher in the DT group. CONCLUSION: Patients with SBEM who underwent thoracentesis after 24 h from presentation (DT) had higher rates of mortality and ICU admission compared to patients who received early thoracentesis. Thoracentesis should be performed early in patients with suspected SBEM since it may improve survival.

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.

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.

Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists.

Multivalent second-generation TRAIL-R2 agonists are currently in late preclinical development and early clinical trials. Herein, we use a representative second-generation agent, MEDI3039, to address two major clinical challenges facing these agents: lack of predictive biomarkers to enable patient selection and emergence of resistance. Genome-wide CRISPR knockout screens were notable for the lack of resistance mechanisms beyond the canonical TRAIL-R2 pathway (caspase-8, FADD, BID) as well as p53 and BAX in TP53 wild-type models, whereas a CRISPR activatory screen identified cell death inhibitors MCL-1 and BCL-XL as mechanisms to suppress MEDI3039-induced cell death. High-throughput drug screening failed to identify genomic alterations associated with response to MEDI3039; however, transcriptomics analysis revealed striking association between MEDI3039 sensitivity and expression of core components of the extrinsic apoptotic pathway, most notably its main apoptotic effector caspase-8 in solid tumor cell lines. Further analyses of colorectal cell lines and patient-derived xenografts identified caspase-8 expression ratio to its endogenous regulator FLIP(L) as predictive of sensitivity to MEDI3039 in several major solid tumor types and a further subset indicated by caspase-8:MCL-1 ratio. Subsequent MEDI3039 combination screening of TRAIL-R2, caspase-8, FADD, and BID knockout models with 60 compounds with varying mechanisms of action identified two inhibitor of apoptosis proteins (IAP) that exhibited strong synergy with MEDI3039 that could reverse resistance only in BID-deleted models. In summary, we identify the ratios of caspase-8:FLIP(L) and caspase-8:MCL-1 as potential predictive biomarkers for second-generation TRAIL-R2 agonists and loss of key effectors such as FADD and caspase-8 as likely drivers of clinical resistance in solid tumors.

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.

Acute thrombosis of a giant perimedullary arteriovenous fistula in a pediatric HHT patient.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder that results in arteriovenous malformations (AVMs) in the nose, mucocutaneous surfaces and visceral organs, including lung, brain, liver, bowel and rarely spinal cord. We describe a case of a young child with HHT who presented with acute paraparesis due to acute thrombosis of a spinal perimedullary arteriovenous fistula. Patient underwent coil embolization of spinal arteriovenous shunt with resolution of clinical symptoms. This case highlights the possibility of catastrophic complications in young children with HHT, the potential preventive role of screening for spinal AVMs in HHT and the importance of timely intervention.

Outcomes of liver transplantation in patients with hepatopulmonary syndrome in the pre and post-MELD eras: A systematic review.

BACKGROUND: The lack of large hepatopulmonary syndrome cohorts undergoing liver transplantation (LT) has resulted in limited information about post-LT outcomes and expectations. METHODS: The long and short-term outcomes of LT in patients with hepatopulmonary syndrome (HPS) were evaluated before and after the implementation of Model for Endstage Liver Disease (MELD) score in 2002, granting exception points for patients with HPS. PubMed/Medline, Embase, Web of Science and Scopus databases were searched for published and unpublished studies from 01/1990 to 04/2019. Studies that included HPS patients who underwent LT and reported post-LT outcomes and HPS severity were reviewed. After reviewing the full text of 1421 articles, 30 were included in the pre-MELD era (before 2002) and 60 in the post-MELD era. RESULTS: A total of 598 patients (210 children and 388 adults) with HPS who underwent LT were included in this systematic review. In children, 5-year survival probability was similar in the pre and post-MELD groups (85.7% vs. 97.4; p = 0.09). Median post-transplant PaO2 in room air was higher in the post-MELD group (71 [53-87] vs. 97 [80-108] mmHg: p = 0.008). In adults, 5-year survival probability was higher in the post-MELD era (73 vs. 87.3%; p = 0.008). Median post-transplant PaO2 in room air was higher in post-MELD group (75 [63-85] vs. 87 [75-95] mmHg; p = 0.001).. CONCLUSIONS: After MELD exception implementation, survival rates and post-transplant oxygenation improved in adult patients with HPS who underwent liver transplantation, whereas only post-transplant oxygenation improved in children.

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.