Seroprevalence of SARS-CoV-2 IgG in people with cystic fibrosis.

Background: When the first known US case of COVID-19 (Coronavirus Disease 2019) was reported in early 2020, little was known about the impact of this novel virus on the cystic fibrosis community. As the majority of individuals with CF have chronic lung disease, this population was initially considered to be at high risk for severe disease as infection with a multitude of viruses has proven to cause pulmonary exacerbation. SARS-CoV-2 virus has proven challenging to study given the multiple disease manifestations, range of severity, and wave-like phenomenon that varies geographically. People with CF who become infected with COVID-19 can be asymptomatic or have symptoms ranging from mild cough and congestion to full respiratory failure, similar to the manifestations seen in non-CF individuals. By studying the seroprevalence, clinical course, and antibody durability due to COVID-19 and vaccinations, we will be better equipped to provide appropriate and informed care to people with CF. Methods: Between July 2020 and April 2021 we enrolled 123 people with CF (pwCF) who receive care at the MN CF Center. We monitored their serology every 6 months for SARS-CoV-2 immunoglobulins (nucleocapsid and spike IgG) for evidence of natural and induced immunity. Medication use, pulmonary function, exacerbation history, and hospitalizations were extracted via electronic medical record (EMR). Results: 84% (101/120) of enrolled participants were vaccinated against SARS-CoV-2 during the study. Eighty three percent of the cohort showed evidence of either natural or induced "immunity." The average duration of antibody from induced immunity in participants was 6.1 months and from natural immunity was 7.4 months with an overall average duration of antibody of 6.8 months. Earliest antibody detected was 12 days after a single dose of the BNT162b2 vaccine and antibody was detectable across a span of 13 months. Eleven percent of vaccinated individuals did not have measurable IgG. 36% of non-responders (NRs) were solid organ transplant patients on chronic immunosuppressive therapy. Only 3 people within this cohort were hospitalized due to COVID pneumonia and all three survived. Conclusion: To our knowledge, this is the first report on the seroprevalence and longevity of SARS-CoV-2 IgG to 1 year in adults with CF after the widespread availability of SARS-CoV-2 vaccinations. These data show that pwCF respond to the COVID vaccination and produce long-lasting antibodies similar to the general population.

Yield of chest computed tomography angiogram in cystic fibrosis patients with suspected pulmonary embolism.

INTRODUCTION: Individuals with cystic fibrosis (CF) may be at increased risk of pulmonary embolism (PE). Symptoms of PE overlap substantially with those of CF respiratory exacerbations. CF patients commonly undergo chest computed tomography (CT) angiograms (CTPA) to evaluate for PE, but little is known about the clinical presentation and diagnosis of PE in this population. OBJECTIVES: The objectives of this study are to determine the diagnostic yield of CTPA for PE in adult patients with CF and assess the utility of the Revised Geneva Score (RGS) in this population. METHODS: Retrospective review of all CTPA results was performed on CF patients with suspected PE at a large CF center from 1 January 2011 through 31 March 2017. Patient demographics, medical history, and presenting signs and symptoms were abstracted by chart review. RESULTS: A total of 103 unique CTPA studies were performed in 68 patients. Most were hospitalized at the time of CTPA, predominantly for respiratory manifestations of CF. CTPA identified four patients with PE. The small number of positive studies precluded analysis of predictors of PE. Fewer PE were diagnosed than predicted by the Revised Geneva Score, which was intermediate probability in 77/103 (75%) patients. CONCLUSION: The prevalence of PE in CF patients undergoing CTPA for suspected PE was 4%, which is lower than predicted by the Revised Geneva Score. This may be due to a large overlap in the signs and symptoms of PE and exacerbations of CF lung disease.

Case report of synchronous post-lung transplant colon cancers in the era of colorectal cancer screening recommendations in cystic fibrosis: screening "too early" before it's too late.

BACKGROUND: The increasing life expectancy of individuals with Cystic Fibrosis (CF) is likely to be associated with new age-related challenges, colorectal cancer (CRC) most notably; recent consensus recommendations for CRC screening published in 2018 represent an important early step in addressing the emerging awareness of CF as a gastrointestinal cancer syndrome. These recommendations, however, need to be further refined based on more systematic data. We discuss an illustrative first-ever case of synchronous CRC arising in a post-lung transplant individual with CF within the recommended surveillance interval after a well-documented prior normal colonoscopy. CASE PRESENTATION: A 51-year-old female individual with homozygous F508del CF, presents to clinic with abdominal discomfort and intermittent blood in stools. She had previously undergone bilateral lung transplantation 18 years earlier, as well as two kidney transplants related to immunosuppression-related nephrotoxicity. A diagnostic colonoscopy was performed which revealed the presence of two separate synchronous colon cancers in the cecum and transverse colon; she had undergone a colonoscopy three years prior to this exam which was structurally normal. Endoscopic quality indicators, including a good quality bowel preparation, colonoscopic withdrawal time > 12 min, and quarterly Adenoma Detection Rate (ADR) ranging from 50 to 70% for both male and female patients for the endoscopist from both colonoscopic exams, as well as secondary retrospective comparative review of the pertinent case images, diminish the risk for a "missed" cancer or advanced lesion on the index exam. These cancers did not demonstrate any immunohistochemical features suggestive of Lynch Syndrome, though the rapid progression to cancer within the surveillance interval (possibly non-polypoid in nature) is similar. This cancer presentation within the newly-established recommended colon cancer screening interval warrants concern. CONCLUSIONS: This case prompts serious discussion regarding the length of surveillance intervals in the post-transplant CF population (a population at 20-30 times greater risk for CRC compared to the general non-CF population), as well as the importance of documenting endoscopic quality benchmarks, particularly if a narrative of interval CRC development continues to develop with further prospective monitoring and multi-center experience.

Effects of Signal Disruption Depends on the Substrate Preference of the Lactonase.

Many bacteria produce and use extracellular signaling molecules such as acyl homoserine lactones (AHLs) to communicate and coordinate behavior in a cell-density dependent manner, via a communication system called quorum sensing (QS). This system regulates behaviors including but not limited to virulence and biofilm formation. We focused on Pseudomonas aeruginosa, a human opportunistic pathogen that is involved in acute and chronic lung infections and which disproportionately affects people with cystic fibrosis. P. aeruginosa infections are becoming increasingly challenging to treat with the spread of antibiotic resistance. Therefore, QS disruption approaches, known as quorum quenching, are appealing due to their potential to control the virulence of resistant strains. Interestingly, P. aeruginosa is known to simultaneously utilize two main QS circuits, one based on C4-AHL, the other with 3-oxo-C12-AHL. Here, we evaluated the effects of signal disruption on 39 cystic fibrosis clinical isolates of P. aeruginosa, including drug resistant strains. We used two enzymes capable of degrading AHLs, known as lactonases, with distinct substrate preference: one degrading 3-oxo-C12-AHL, the other degrading both C4-AHL and 3-oxo-C12-AHL. Two lactonases were used to determine the effects of signal disruption on the clinical isolates, and to evaluate the importance of the QS circuits by measuring effects on virulence factors (elastase, protease, and pyocyanin) and biofilm formation. Signal disruption results in at least one of these factors being inhibited for most isolates (92%). Virulence factor activity or production were inhibited by up to 100% and biofilm was inhibited by an average of 2.3 fold. Remarkably, the treatments led to distinct inhibition profiles of the isolates; the treatment with the lactonase degrading both signaling molecules resulted in a higher fraction of inhibited isolates (77% vs. 67%), and the simultaneous inhibition of more virulence factors per strain (2 vs. 1.5). This finding suggests that the lactonase AHL preference is key to its inhibitory spectrum and is an essential parameter to improve quorum quenching strategies.

Prefrontal control of trace eyeblink conditioning in rabbits (Oryctolagus cuniculus) II: effects of type of unconditioned stimulus (airpuff vs. periorbital shock) and unconditioned stimulus intensity.

Previous research has implicated the medial prefrontal cortex (mPFC) in the control of classically conditioned autonomic and somatomotor responses. In eyeblink (EB) classical conditioning prefrontal involvement appears to be limited to paradigms that are more difficult to learn, in that acquisition is slower. These include trace conditioning and discrimination/reversal. Some of this research suggests that the participation of mPFC in classical EB conditioning is related to the intensity or type of unconditioned stimulus (US) employed. In the present two experiments we thus studied the effects of manipulation of periorbital shock intensity as the US in Experiment 1 and in Experiment 2 the intensity of a corneal airpuff as the US on Pavlovian trace EB conditioning. The results indicate that there are optimal intensities of both airpuff and periorbital shock as the US in the demonstration of mPFC control of trace classical EB conditioning.

Prefrontal control of trace versus delay eyeblink conditioning: role of the unconditioned stimulus in rabbits (Oryctolagus cuniculus).

The conditioned eyeblink (EB) response was studied with trace conditioning procedures in rabbits (Oryctolagus cuniculus) with lesions to the medial prefrontal cortex (mPFC) or sham lesions. Three experiments were performed in which either periorbital shock or a corneal airpuff served as the unconditioned stimulus (US) in separate groups of sham or mPFC-lesioned rabbits. Acquisition of the EB conditioned response (CR) was faster and reached a higher asymptote with the eyeshock US than with the airpuff US. However, mPFC lesion-induced trace conditioning deficits were obtained only in the groups that received the airpuff US. All rabbits showed normal delay conditioning and extinction. These results suggest that mPFC mediates trace EB conditioning when emotional arousal is low. However, in circumstances when emotional arousal may be high (i.e., during exposure to aversive periorbital shock), other structures (such as amygdala) may be activated to permit learning even in the absence of input from mPFC.