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Elexacaftor-tezacaftor-ivacaftor (ETI) is known to pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of ivacaftor in rats demonstrated infant cataracts, but cataracts were not reported in human infants exposed to ivacaftor. We describe 3 cases of infants exposed to elexacaftor-tezacaftor-ivacaftor (ETI) in utero and while breast feeding who were found to have bilateral congenital cataracts within six months of birth. None of the infants had significant visual impairment from the cataracts nor any report of elevated liver function testing. These data highlight the need to counsel females who continue ETI throughout pregnancy and while breast feeding to consider cataract screen for their infants.

Bronchiectasis refers to both a clinical disease and a radiological appearance that has multiple causes and can be associated with a range of conditions. Disease heterogeneity and the absence of standardised definitions have hampered clinical trials of treatments for bronchiectasis and are important challenges in clinical practice. In view of the need for new therapies for non-cystic fibrosis bronchiectasis to reduce the disease burden, we established an international taskforce of experts to develop recommendations and definitions for clinically significant bronchiectasis in adults to facilitate the standardisation of terminology for clinical trials. Systematic reviews were used to inform discussions, and Delphi processes were used to achieve expert consensus. We prioritised criteria for the radiological diagnosis of bronchiectasis and suggest recommendations on the use and central reading of chest CT scans to confirm the presence of bronchiectasis for clinical trials. Furthermore, we developed a set of consensus statements concerning the definitions of clinical bronchiectasis and its specific signs and symptoms, as well as definitions for chronic bacterial infection and sustained culture conversion. The diagnosis of clinically significant bronchiectasis requires both clinical and radiological criteria, and these expert recommendations and proposals should help to optimise patient recruitment into clinical trials and allow reliable comparisons of treatment effects among different interventions for bronchiectasis. Our consensus proposals should also provide a framework for future research to further refine definitions and establish definitive guidance on the diagnosis of bronchiectasis.

Rationale: Although platelets are considered key inflammatory mediators in respiratory diseases, their role in bronchiectasis has not been fully explored. Objectives: We hypothesized that thrombocytosis in stable state may be associated with bronchiectasis severity and worse clinical outcomes. Methods: Patients with bronchiectasis have been enrolled from 10 centers in Europe and Israel, with platelet count recorded during stable state. The primary outcome was 5-year all-cause mortality. Secondary outcomes included exacerbations, hospitalizations, and mortality at 1, 2, and 3-year follow-up. Analyses were conducted using logistic regression after adjustment for confounding variables. Results: Among the 1,771 patients (median age, 67 yr; 63.4% female) included, 136 (7.7%) had thrombocytosis. Patients with thrombocytosis had a significantly higher disease severity, worse quality of life, higher number of exacerbations and hospitalizations, and higher mortality rate at both 3-year (23 [22.8%] vs. 83 [8.5%], respectively; P,0.01) and 5-year (26 [35.1%] vs. 116 [15.9%], respectively; P,0.01) in comparison with those with normal platelet count. Thrombocytosis was significantly associated with hospitalizations because of severe exacerbations (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.20-2.79; P=0.01) after 1-year followup, as well as increased 3-year (OR, 3.06; 95% CI, 1.74-5.39; P,0.01) and 5-year (OR, 2.46; 95% CI, 1.39-4.37; P,0.01) mortality. Conclusions: Platelets represent a cheap and easy-to-evaluate biomarker, and the presence of thrombocytosis during stable state is associated with disease severity, hospitalizations because of exacerbations, poor quality of life, and mortality in adults with bronchiectasis.

People with cystic fibrosis (pwCF) have experienced increased survival and wellbeing in recent decades, such that more than half of those living with CF are adults. Consequently, sexual and reproductive health is increasingly important for pwCF, because many are considering parenthood. Most men and some women with CF (wwCF) will have reduced fertility, which in both sexes is multifactorial. However, unplanned pregnancies in women are not rare, and contraception and its interaction with CF complications need to be addressed by the CF team. Reduced fertility may be overcome in most pwCF through use of assisted reproductive technologies; however, the risk of having offspring with CF must be considered. Most wwCF will have normal pregnancies, but premature birth is common, especially in the setting of reduced lung function and CF-related diabetes (CFRD); optimization of treatment is recommended during pregnancy planning. Parenting imposes an increased burden on pwCF, with the challenges of caring for the newborn, postpartum physiologic changes, and maintaining CF treatments. Most drugs used to treat CF are considered safe in pregnancy and lactation, but exceptions need to be acknowledged, including the limited data regarding safety of CF transmembrane conductance regulator (CFTR) modulators during conception, pregnancy, and lactation. Because most pwCF are eligible for highly effective CFTR modulators, fertility, contraception, and pregnancy in people with CF is changing. Prospective studies regarding these issues in people treated with CFTR modulators are paramount to provide evidence-based guidance for management in the current era of CF care.

Pulmonary exacerbations (PExs) are events in the course of bronchiectasis which are defined as an increase in disease symptoms lasting a period of a few days. It is established that the tendency toward having PEx is stable throughout the course of the disease. Certain conditions were found to be associated with an increased risk of developing a PEx. Among these are chronic airway infection with Pseudomonas aeruginosa or Aspergillus species, concomitant airway diseases (asthma, chronic obstructive pulmonary disease, and chronic rhinosinusitis), genetic factors such as primary ciliary dyskinesia, and nutritional factors. The immediate events underlying the onset of a PEx are less clearly determined. Although acute changes in bacterial airway composition have been the paradigm for decades, recent microbiome-focused research has not uniformly established such acute changes at the onset of PEx. Other acute changes such as air pollution, viral infection, and changes in bacterial metabolic activity have also been implicated as causes of a PEx. Despite these gaps in our knowledge of the biology of PEx, antimicrobial therapy directed against the identified pathogens in sputum is currently the recommended therapeutic strategy. Various long-term therapies, including antimicrobial and anti-inflammatory strategies, have been proven effective in reducing the frequency of PEx, leading to a recommendation for the use of these strategies in people with frequent PEx.

Background With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. Aim To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. Methods A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. Results Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. Conclusion Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

Locked-nucleotide analog antagonists (LNAA) to four varicella zoster virus small non-coding RNA (VZVsncRNA 10–13) derived from the mRNA of the open reading frame (ORF) 61 gene individually reduce VZV replication in epithelial cells and fibroblasts. To study the potential roles VZVsncRNA 10–13 have in neuronal infection we generated two recombinant VZV; one in which 8 nucleotides were changed in VZVsncRNA10 without altering the encoded residues of ORF61 (VZVsnc10MUT) and a second containing a 12-nucleotide deletion of the sequence common to VZVsncRNA12 and 13, located in the ORF61 mRNA leader sequence (VZVsnc12-13DEL). Both were developed from a VZV BAC with a green fluorescent protein (GFP) reporter fused to the N terminal of the capsid protein encoded by ORF23. The growth of both mutant VZV in epithelial cells and fibroblasts was similar to that of the parental recombinant virus. Both mutants established productive infections and experimental latency in neurons derived from human embryonic stem cells (hESC). However, neurons that were latently infected with both VZV mutant viruses showed impaired ability to reactivate when given stimuli that successfully reactivated the parental virus. These results suggest that these VZVsncRNA may have a role in VZV latency maintenance and/or reactivation. The extension of these studies and confirmation of such roles could potentially inform the development of a non-reactivating, live VZV vaccine.

Inhaled ultrafine particle (UFP) content in exhaled breath condensate (EBC) was observed as an airway inflammatory marker and an indicator of exposure to particulate matter (PM). The exceptional decline in air pollution during the COVID-19 lockdown was an opportunity to evaluate the effect of environmental changes on UFP airway content. We collected EBC samples from 30 healthy subjects during the first lockdown due to COVID-19 in Israel (March–April 2020) and compared them to EBC samples retrieved during April–June 2016 from 25 other healthy subjects (controls) living in the same northern Israeli district. All participants underwent EBC collection and blood sampling. Ambient air pollutant levels were collected from the Israeli Ministry of Environmental Protection’s online database. Data were acquired from the monitoring station closest to each subject’s home address, and means were calculated for a duration of 1 month preceding EBC collection. UFP contents were measured in the EBC and blood samples by means of the NanoSight LM20 system. There was a dramatic reduction in NO, NO2, SO2, and O3 levels during lockdown compared to a similar period in 2016 (by 61%, 26%, 50%, and 45%, respectively). The specific NO2 levels were 8.3 ppb for the lockdown group and 11.2 ppb for the controls (p = 0.01). The lockdown group had higher UFP concentrations in EBC and lower UFP concentrations in serum compared to controls (0.58 × 108/mL and 4.3 × 108/mL vs. 0.43 × 108/mL and 6.7 × 108/mL, p = 0.05 and p = 0.03, respectively). In this observational study, reduced levels of air pollution during the COVID-19 lockdown were reflected in increased levels of UFP airway contents. The suggested mechanism is that low airway inflammation levels during lockdown resulted in a decreased UFP translocation to serum. Further studies are needed to confirm this hypothesis.

Rationale: Bronchiectasis is classically considered a neutrophilic disorder, but eosinophilic subtypes have recently been described. Objectives: To use multiple datasets available through the European Multicentre Bronchiectasis Audit and Research Collaboration to characterize eosinophilic bronchiectasis as a clinical entity focusing on the impact of eosinophils on bronchiectasis exacerbations. Methods: Patients were included from five countries to examine the relationships between blood eosinophil counts and clinical phenotypes after excluding coexisting asthma. 16S rRNA sequencing was used to examine relationships between eosinophil counts and the sputum microbiome. A post hoc analysis of the PROMIS (Inhaled Promixin in the Treatment of Non–Cystic Fibrosis Bronchiectasis) phase 2 trial was used to examine the impact of blood eosinophil counts on exacerbations in patients with Pseudomonas aeruginosa infection. Measurements and Main Results: A relationship between sputum and blood eosinophil counts was demonstrated in two cohorts. In analysis of 1,007 patients from five countries, 22.6% of patients had blood eosinophil counts of ≽300 cells/μl. Counts of

Bronchiectasis is characterized by inflammation and abnormal dilatation of the airways secondary to various etiologies. A diagnosis of bronchiectasis requires that both radiological and clinical features are present. Determination of the etiology of bronchiectasis is important to allow specific treatment and should be guided by clinical features. The prognosis of bronchiectasis is highly variable, with severe cases suffering frequent exacerbations and hospitalizations, debilitating symptoms, and elevated mortality. Treatment is demanding, but adherence to treatment is associated with improved outcomes and should be assessed and reinforced. A partnership between patients and health care professionals is key to successful outcomes.

Left untreated, obstructive sleep-disordered breathing (OSDB) are associated with adverse effects on growth and development. History and physical examination alone are used for diagnosing children with OSDB, as polysomnography is not always feasible. Our objective was to develop and validate a Hebrew version of the Pediatric Sleep Questionnaire (PSQ) to help to diagnose and follow-up children before and after adenotonsillectomy surgery for OSDB. We conducted a prospective, nonrandomized, controlled trial in an academic medical center. We enrolled parents of children younger than 5 years of age planned for tonsillectomy with or without adenoidectomy due to obstructive airway indication. The parents completed the validated Hebrew version of PSQ questionnaire before and after surgery. We translated the questionnaire through forward–backward translation method. Our main outcome measures were reliability, validity, and responsiveness of the Hebrew version of PSQ. Overall, 45 parents of children with OSDB and 34 controls filled out the questionnaires. We found significant differences between the PSQ scores before and after surgery (p

PURPOSES Escherichia coli is one of the most common pathogens in nosocomial and community-acquired infections, but is an uncommon respiratory pathogen. However, this pathogen may at times be seen in respiratory secretions. The study aims to determine the clinical and prognostic value of E. coli in respiratory secretions. METHODS Cultures of respiratory secretions from hospitalized and outpatients between 2009 and 2016 were screened for isolation of E. coli. We defined three groups of patients: "Sensitive (S)"-growth of E. coli sensitive to all antimicrobials tested; Intermediate (I)-resistant to 1-2 antimicrobial classes; and "Resistant (R)"-resistant to at least three antibiotic classes. We compared factors associated with resistant strains and outcomes between the groups. RESULTS Eighty patients with E. coli isolates from respiratory secretions were identified while screening 177 712 (4.5: 10 000 samples). Of the E. Coli-positive cultures, 11 were from ambulatory patients, 31 patients were hospitalized and 37 were hospitalized and intubated. Ten people had bronchiectasis and 29 had COPD. Patients with resistant E. coli had significantly more hospitalization days prior to positive culture (S = 1.2 ± 1.89 days, I = 1.23 ± 1.5 days and R = 3.7 ± 5.4 days, respectively; P = 0.002). Mortality was higher in patients with a resistant strain (R) versus (I) or (S) (76.7%, 31.8% and 26.7%, respectively; P

Parents of children with any chronic illness may experience increased anxiety and reduced health-related quality of life (QoL). Our objective was to evaluate the change in parental QoL before vs after tonsillectomy. Our hypothesis was that pediatric tonsil surgery with or without adenoidectomy would improve parental QoL.A prospective cohort study.An otolaryngology department in a tertiary academic center.We enrolled parents of 79 children5 years old. Adenotonsillectomy due to an obstructive airway indication was performed in 45 children. A group of 34 parents to healthy children served as a control group. Initially, we validated a modified version of the PAR-ENT-QoL questionnaire; then, we analyzed QoL parameters among parents of children with obstructive sleep-disordered breathing before and after surgical treatment.We found significant differences between the QoL score before and after surgery (These results highlight the importance of timely diagnosis and treatment of children with obstructive sleep-disordered breathing, as this condition may affect not only the children themselves but also their caregivers.

Cystic fibrosis is a monogenic disease considered to affect at least 100 000 people worldwide. Mutations in CFTR, the gene encoding the epithelial ion channel that normally transports chloride and bicarbonate, lead to impaired mucus hydration and clearance. Classical cystic fibrosis is thus characterised by chronic pulmonary infection and inflammation, pancreatic exocrine insufficiency, male infertility, and might include several comorbidities such as cystic fibrosis-related diabetes or cystic fibrosis liver disease. This autosomal recessive disease is diagnosed in many regions following newborn screening, whereas in other regions, diagnosis is based on a group of recognised multiorgan clinical manifestations, raised sweat chloride concentrations, or CFTR mutations. Disease that is less easily diagnosed, and in some cases affecting only one organ, can be seen in the context of gene variants leading to residual protein function. Management strategies, including augmenting mucociliary clearance and aggressively treating infections, have gradually improved life expectancy for people with cystic fibrosis. However, restoration of CFTR function via new small molecule modulator drugs is transforming the disease for many patients. Clinical trial pipelines are actively exploring many other approaches, which will be increasingly needed as survival improves and as the population of adults with cystic fibrosis increases. Here, we present the current understanding of CFTR mutations, protein function, and disease pathophysiology, consider strengths and limitations of current management strategies, and look to the future of multidisciplinary care for those with cystic fibrosis.

The focus for International Women's Day 2020 is gender equity:'We can actively choose to challenge stereotypes, fight bias, broaden perceptions, improve situations and celebrate women's achievements. Collectively, each one of us can help create a gender equal world.' We have come together as an international group of women holding senior positions within CF to raise awareness. There is growing recognition of gender imbalance within our sector in senior leadership, grant and publication success. Several institutions, such as National Institutes of Health, have missions to tackle this. The issues raised by our panellists were wide-ranging: decisions around starting a family, impact on career progression; experiences of bias in appointments or promotions; selfbelief. We hope that raising these issues will encourage future leaders in CF to step up, to build teams based on fairness, equity and diversity, and to catalyse steps towards this goal in their institutions and society more widely.

Non-tuberculous mycobacteria pulmonary disease (NTM-pd) commonly complicates bronchiectasis. However, clinical and radiological features of NTM-pd and bronchiectasis are very similar. We aimed to develop a radiologic prediction tool for bronchiectasis to identify NTM-pd. We reviewed clinical, laboratory and radiological data in patients with bronchiectasis. Radiologic features on CT scans and the individual components of the Bhalla scoring system were compared between people with and without NTM-pd. Logistic regression and receiver-operating curve (ROC) analysis were performed to predict NTM-pd. People with NTM-pd had more pulmonary segments with bronchiectasis (13 ± 5 vs. 11 ± 5, p = 0.03), presence of mucus plugging (47% vs. 19%, p

Background The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. Methods Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. Results Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25–38.2) years, median (range). Sweat chloride was 106 ± 13 meq/L, mean ± SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40–121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1–14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. Conclusion In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

Introduction Chronic infection is associated with adverse outcomes among people with bronchiectasis. However, it is not known which factors are associated with a bacterial infection, and with persistence of an infection after the first episode. We aimed to determine factors associated with a new infection and with chronicity of Pseudomonas aeruginosa (PA) and H. influenzae (HI), the most common organisms in bronchiectasis infection. Methods Using an Israeli population database, we identified individuals diagnosed with bronchiectasis. Cox proportional hazard models were used to assess risk factors for first isolation and Logistic regression for chronicity of infection after a first isolation of PA and HI. Results We included 1305 people with a median of 5 respiratory samples per individual. PA was initially isolated in 297 people, of whom 97 (33%) developed chronic PA infection. HI was newly identified in 169 people, of whom 39 (23%) developed chronic infection (p = 0.029). Factors associated with increased risk of a new infection with PA were COPD (HR 1.87 [1.52–2.28], previous isolation of HI (HR 1.38 [1.07–1.78]), and alcohol abuse (HR 2.22 [1.13–4.3]). Younger age was associated with increased risk of HI infection, while COPD was associated with a lower risk of HI infection. Prescription of an anti- PA antibiotic was associated with chronic PA after a new infection (OR = 1.8 [1.09–2.9], p = 0.02). A landmark analysis showed that survival was worse in people with chronic PA infection vs. single or intermittent infection (Log rank: p = 0.034) Conclusions Younger age and presence of PCD are associated with a new isolation of HI. A new infection with PA is associated with previous HI infection, PCD, COPD, and alcohol abuse. Unexpectedly, treatment with appropriate anti-PA antimicrobials was not associated with a reduced risk of chronicity.

Most herpesviruses use both host and viral small non-coding RNAs (sncRNA), especially microRNA, to modulate infection. Bioinformatic analyses of NGS data obtained from Varicella Zoster virus (VZV)-infected cells predicted 24 VZVsncRNA, seven of which were confirmed to be expressed in infected fibroblasts and neurons using stem-loop quantitative reverse transcription PCR (SL-PCR). We here assayed for the expression of all 24 of the bioinformatically predicted VZVsncRNA in cells productively infected by VZV using SL-PCR. 23 of the 24 predicted sequences were detected in VZV-infected ARPE19 cells and 19 of the 24 sequences in infected human neurons generated by two methods from embryonic stem cells. We also show that blocking one of two newly-tested VZV-encoded sncRNA using locked nucleotide antagonists significantly increased viral replication. These findings suggest that further study of VZV encoded sncRNA could elucidate an additional level of regulation of the life cycle of this pathogenic human herpesvirus.

The definition of a disease requires that distinguishing signs and symptoms are present that are common, and that the constellation of signs and symptoms differentiate the condition from other causes. In bronchiectasis, anatomical changes, airways inflammation and airway infection are the distinguishing features that are common to this disease. However, bronchiectasis is a heterogenous disease: signs and symptoms are shared with other airway diseases, there are multiple aetiologies and certain phenotypes of bronchiectasis have distinct clinical and laboratory features that are not common to all people with bronchiectasis. Furthermore, response to therapeutic interventions in clinical trials is not uniform. The concept of bronchiectasis as a treatable trait has been suggested, but this may be too restrictive in view of the heterogeneity of bronchiectasis. It is our opinion that bronchiectasis should be defined as a disease in its own right, but one that shares several pathophysiological features and “treatable traits” with other airway diseases. These traits define the large heterogeneity in the pathogenesis and clinical features and suggest a more targeted approach to therapy.

Frequent chronic obstructive pulmonary disease (COPD) exacerbators are at a higher risk of adverse health outcomes when compared to infrequent exacerbators. A COPD frequent exacerbator phenotype and its definition has been reported. Haptoglobin (Hp) polymorphism has been associated with differing clinical outcomes in cardiovascular and renal disease. The Hp 2-2 phenotype has been found to have bacteriostatic properties, while the Hp 1-1 phenotype was found to be associated with infections.To determine the correlation in haptoglobin phenotypes and the frequent exacerbator status compared to COPD non-exacerbators.Inclusion criteria included previous diagnosis of COPD and presence of at least two documented exacerbations of COPD in the previous 12 months (frequent exacerbator group) or absence of such exacerbations in the previous 24 months (non-exacerbator group). Descriptive data was analyzed using Fisher's exact test and the nonparametric Kruskal-Wallis test. Multivariate logistic regression analysis was performed.The multivariate logistic regression yielded a model in which haptoglobin phenotype did not have a statistically significant association with frequent exacerbator status. Smoking status was found to be negatively related with the frequent exacerbator status (odds ratio [OR] 0.240, 95% confidence interval (95%CI) 0.068-0.843, P = 0.03). Number of pack-years was negatively related to being a frequent exacerbator (OR 0.979, 95%CI 0.962-0.996, P = 0.02).We found no relationship between haptoglobin polymorphism and frequent exacerbator status. However, frequent exacerbator status had a statistically significant association with COPD Assessment Test scores and pack-years and a negative correlation with current smoking status.

Objectives In all patients with cystic fibrosis (CF), gastrointestinal (GI) tract CF transmembrane conductance regulator dysfunction occurs early in life. The identical pathophysiological triad of obstruction, infection, and inflammation causes disease of the airways and in the intestinal tract (CF enteropathy). Mucus accumulation within GI tract is a niche for abnormal microbial colonization, leading to dysbiosis. Fecal calprotectin (FC) is a neutrophil cytosolic protein released during apoptosis and necrosis and reflects inflammatory status. Systemic antibiotic treatment for pulmonary exacerbations has been shown to improve systemic inflammatory markers and serum and sputum calprotectin. Antibiotic treatment aimed at pulmonary complaints may improve GI tract inflammatory status. We hypothesized that high levels of FC present during pulmonary exacerbation are due, in part, to multiorgan dysbiosis and thus should diminish with systemic antibiotic treatment. Methods This prospective pilot study enrolled 14 patients with CF, with no current GI symptoms. FC levels and lung function were measured at the beginning and end of systemic antibiotic treatment. Results Compared to preantibiotic treatment baseline values, end of treatment FC levels declined significantly after antibiotic treatment, P = 0.004 and similarly, there was significant improvement in forced expiratory volume in 1 second, P = 0.002. Conclusions High levels of FC during respiratory exacerbation may reflect a systemic exacerbation rather than solely pulmonary. Antibiotic treatment lowered the FC levels possibly by its impact on the intestinal microbiome.

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug–drug interactions, are discussed.

Background In recent years, it has become increasingly prevalent internationally to record and archive digital recordings of endoscopic procedures. This emerging documentation tool raises weighty educational, ethical and legal issues – which are viewed as both deterrents and incentives to its adoption. We conducted a survey study aimed at evaluating the use of DRD in endoscopic procedures, to examine physicians’ support of this practice and to map the considerations weighed by physicians when deciding whether or not to support a more extensive use of DRD. Methods Israeli physicians from specialties that employ endoscopic technics were surveyed anonymously for demographic background, existence and use of recording equipment, existence of institutional guidelines regarding DRD, and self-ranking (on a scale from 1 to 7) of personal attitudes regarding DRD. Results 322 physicians were surveyed. 84% reported performing routine endoscopic procedures, 78% had the required equipment for digital recording, and 64% of them stated that they never or only rarely actually recorded the procedure. General surgeons had the second highest rate of DRD equipment (96.5%) but the lowest rates of DRD practice (17.5%). The average ranking of support of DRD by all participants was 5.07 ± 1.9, indicating a moderately high level of support. Significant positive correlation exists between actual DRD rates and average support of DRD (p

Background The literature is replete with attempts to design and promote customized guidelines to reduce infections during the care continuum. Paradoxically, these efforts sometimes result in gray areas where many staff members are unaware of what is required of them, which then leads to confusion, frustration, and uncertainty. We coined the phrase “gray areas” in this context to encompass the variety of situations on the care continuum that are not addressed in the accepted guidelines, and where staff members are unsure of how to proceed. The purpose of the present study was to characterize the gray areas that were reported by staff and to identify the practices of Positive Deviance (PD) individuals. We define to PD individuals as people who independently develop creative solutions to solve problems not identified by the majority in their community. Methods A qualitative constructivist research methodology was used that included personal interviews, observations and video recordings of identified PD practices to enhance infection control. The study was conducted January through March 2018, in two Intensive Care Units (ICU) units at Hadassah Hospital, Jerusalem, Israel. Personal interviews were conducted with 82 staff members from the General ICU (GICU) and Medical ICU (MICU). Results The study confirmed that guidelines cannot cover all the different situations that arise during the care continuum and can paradoxically result in the increased spread of hospital infections. Our study found there are numerous individuals who independently develop and implement solutions for gray areas. The creative and practical solutions of PD individuals can address the barriers and difficulties on the care continuum that were encountered by the staff in their communities. For example, inserting a central venous line is a complex practice in the general guidelines, while the PDs provided clear situation-specific solutions not covered in the guidelines. Conclusions The recommendations of the present study are to encourage hospital personnel to create their own solutions for various situations on the care continuum, and to disseminate them within their units to achieve a bottom up change, in lieu of investing in new or specific written guidelines. Electronic supplementary material The online version of this article (10.1186/s13756-018-0418-x) contains supplementary material, which is available to authorized users.

Background Most of the studies on hospital infections have focused on the perceptions and reported behavior of the medical personnel. This research explore the practices undertaken both by Israeli patients and visitors, in order to maintain a hygienic hospital environment, and to locate the variables that are associated with them. Methods An online survey of national representative sample of Israeli hospital's visitors and patients adult population, who were hospitalized in the five years before the interview (n=209), and who visited patients in hospitals in the three years before the interview (n=454). Results Only a minority of patients (24%) comment to medical personnel about maintaining hygiene, while a majority (67%-69%) took active steps to maintain a hygienic environment. The main variables that were found to be associated with patients' making comments were level of religiousness and gender, whereas priorities, namely whether hospital infections were a high priority, and the frequency of the patient's visits to hospital outpatient clinics, were associated with self-initiated action. Conclusions In order to reduce barriers to commenting to hospital personnel, we propose framing the subject of hospital hygiene as a matter of health literacy and a subject of public discourse, rather than a sole medical issue

Objective: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. Methods: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. Results: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03–3.5], p =.04) and older age (OR 3.9 [2.1–7.3] p

Bronchiectasis is anatomically defined by irreversible distortion of the bronchi. Clinically, its manifestations are cough with sputum production and a predisposition to pulmonary infections. Unlike asthma and COPD, where ample clinical data are present regarding the course and effective treatment, knowledge of bronchiectasis has yet to evolve. Lately, bronchiectasis is gaining renewed attention among the medical community, with growing basic and clinical research-based data. In Israel, no registered treatments exist for bronchiectasis, which makes it difficult to treat these patients. This paper is a summary of the position of the Israeli Pulmonology Association and the Israeli Pediatric Pulmonology Association for diagnosis and treatment of bronchiectasis.

Bronchiectasis is a clinical and radiological diagnosis associated with cough, sputum production and recurrent respiratory infections. The clinical presentation inevitably overlaps with other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). In addition, 4–72% of patients with severe COPD are found to have radiological bronchiectasis on computed tomography, with similar frequencies (20–30%) now being reported in cohorts with severe or uncontrolled asthma. Co-diagnosis of bronchiectasis with another airway disease is associated with increased lung inflammation, frequent exacerbations, worse lung function and higher mortality. In addition, many patients with all three disorders have chronic rhinosinusitis and upper airway disease, resulting in a complex “mixed airway” phenotype.The management of asthma, bronchiectasis, COPD and upper airway diseases has traditionally been outlined in separate guidelines for each individual disorder. Recognition that the majority of patients have one or more overlapping pathologies requires that we re-evaluate how we treat airway disease. The concept of treatable traits promotes a holistic, pathophysiology-based approach to treatment rather than a syndromic approach and may be more appropriate for patients with overlapping features.Here, we review the current clinical definition, diagnosis, management and future directions for the overlap between bronchiectasis and other airway diseases.

The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) is the ERS Clinical Research Collaboration born to develop scientific, educational and advocacy activities for bronchiectasis at an international levelhttp://ow.ly/EHr030mxEcC

Many herpesviruses express small noncoding RNAs (sncRNAs), including microRNAs (miRNAs), that may play roles in regulating lytic and latent infections. None have yet been reported in varicella-zoster virus (VZV; also known as human herpesvirus 3 [HHV-3]). Here we analyzed next-generation sequencing (NGS) data for small RNAs in VZV-infected fibroblasts and human embryonic stem cell-derived (hESC) neurons. Two independent bioinformatics analyses identified more than 20 VZV-encoded 20- to 24-nucleotide RNAs, some of which are predicted to have stem-loop precursors potentially representing miRNAs. These sequences are perfectly conserved between viruses from three clades of VZV. One NGS-identified sequence common to both bioinformatics analyses mapped to the repeat regions of the VZV genome, upstream of the predicted promoter of the immediate early gene open reading frame 63 (ORF63). This miRNA candidate was detected in each of 3 independent biological repetitions of NGS of RNA from fibroblasts and neurons productively infected with VZV using TaqMan quantitative PCR (qPCR). Importantly, transfected synthetic RNA oligonucleotides antagonistic to the miRNA candidate significantly enhanced VZV plaque growth rates. The presence of 6 additional small noncoding RNAs was also verified by TaqMan qPCR in productively infected fibroblasts and ARPE19 cells. Our results show VZV, like other human herpesviruses, encodes several sncRNAs and miRNAs, and some may regulate infection of host cells. IMPORTANCE Varicella-zoster virus is an important human pathogen, with herpes zoster being a major health issue in the aging and immunocompromised populations. Small noncoding RNAs (sncRNAs) are recognized as important actors in modulating gene expression, and this study demonstrates the first reported VZV-encoded sncRNAs. Many are clustered to a small genomic region, as seen in other human herpesviruses. At least one VZV sncRNA was expressed in productive infection of neurons and fibroblasts that is likely to reduce viral replication. Since sncRNAs have been suggested to be potential targets for antiviral therapies, identification of these molecules in VZV may provide a new direction for development of treatments for painful herpes zoster.

Laparoscopic left colectomy (LLC) became the standard of care for treating distal transverse and descending colon cancer in many centers. Most centers use laparoscopic-assisted colectomy with extracorporeal anastomosis (LAC/EA). A totally laparoscopic colectomy with intracorporeal anastomosis (TLC/IA) has been proposed. The purpose of our study is to compare these two techniques. A series of 52 patients undergoing LLC for left-sided colon cancer was retrospectively evaluated. Thirty-three patients underwent TLC/IA, and 19 underwent LAC/EA. The following data were collected: gender, age, body mass index, American Society of Anesthesiologists risk class, operation duration, conversion to laparotomy, intraoperative complications, postoperative complications, postoperative course (duration of stay, time to first flatus), number of excised lymph nodes, readmission, and reoperation rates. Data were prospectively recorded in a colorectal cancer database and retrospectively analyzed. The only demographic parameter that differed significantly between the groups was age (64.2 ± 12.4 years for the TLC/IA group, vs. 72.7 ± 2.1 years for LAC/EA, p = 0.0116). The mini-laparotomy incision was significantly shorter in the TLC/IA than in the LAC/EA group (5.8 ± 0.9 vs. 8.2 ± 0.9 cm, respectively, p

Chronic infection with Pseudomonas aeruginosa is associated with poor outcomes in patients with cystic fibrosis (CF). It leads to a reduced quality of life, acceleration of the decline in lung function, and increased frequency and severity of pulmonary exacerbations. Tobramycin, administered by inhalation as a long-term therapy, decreases bacterial density in airways, reduces exacerbation frequency, and improves quality of life and lung function in patients with chronic P. aeruginosa infection. In the last decade, tobramycin inhalation has become an important contributor to CF treatment as a means to control chronic infection and as a first-line treatment for the eradication of early acquisition of P. aeruginosa. Recently, a dry powder inhalation (DPI) form of tobramycin has become available, which is more convenient for administration and has comparable efficacy to the tobramycin solution. This DPI, the Podhaler™ (Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA), requires less time for treatment delivery and is more portable than a nebulizer, and so is a welcome additional therapeutic option for many patients.

Lung cancer is the leading cause of cancer death worldwide. Survival is largely dependent on the stage of diagnosis: the localized disease has a 5-year survival greater than 55%, whereas, for spread tumors, this rate is only 4%. Therefore, the early detection of lung cancer is key for improving prognosis. In this study, we present an innovative, non-invasive, cancer detection approach based on measurements of the metabolic activity profiles of immune system cells. For each Liquid ImmunoBiopsy test, a 384 multi-well plate is loaded with freshly separated PBMCs, and each well contains 1 of the 16 selected stimulants in several increasing concentrations. The extracellular acidity is measured in both air-open and hermetically-sealed states, using a commercial fluorescence plate reader, for approximately 1.5 h. Both states enable the measurement of real-time accumulation of ‘soluble’ versus ‘volatile’ metabolic products, thereby differentiating between oxidative phosphorylation and aerobic glycolysis. The metabolic activity profiles are analyzed for cancer diagnosis by machine-learning tools. We present a diagnostic accuracy study, using a multivariable prediction model to differentiate between lung cancer and control blood samples. The model was developed and tested using a cohort of 200 subjects (100 lung cancer and 100 control subjects), yielding 91% sensitivity and 80% specificity in a 20-fold cross-validation. Our results clearly indicate that the proposed clinical model is suitable for non-invasive early lung cancer diagnosis, and is indifferent to lung cancer stage and histological type.

Background Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse. Aim Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation. Methods Data obtained from CF patients receiving ivacaftor for one year. Results Eight CF patients, mean age 21 ± 10 years, received ivacaftor. After one year, significant improvement was found in FEV 1 , increasing from 74% to 88% (p 25-75 , 59%–76% (p = 0.019). Sweat chloride concentration decreased from 116 ± 8 mmol/L to 51 ± 17 mmol/L (p Conclusions Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Background Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD. Methods Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized . These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters. Results Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV 1 ) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV 1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results. Conclusions Lung PA colonization in PCD is associated with more severe disease as shown by the FEV 1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients.

Plants growing in the Judea region are widely used in traditional medicine. This phytogeographic zone stands out in its climatic conditions and biodiversity. Consequently, both endemic and widely distributed Mediterranean plants growing in the area have unique chemotypes characterized by accumulation of relatively high levels of phytosteroids. Our comprehensive analysis revealed that many of the plants growing in the Judea region may hold a geroprotective potential. With this in mind, we undertook a wide screen of dozens of candidate herbal extracts for their cell protective, wound-healing, anti-inflammatory, and anti-cancer activities. The results obtained thus far have clearly shown that the extracts tested (1) protect normal human fibroblasts from genotoxic stress (prevent DNA double-strand beaks, increase cell survival and reduce the number of cells undergoing cellular senescence), (2) decrease secretion of pro-inflammatory cytokines, (3) promote wound healing, and (4) exert more pronounced cytotoxicity toward cancer cells.

Immunological responses to infection are impaired in bronchiectasis. Autoimmune antibodies to neutrophil components may impair clearance of Pseudomonas and thus contribute to the chronicity of infection.http://ow.ly/MGm230n4AEF

SummaryBackgroundThe term “obesity paradox”, refers to lower mortality rates in obese patients, and is evident in various chronic cardiovascular disorders. There is however, only scarce data regarding the clinical implication of obesity and pulmonary hypertension (PH). Therefore, in the current study, we evaluated the possible prognostic implications of obesity in PH patients.MethodsWe assessed 105 consecutive PH patients for clinical and hemodynamic parameters, focusing on the possible association between Body Mass Index (BMI) and mortality. Follow-up period was 19 ± 13 months.ResultsSixty-one patients (58%) had pre-capillary PH and 39 patients (37%) out-of-proportion post-capillary PH. During follow-up period, 30 patients (29%) died. Death was associated with reduced functional-class, inverse-relation with BMI, higher pulmonary artery and right atrial pressures, pulmonary vascular resistance and signs of right ventricular failure. In multivariate analysis, obesity (BMI ≥ 30 kg/m²), was the variable most significantly correlated with improved survival [H.R 0.2, 95% C.I 0.1–0.6; p = 0.004], even after adjustment for baseline characteristics. Obese and very-obese (BMI ≥ 35 kg/m²) patients had significantly less mortality rates during follow-up (12% and 8%, respectively) than non-obese patients (41%), p = 0.01. The tendency of survival benefit for the obese vs. non-obese patients was maintained both in the pre-capillary (10% vs. 46% mortality, p = 0.008) and disproportional post-capillary PH patients (11% vs. 40% mortality, p = 0.04).ConclusionsObesity was significantly associated with lower mortality in both pre-capillary and disproportional post-capillary PH patients. It seems that in PH, similarly to other chronic clinical cardiovascular disease states, there may be a protective effect of obesity, compatible with the “obesity paradox”.

Ivacaftor, a CFTR potentiator, has been found to improve CFTR function and clinical outcomes in patients with cystic fibrosis (CF) gating mutations. We investigated the effects of ivacaftor on CFTR functional measurement in CF patients carrying gating mutations other than p.Gly551Asp. Two siblings aged 13 and 12 carrying the p.Ser549Asn mutation, two sisters (45 and 43years old) compound heterozygotes for p.Asp1152His and p.Gly1244Glu, a 37year old man homozygous for the p.Gly1244Glu mutation, and a 7year old girl with p.Arg352Gln and p.Gly1244Glu mutations commenced treatment with ivacaftor. NPD was performed in all the patients and approached normal for four patients who had also clinical improvement (p.Ser549Asn compound heterozygotes, and p.Asp1152His/p.Gly1244Glu siblings). Beta-adrenergic sweat chloride secretion performed in thep.Asp1152His/p.Gly1244Glu patients improved significantly. The p.Gly1244Glu mutation homozygous patient, who had undergone an ileal resection with ileostomy and enterocutaneous fistula, did not respond clinically to ivacaftor and did not modify his sweat test. These results highlight the importance of different CFTR activity measurements to explore CFTR modulator efficacy.

Essentials We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE. SummaryBackground Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management. Methods Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed. Results In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7–8.3%), 4.7% (95% CI 3.0–6.8%), and 37% (95% CI 28–47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3–3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91–7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6–10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50–2.4). Conclusion These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.

Bacterial airway colonization is frequent among lung transplant recipients. These patients are often treated with antibiotics, which may lead to selection of resistant bacteria. The purpose of this study was to assess whether antibiotic treatment causes acquisition of quinolone-resistant Gram-negative bacteria (QR-GNB), and the effect of such colonization on mortality and on lung rejection. We retrospectively examined data from non-cystic fibrosis, non-bronchiectases lung transplant recipients for antibiotic treatment, GNB in respiratory secretions, bronchiolitis obliterans syndrome (BOS), and mortality. Of 126 patients included, 86 patients had QR-GNB, 22 had quinolone-sensitive bacteria (QS-GNB), and 17 had no growth. Median antibiotic exposure, defined as the fraction of days with antibiotic treatment, was 2.8% in patients without growth, 11.1% in patients with QS-GNB (p=0.012), and 26% in patients with QR-GNB (p

Background: The routine use of multidetector computed tomography has led to increased detection of unsuspected pulmonary embolism (UPE), with questionable benefit for diagnosis and treatment. Objective: The purpose of this work was to compare the clinical characteristics and prognosis of patients with UPE to patients with suspected PE (SPE). Methods: We retrospectively reviewed the charts of patients diagnosed with PE in a community-based university hospital between the years 2002 and 2007. UPE was defined as PE detected on CT scans performed for indications other than suspicion of PE. We compared patients with UPE to patients with SPE for differences in clinical features, electrocardiogram, imaging and echocardiographic findings. We also assessed the long-term outcomes using electronic patient records. Results: Of 500 patients with PE, 408 had SPE and 92 had UPE. Patients with UPE were similar to patients with SPE regarding age and sex distribution. Malignancy was more prevalent in UPE patients (39 vs. 23%, p < 0.0068). UPE patients had significantly less tachypnea (37 vs. 57%, p = 0.0005), dyspnea (47 vs. 87%, p < 0.0001), chest pain (19 vs. 42%, p < 0.0001) and hypoxemia (36 vs. 55%, p = 0.0011). Mortality was higher in UPE patients (70.3 vs. 53%, p = 0.0029). The hazard ratio after adjustment for confounders including age, sex and malignancy was 1.546 (95% CI: 1.139–2.099, p = 0.0052). Conclusions: We suggest that UPE is more prevalent in patients with a malignancy and is associated with higher mortality despite a less severe clinical presentation. UPE may be a marker of poor prognosis.

Culture of NTM from people with bronchiectasis is negatively associated with smoking and low socioeconomic status http://ow.ly/E3jR30j553X

The use of a standardised aetiological algorithm in bronchiectasis can improve the diagnosis of underlying cause http://ow.ly/5dga30gxrq3

The purpose of the present study was to evaluate the effect of transforming-growth factor-alpha (TGF-alpha) on enterocyte apoptosis following methotrexate (MTX) induced intestinal mucositis in a rat and in Caco-2 cells. Non-pretreated and pretreated with MTX Caco-2 cells were incubated with increasing concentrations of TGF-alpha. Cell apoptosis was determined by FACS cytometry. Adult rats were divided into four groups: Control, Control-TGF-alpha, MTX, and MTX- TGF-alpha rats. Three days later rats were sacrificed. Enterocyte apoptosis were measured at sacrifice. RT-PCR and Western Blotting was used to determine the level of Bax and Bcl-2 mRNA and protein. Real time PCR was used to measure epidermal growth factor receptor (EGFr) expression along the villus-crypt axis. The in vitro experiment has shown that treatment with TGF-alpha of Caco-2 cells results in a significant inhibition of cell apoptosis in a dose-dependent manner. In vivo experiment, a decreased levels of apoptosis in MTX- TGF-alpha rats corresponded with the decrease in Bax and with the increase in Bcl-2 at both mRNA and protein levels. The inhibiting effect of TGF-alpha on enterocyte apoptosis was strongly correlated with EGFr expression along the villus-crypt axis. In conclusion, treatment with TGF-alpha inhibits enterocyte apoptosis following MTX- injury in the rat.

Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative-stress-induced cytotoxicity or CS; (iii) a CS-like morphology (even at the proliferative phase); and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α-SMA. Our findings suggest that CS could serve as a bridge connecting lung aging and its quite frequent outcome -- pulmonary fibrosis, and be an important player in the disease progression. Consequently, targeting senescent cells offers the potential of being a promising therapeutic approach.