Publications by authors named "Carla Colombo"

189 Publications

Change in Nutrient and Dietary Intake in European Children with Cystic Fibrosis after a 6-Month Intervention with a Self-Management mHealth Tool.

Nutrients 2021 May 26;13(6). Epub 2021 May 26.

Instituto de Investigación Sanitaria La Fe-Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain.

Cystic Fibrosis (CF) is a life-long genetic disease, causing increased energy needs and a healthy diet with a specific nutrient distribution. Nutritional status is an indicator of disease prognosis and survival. This study aimed at assessing the effectiveness of a self-management mobile app in supporting patients with CF to achieve the dietary goals set by the CF nutrition guidelines. A clinical trial was conducted in pancreatic insufficient children with CF, followed in six European CF centres, where the self-management app developed within the MyCyFAPP project was used for six months. To assess secondary outcomes, three-day food records were compiled in the app at baseline and after 3 and 6 months of use. Eighty-four subjects (mean 7.8 years old) were enrolled. Compared to baseline, macronutrient distribution better approximated the guidelines, with protein and lipid increasing by 1.0 and 2.1% of the total energy intake, respectively, by the end of the study. Consequently, carbohydrate intake of the total energy intake decreased significantly (-2.9%), along with simple carbohydrate intake (-2.4%). Regarding food groups, a decrease in ultra-processed foods was documented, with a concomitant increase in meat and dairy. The use of a self-management mobile app to self-monitor dietary intake could become a useful tool to achieve adherence to guideline recommendations, if validated during a longer period of time or against a control group.
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http://dx.doi.org/10.3390/nu13061801DOI Listing
May 2021

Cystic Fibrosis, New Frontier: Exploring the Functional Connectivity of the Brain Default Mode Network. Comment on Elce et al. Impact of Physical Activity on Cognitive Functions: A New Field for Research and Management of Cystic Fibrosis. 2020, , 489.

Diagnostics (Basel) 2021 May 31;11(6). Epub 2021 May 31.

Department of Neuroradiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Miano, Italy.

We read with great interest the paper entitled "Impact of physical activity of cognitive functions: a new field for research and management of Cystic Fibrosis" by Elce et al. [...].
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http://dx.doi.org/10.3390/diagnostics11061001DOI Listing
May 2021

Vaccines in Children with Inflammatory Bowel Disease: Brief Review.

Vaccines (Basel) 2021 May 11;9(5). Epub 2021 May 11.

Università degli Studi di Milano, 20122 Milan, Italy.

Incidence of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), is increasing worldwide. Children with IBDs have a dysfunctional immune system and they are frequently treated with immunomodulating drugs and biological therapy, which significantly impair immune system functions and lead to an increased risk of infections. Vaccines are essential to prevent at least part of these infections and this explains why strict compliance to the immunization guidelines specifically prepared for IBD patients is strongly recommended. However, several factors might lead to insufficient immunization. In this paper, present knowledge on the use of vaccines in children with IBDs is discussed. Literature review showed that despite a lack of detailed quantification of the risk of infections in children with IBDs, these children might have infections more frequently than age-matched healthy subjects, and at least in some cases, these infections might be even more severe. Fortunately, most of these infections could be prevented when recommended schedules of immunization are carefully followed. Vaccines given to children with IBDs generally have adequate immunogenicity and safety. Attention must be paid to live attenuated vaccines that can be administered only to children without or with mild immune system function impairment. Vaccination of their caregivers is also recommended. Unfortunately, compliance to these recommendations is generally low and multidisciplinary educational programs to improve vaccination coverage must be planned, in order to protect children with IBD from vaccine-preventable diseases.
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http://dx.doi.org/10.3390/vaccines9050487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151471PMC
May 2021

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020.

J Cyst Fibros 2021 Apr 18. Epub 2021 Apr 18.

Centre for Cystic Fibrosis, Hospital de Santa Maria, Lisbon, Portugal.

Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF).

Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection.

Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133).

Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination.
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http://dx.doi.org/10.1016/j.jcf.2021.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053246PMC
April 2021

SARS-CoV-2 infection in cystic fibrosis: A multicentre prospective study with a control group, Italy, February-July 2020.

PLoS One 2021 13;16(5):e0251527. Epub 2021 May 13.

Azienda Ospedaliera-Universitaria Integrata di Verona, Verona, Italy.

Objective: To describe the symptoms and clinical course of SARS-CoV-2 infection in patients with cystic fibrosis (CF).

Methods: We carried out a prospective multicentre cohort study based on 32 CF centres and 6597 patients. Centres were contacted to collect baseline and follow-up data of patients who reported symptoms suggestive of COVID-19 or who had contact with a positive/suspected case between the end of February and July 2020. Symptoms and clinical course of the infection were compared between patients who tested positive by molecular testing (cases) and those who tested negative (controls).

Results: Thirty patients were reported from the centres, 16 of them tested positive and 14 tested negative. No differences in symptoms and outcome of the disease were observed between groups. Fever, cough, asthenia and dyspnea were the most frequently reported symptoms. Eight cases (50%) were hospitalized but none required ICU admission. Two adults with a history of lung transplant required non-invasive ventilation, none required ICU admission and all patients fully recovered without short-term sequelae.

Conclusions: The course of SARS-CoV-2 in our patients was relatively favorable. However, COVID-19 should not be considered a mild disease in CF patients, particularly for those with severely impaired respiratory function and organ transplant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251527PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118547PMC
May 2021

A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres.

J Cyst Fibros 2021 Apr 18. Epub 2021 Apr 18.

Cystic Fibrosis Regional Support Center, Department of Pediatrics, University of Brescia, ASST Spedali Civili Brescia, Brescia, Italy.

Objective: We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres.

Methods: All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected.

Results: We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%).

Conclusions: We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.
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http://dx.doi.org/10.1016/j.jcf.2021.03.015DOI Listing
April 2021

Diet as a possible influencing factor in thyroid cancer incidence: the point of view of the nutritionist.

Panminerva Med 2021 04 20. Epub 2021 Apr 20.

Endocrinology Unit, Department of Clinical Medicine and Surgery, Centro Italiano per la Cura e il Benessere del Paziente con Obesità (C.I.B.O), University Medical School of Naples, Naples, Italy.

The incidence of differentiated thyroid cancer has increased in the last decades all over the world. Different environmental factors are possible perpetrators of this exponential growth. Nutritional factors are among the main environmental factors studied for thyroid cancer in recent years. This review aims to overview the main dietary factors involved in thyroid cancer risk, providing specific nutrition recommendations from the endocrinological Nutritionist point of view. Among the single food, fish and shellfish are the primary natural source of iodine, selenium and vitamin D in the human diet. These nutrients are essential for the synthesis of thyroid hormones; however, their consumption is not consistently related to thyroid cancer risk. The high intake of fruit and vegetables, probably due to their vitamin and antioxidant content, shows a weak inverse association with thyroid cancer risk. Alcohol, meat, or other food groups/nutrients showed no significant effect on thyroid cancer. In conclusion, to date, no definite association among dietary factors, specific dietary patterns, and thyroid cancer, and its clinical severity and aggressiveness have been found. However, it is essential to underline that in the future, prospective studies should be carried out to precisely evaluate the qualitative and quantitative intake of nutrients by patients to establish with more confidence a potential correlation between food intake and the occurrence and development of thyroid cancer.
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http://dx.doi.org/10.23736/S0031-0808.21.04213-0DOI Listing
April 2021

Remote support by multidisciplinary teams: A crucial means to cope with the psychological impact of the SARS-COV-2 pandemic on patients with cystic fibrosis and inflammatory bowel disease in Lombardia.

Int J Clin Pract 2021 Apr 13:e14220. Epub 2021 Apr 13.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre, Milano, Italy.

Background: During Coronavirus Disease 2019 (COVID-19) outbreak in Lombardia, people were recommended to avoid visiting emergency departments and attending routine clinic visits. In this context, it was necessary to understand the psychological reactions of patients with chronic diseases. We evaluated the psychological effects on patients with chronic respiratory conditions and inflammatory bowel disease (IBD) through the analysis of their spontaneous contacts with their referral centres.

Methods: Cross-sectional study was conducted from February 23 to April 27, 2020 in patients, or their parents, who contacted their multidisciplinary teams (MDT). E-mails and phone calls directed to the MDT of the centre for cystic fibrosis (CF) in Milano and for paediatric IBD in Bergamo, were categorised according to their contents as information on routine disease management, updates on the patient's health status, COVID-19 news monitoring, empathy towards health professionals, positive feedback and concern of contagion during the emergency.

Results: One thousand eight hundred and sixteen contacts were collected during the study period. In Milano, where the majority of patients were affected by CF, 88.7% contacted health professionals by e-mail, with paediatricians receiving the largest volume of emails and phone calls compared with other professionals (P< .001). Compared with Milano, the centre for IBD in Bergamo recorded more expression of empathy towards health professionals and thanks for their activity in the COVID-19 emergency (52.4% vs 12.7%, P< .001), as well as positive feedback (64.3% vs 2.7%, P = .003).

Conclusion: One of the most important lessons we can learn from COVID-19 is that it is not the trauma itself that can cause psychological consequences but rather the level of balance, or imbalance, between fragility and resources. To feel safe, people need to be able to count on the help of those who represent a bulwark against the threat. This is the role played, even remotely, by health professionals.
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http://dx.doi.org/10.1111/ijcp.14220DOI Listing
April 2021

Ursodeoxycholic acid and liver disease associated with cystic fibrosis: A multicenter cohort study.

J Cyst Fibros 2021 Apr 1. Epub 2021 Apr 1.

Queen Silvia Children's Hospital, Gothenburg, Sweden.

Background: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA.

Methods: We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model.

Results: Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12).

Conclusions: CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.
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http://dx.doi.org/10.1016/j.jcf.2021.03.014DOI Listing
April 2021

Chronic infection by nontypeable fuels airway inflammation.

ERJ Open Res 2021 Jan 22;7(1). Epub 2021 Mar 22.

IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Emerging bacterial pathogens Unit, Milan, Italy.

Nontypeable (NTHi) is commonly isolated from airways of patients suffering from chronic respiratory diseases, such as COPD or cystic fibrosis (CF). However, to what extent NTHi long-term infection contributes to the lung inflammatory burden during chronic airway disease is still controversial. Here, we exploited human respiratory samples from a small cohort of CF patients and found that patients chronically infected with NTHi had significantly higher levels of interleukin (IL)-8 and CXCL1 than those who were not infected. To better define the impact of chronic NTHi infection in fuelling inflammatory response in chronic lung diseases, we developed a new mouse model using both laboratory and clinical strains. Chronic NTHi infection was associated with chronic inflammation of the lung, characterised by recruitment of neutrophils and cytokine release keratinocyte-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2), granulocyte colony-stimulating factor (G-CFS), IL-6, IL-17A and IL-17F) at 2 and 14 days post-infection. An increased burden of T-cell-mediated response (CD4 and γδ cells) and higher levels of pro-matrix metalloproteinase 9 (pro-MMP9), known to be associated with tissue remodelling, were observed at 14 days post-infection. Of note we found that both CD4IL-17 cells and levels of IL-17 cytokines were enriched in mice at advanced stages of NTHi chronic infection. Moreover, by immunohistochemistry we found CD3, B220 and CXCL-13 cells localised in bronchus-associated lymphoid tissue-like structures at day 14. Our results demonstrate that chronic NTHi infection exerts a pro-inflammatory activity in the human and murine lung and could therefore contribute to the exaggerated burden of lung inflammation in patients at risk.
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http://dx.doi.org/10.1183/23120541.00614-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983230PMC
January 2021

The thyroid risk score (TRS) for nodules with indeterminate cytology.

Endocr Relat Cancer 2021 Apr;28(4):225-235

Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy.

Cytology is the gold standard method for the differential diagnosis of thyroid nodules, though 25-30% of them are classified as indeterminate. We aimed to set up a 'thyroid risk score' (TRS) to increase the diagnostic accuracy in these cases. We prospectively tested 135 indeterminate thyroid nodules. The pre-surgical TRS derived from the sum of the scores assigned at cytology, EU-TIRADS classification, nodule measurement, and molecular characterization, which was done by our PTC-MA assay, a customized array able to cost-effectively evaluate 24 different genetic alterations including point mutations and gene fusions. The risk of malignancy (ROM) increased paralleling the score: in the category >4 and ≤ 6 (low suspicion), >6 ≤ 8 (intermediate suspicion), and >8 (high suspicion); ROM was 10, 47 and 100%, respectively. ROC curves selected the score >6.5 as the best threshold to differentiate between malignant and benign nodules (P < 0.001). The TRS > 6.5 had a better performance than the single parameters evaluated separately, with an accuracy of 77 and 82% upon inclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among malignant or benign cases, respectively. In conclusion, for the first time, we generated a score combining a cost-effective molecular assay with already validated tools, harboring different specificities and sensitivities, for the differential diagnosis of indeterminate nodules. The combination of different parameters reduced the number of false negatives inherent to each classification system. The TRS > 6.5 was highly suggestive for malignancy and retained a high accuracy in the identification of patients to be submitted to surgery.
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http://dx.doi.org/10.1530/ERC-20-0511DOI Listing
April 2021

Total Thyroidectomy Versus Lobectomy for Thyroid Cancer: Single-Center Data and Literature Review.

Ann Surg Oncol 2021 Feb 10. Epub 2021 Feb 10.

Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.

Background: Controversies remain about the ideal risk-based surgical approach for differentiated thyroid cancer (DTC).

Methods: At a single tertiary care institution, 370 consecutive patients with low- or intermediate-risk DTC were submitted to either lobectomy (LT) or total thyroidectomy (TT) and were followed up.

Results: Event-free survival by Kaplan-Meier curves was significantly higher after TT than after LT for the patients with either low-risk (P = 0.004) or intermediate-risk (P = 0.032) tumors. At the last follow-up visit, the prevalence of event-free patients was higher in the TT group than in the LT low-risk group (95% and 87.5%, respectively; P = 0.067) or intermediate-risk group (89% and 50%; P = 0.008). No differences in persistence prevalence were found among microcarcinomas treated by LT or TT (low risk, P = 0.938 vs. intermediate-risk, P = 0.553). Nevertheless, 15% of the low-risk and 50% of the intermediate-risk microcarcinomas treated by LT were submitted to additional treatments. On the other hand, macrocarcinomas were significantly more persistent if treated with LT than with TT (low-risk, P = 0.036 vs. intermediate-risk, P = 0.004). Permanent hypoparathyroidism was more frequent after TT (P = 0.01). After LT, thyroglobulin (Tg)/thyroid-stimulating hormone (TSH) had shown decreasing trend in 68% of the event-free patients and an increasing trend in the persistent cases.

Conclusions: Lobectomy can be proposed for low-risk microcarcinomas, although in a minority of cases, additional treatments are needed, and a longer follow-up period usually is required to confirm an event-free outcome compared with that for patients treated with TT. On the other hand, to achieve an excellent response, TT should be favored for intermediate-risk micro- and macro-DTCs despite the higher frequency of postsurgical complications.
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http://dx.doi.org/10.1245/s10434-020-09481-8DOI Listing
February 2021

Clinical and Genetic Features of a Large Monocentric Series of Familial Non-Medullary Thyroid Cancers.

Front Endocrinol (Lausanne) 2020 7;11:589340. Epub 2021 Jan 7.

Department of Endocrine and Metabolic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milan, Italy.

Several low penetration susceptibility risk loci or genes have been proposed in recent years with a possible causative role for familial non-medullary thyroid cancer (FNMTC), though the results are still not conclusive or reliable. Among all the candidates, here fully reviewed, a new extremely rare germline variant c.3607A>G (p.Y1203H) of the gene, has been recently reported to co-segregate with the affected members of one non-syndromic FNMTC family. We aimed to validate this finding in our series of 33 unrelated FNMTC Italian families, previously found to be negative for two susceptibility germline variants in the and genes. Unfortunately, the p.Y1203H variant was not found in either the 74 affected or the 12 not affected family members of our series. We obtained interesting data by comparing the clinico-pathological data of the affected members of our kindreds with a large consecutive series of sporadic cases, followed at our site. We found that familial tumors had a statistically significant more aggressive presentation at diagnosis, though not resulting in a worst outcome. In conclusion, we report genetic and clinical data in a large series of FNMTC kindreds. Our families are negative for variants reported as likely causative, namely those lying in the , and genes. The extensive review of the current knowledge on the genetic risk factors for non-syndromic FNMTCs underlies how the management of these tumors remains mainly clinical. Despite the more aggressive presentation of familial cases, an appropriate treatment leads to an outcome similar to that observed for sporadic cases.
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http://dx.doi.org/10.3389/fendo.2020.589340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817808PMC
June 2021

A case of testicular atrophy associated with cystic fibrosis.

Endocrinol Diabetes Metab Case Rep 2020 Sep 23;2020. Epub 2020 Sep 23.

Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Summary: An 8-year-old boy with cystic fibrosis came to our attention for an empty scrotum. General physical examination showed a normal penis and hypoplastic scrotum with non-palpable testes bilaterally. Routine blood investigations showed low levels of LH, testosterone, inhibin B and antiMullerian hormone and elevated levels of FSH. Karyotype was normal. An abdominal ultrasound confirmed the absence of the testes into the scrotum, in the inguinal region and abdomen. At laparoscopy were noted bilaterally hypotrophic spermatic vessels, absence of the vas deferens and a closed inner ring. Inguinal exploration found out a small residual testis and histological examination showed fibrotic tissue. This is the first case of testicular atrophy associated to CFTR mutation described. The process that led to bilateral testicular and vas deferens atrophy remains unexplained, a possible influence of CFTR dysfunction cannot be ruled out, although it is possible that these conditions are independently associated.

Learning Points: Cystic fibrosis produces a multisystemic disease which can affect also the reproductive tract. Nearly 97-98% of male patients are infertile because of congenital bilateral absence of vas deferens. A correlation between cystic fibrosis and bilateral testicular atrophy could be possible.
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http://dx.doi.org/10.1530/EDM-20-0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576656PMC
September 2020

ASO Author Reflections: Total Thyroidectomy Versus Lobectomy for Differentiated Thyroid Cancer.

Ann Surg Oncol 2021 Jan 8. Epub 2021 Jan 8.

Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.

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http://dx.doi.org/10.1245/s10434-020-09482-7DOI Listing
January 2021

CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

Diagnostics (Basel) 2020 Dec 12;10(12). Epub 2020 Dec 12.

Cystic Fibrosis Regional Reference Center, Paediatric Unit, Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Background: There are no predictive factors of evolution of cystic fibrosis (CF) screen positive inconclusive diagnosis subjects (CFSPIDs).

Aim: to define the role of the second variant as a predictive factor of disease evolution in CFSPIDs carrying the D1152H variant.

Methods: We retrospectively evaluated clinical characteristics and outcome of CFSPIDs carrying the D1152H variant followed at five Italian CF centers. CFSPIDs were divided in two groups: Group A: compound heterozygous for D1152H and a CF-causing variant; Group B: compound heterozygous for D1152H and a: (i) non CF-causing variant, (ii) variant with varying clinical consequences, or (iii) variant with unknown significance. The variants were classified according to CFTR2 mutation database.

Results: We enrolled 43 CFSPIDs with at least one D1152H variant: 28 (65.1%) were classified in the group A, and 15 (34.9%) in the Group B. CFSPIDs of group A had the first IRT significantly higher compared to those of group B ( < 0.05) and had a more severe clinical outcome during the follow-up. At the end of the study period, after a mean follow-up of 40.6 months (range 6-91.6), 4 (9.3%) out of 43 CFSPIDs progressed to CFTR-RD or CF. All these subjects were in the group A.

Conclusions: The genetic profile could help predict the risk of disease evolution in CFSPIDs carrying D1152H, revealing the subjects that need a more frequent follow-up.
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http://dx.doi.org/10.3390/diagnostics10121080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764752PMC
December 2020

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.

J Cyst Fibros 2021 01 3;20(1):25-30. Epub 2020 Dec 3.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Paediatric Respiratory Medicine, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Electronic address:

Background: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams.

Methods: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020.

Results: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease.

Conclusions: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease.
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http://dx.doi.org/10.1016/j.jcf.2020.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713571PMC
January 2021

Longitudinal Assessment of Patients With Cystic Fibrosis Lung Disease With Multivolume Noncontrast MRI and Spirometry.

J Magn Reson Imaging 2021 05 10;53(5):1570-1580. Epub 2020 Dec 10.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Centro Fibrosi Cistica, Milan, Italy.

Background: MRI has been suggested as a radiation-free imaging modality to investigate early structural alterations and regional functional impairment in cystic fibrosis (CF) lung disease.

Purpose/hypothesis: To compare functional and morphological MRI changes over the course of the disease to changes in spirometry.

Study Type: Longitudinal retrospective study.

Population: Twenty patients with CF lung disease (at baseline, age = 16.5 (13.3-20.6) years, forced expiratory volume in 1 second (as % of predicted [%pred]) FEV = 71 (59-87) %pred, forced expiratory flow at 25-75% of forced vital capacity FEF = 39 (25-63) %pred.

Field Strength/sequence: 1.5T / T -weighted HASTE; T -weighted TSE-PROPELLER; T -weighted bSSFP; T -weighted 3D GRE.

Assessment: Nonenhanced chest MRI and spirometry were retrospectively collected over a 3-year period from the initial recruitment visit. Images acquired at end-inspiration and end-expiration were registered by software using the optical flow method to measure expiratory-inspiratory differences in MR signal-intensity (Δ H-MRI). Measures of CF functional impairment were defined from Δ H-MRI: Δ H-MRI median, Δ H-MRI quartile coefficient of variation (QCV), and percent low-signal-variation volume (LVV). MR images were also evaluated by three readers using a CF-specific scoring system.

Statistical Tests: Spearman correlation analysis, Spearman rank correlation analysis, linear mixed-effect model analysis, intraclass correlation coefficient.

Results: Functional imaging parameters and total morphological score correlated with all spirometric measures, as did subscores of bronchial wall thickening/bronchiectasis, mucus plugging, and consolidation. Overall, the percent change of Δ1H-MRI median correlated with the percent change of FEV (ΔFEV , r = 0.41, P < 0.01) and the percent change of FEF (ΔFEF25-75%, r = 0.38, P < 0.01). The percent change of LVV correlated with ΔFEV (r = -0.47, P < 0.001) and ΔFEF (r = -0.50, P < 0.001).

Data Conclusion: These preliminary results suggest that nonenhanced multivolume MRI may provide a feasible tool to regionally map early pulmonary alterations for longitudinal evaluation of CF lung disease, without exposing the patients to ionizing radiation.

Level Of Evidence: 3T TECHNICAL EFFICACY STAGE: 5.
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http://dx.doi.org/10.1002/jmri.27461DOI Listing
May 2021

Clinical evaluation of an evidence-based method based on food characteristics to adjust pancreatic enzyme supplements dose in cystic fibrosis.

J Cyst Fibros 2020 Dec 2. Epub 2020 Dec 2.

Instituto de Investigación Sanitaria La Fe de Valencia. Cystic Fibrosis Unit. 46026 Valencia, Spain.

Background: Patients with cystic fibrosis (CF) and pancreatic insufficiency need pancreatic enzyme replacement therapy (PERT) for dietary lipids digestion. There is limited evidence for recommending the adequate PERT dose for every meal, and controlling steatorrhea remains a challenge. This study aimed to evaluate a new PERT dosing method supported by a self-management mobile-app.

Methods: Children with CF recruited from 6 European centres were instructed to use the app, including an algorithm for optimal PERT dosing based on in vitro digestion studies for every type of food. At baseline, a 24h self-selected diet was registered in the app, and usual PERT doses were taken by the patient. After 1 month, the same diet was followed, but PERT doses were indicated by the app. Change in faecal fat and coefficient of fat absorption (CFA) were determined.

Results: 58 patients (median age 8.1 years) participated. Baseline fat absorption was high: median CFA 96.9%, median 2.4g faecal fat). After intervention CFA did not significantly change, but range of PERT doses was reduced: interquartile ranges narrowing from 1447-3070 at baseline to 1783-2495 LU/g fat when using the app. Patients with a low baseline fat absorption (CFA<90%, n=12) experienced significant improvement in CFA after adhering to the recommended PERT dose (from 86.3 to 94.0%, p=0.031).

Conclusion: the use of a novel evidence-based PERT dosing method, based on in vitro fat digestion studies incorporating food characteristics, was effective in increasing CFA in patients with poor baseline fat absorption and could safely be implemented in clinical practice.
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http://dx.doi.org/10.1016/j.jcf.2020.11.016DOI Listing
December 2020

Personalized treatment for differentiated thyroid cancer: current data and new perspectives.

Minerva Endocrinol (Torino) 2021 Mar 19;46(1):62-89. Epub 2020 Nov 19.

Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.

More conservative and personalized treatment options have been developed in recent years to face the rising diagnosis of low-risk differentiated thyroid carcinoma (DTC). The present review describes the change towards a more risk-adapted management either in the treatment or in the follow-up of DTC. Particular attention is given to the innovations introduced by the latest guidelines for low-risk tumors, starting from the most appropriate extension of surgery up to the postoperative management. The emerging role of active surveillance for low-risk microcarcinoma is discussed, as well as the development of percutaneous strategies in the setting of malignant thyroid disease. The recent use of approved new systemic target therapies for advanced radioiodine refractory thyroid cancer is reported, together with the description of new compounds in trial. Finally, we provide some considerations to improve the risk evaluation in a presurgical setting, especially related to the rising role of genetics, to enable better risk-based cancer management and personalized treatment choices.
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http://dx.doi.org/10.23736/S0391-1977.20.03342-8DOI Listing
March 2021

The molecular and gene/miRNA expression profiles of radioiodine resistant papillary thyroid cancer.

J Exp Clin Cancer Res 2020 Nov 16;39(1):245. Epub 2020 Nov 16.

Department of Research, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance.

Methods: We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI-/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes.

Results: A different molecular profile according to the RAI class was observed: BRAF cases were more frequent in RAI-/D+ (P = 0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI-/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF-/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAF mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAF than in gene fusions tumors.

Conclusions: The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAF tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.
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http://dx.doi.org/10.1186/s13046-020-01757-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667839PMC
November 2020

The global impact of SARS-CoV-2 in 181 people with cystic fibrosis.

J Cyst Fibros 2020 11 4;19(6):868-871. Epub 2020 Nov 4.

Instituto da Criança HCFMUSP, São Paulo, Brazil.

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group.
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http://dx.doi.org/10.1016/j.jcf.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641525PMC
November 2020

New perspectives in differentiated thyroid cancer.

Authors:
Carla Colombo

Minerva Endocrinol (Torino) 2021 03 26;46(1):3-4. Epub 2020 Oct 26.

Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, San Luca Hospital, Milan, Italy -

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http://dx.doi.org/10.23736/S0391-1977.20.03345-3DOI Listing
March 2021

Congenital Cytomegalovirus Infection: Update on Diagnosis and Treatment.

Microorganisms 2020 Oct 1;8(10). Epub 2020 Oct 1.

Paediatric Clinic Pietro Barilla Children's Hospital, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy.

Congenital cytomegalovirus (cCMV) infection is the most common congenital viral infection and is the leading non-genetic cause of sensorineural hearing loss (SNLH) and an important cause of neurodevelopmental disabilities. The risk of intrauterine transmission is highest when primary infection occurs during pregnancy, with a higher rate of vertical transmission in mothers with older gestational age at infection, while the risk of adverse fetal effects significantly increases if fetal infection occurs during the first half of pregnancy. Despite its prevalence and morbidity among the neonatal population, there is not yet a standardized diagnostic test and therapeutic approach for cCMV infection. This narrative review aims to explore the latest developments in the diagnosis and treatment of cCMV infection. Literature analysis shows that preventive interventions other than behavioral measures during pregnancy are still lacking, although many clinical trials are currently ongoing to formulate a vaccination for women before pregnancy. Currently, we recommend using a PCR assay in blood, urine, and saliva in neonates with suspected cCMV infection. At present, there is no evidence of the benefit of antiviral therapy in asymptomatic infants. In the case of symptomatic cCMV, we actually recommend treatment with oral valganciclovir for a duration of 12 months. The effectiveness and tolerability of this therapy option have proven effective for hearing and neurodevelopmental long-term outcomes. Valganciclovir is reserved for congenitally-infected neonates with the symptomatic disease at birth, such as microcephaly, intracranial calcifications, abnormal cerebrospinal fluid index, chorioretinitis, or sensorineural hearing loss. Treatment with antiviral drugs is not routinely recommended for neonates with the mildly symptomatic disease at birth, for neonates under 32 weeks of gestational age, or for infants more than 30 days old because of insufficient evidence from studies. However, since these populations represent the vast majority of neonates and infants with cCMV infection and they are at risk of developing late-onset sequelae, a biomarker able to predict long-term sequelae should also be found to justify starting treatment and reducing the burden of CMV-related complications.
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http://dx.doi.org/10.3390/microorganisms8101516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599523PMC
October 2020

Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with cystic fibrosis.

J Cyst Fibros 2021 01 1;20(1):78-85. Epub 2020 Oct 1.

Imperial College and Royal Brompton Hospital, London, and Queen's University, Belfast, United Kingdom.

Background: Few therapies specifically address the chronic airway inflammation in cystic fibrosis (CF) that contributes to progressive destruction of lung tissue and loss of lung function. Lenabasum is a cannabinoid type 2 receptor (CB2) agonist that resolves inflammation in a number of in vitro and in vivo models.

Methods: A Phase 2 double-blind, randomized, placebo-controlled study assessed the safety and tolerability of lenabasum in adults with CF. Subjects with FEV% (ppFEV) ≥40% predicted were randomized to lenabasum 1 or 5 mg or placebo once daily (QD) (Weeks 1-4), then 20 mg QD, 20 mg twice daily (BID) or placebo (Weeks 5-12), with follow-up at Week 16. Pulmonary exacerbations (PEx) were recorded and biomarkers of blood and lung inflammation were measured.

Results: Of 89 subjects randomized, 51 lenabasum and 23 placebo-only subjects completed the study. No deaths or serious or severe adverse events (AE) were considered related to lenabasum. Most AEs were mild/moderate, and the most common were PEx, hemoptysis, dry mouth, and upper respiratory infection. Three lenabasum and one placebo-only subjects discontinued the study for a treatment related AE. New PEx were treated with intravenous antibiotics in 4.0% of lenabasum-treated vs. 11.4% of placebo-treated subjects, during Weeks 1-4 and 5.2% compared to 13.0% during Weeks 5-12 (p<0.2). No significant differences in ppFEV1 were observed between treatment groups. Sputum neutrophils, eosinophils, and neutrophil elastase were numerically reduced, and significant (p<0.05) reductions in IL-8 and immunoglobulin G levels occurred with lenabasum.

Conclusions: The safety findings of lenabasum, coupled with biomarker data, support further testing in a larger study with a longer duration.
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http://dx.doi.org/10.1016/j.jcf.2020.09.008DOI Listing
January 2021

Lenvatinib as first-line treatment for advanced thyroid cancer: long progression-free survival.

Endocrine 2021 May 3;72(2):462-469. Epub 2020 Sep 3.

Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.

Purpose: Lenvatinib (LEN) has been approved for the treatment of patients with progressive radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Real-life studies reported a lower progression-free survival (PFS) than the registration study, likely due to the more advanced stage of tumors, the more frequent pretreatment with other TKIs, the limited follow-up, and the worse clinical condition of the patients included.

Methods: We evaluated the clinical data of our cohort of 13 consecutive patients, all receiving LEN as a first-line TKI treatment, and followed-up in a single tertiary Center.

Results: All patients had an ECOG of 0-1 and regional or distant metastases were documented in 61.5% and 77% of patients, respectively. Median PFS was 22 months (95% CI 14-35) with partial response in 69% and stable disease in 31% of patients. All patients experienced at least one adverse event (AE), the most frequent being fatigue, anorexia, diarrhea, and hypertension. The daily dose was reduced in 70% of patients and only one patient (7.7%) discontinued the drug for AEs.

Conclusion: In this series of RAI-R DTC patients, with the unique features to have an ECOG 0 or 1 and to be naive for TKI treatments, PFS was the longest among all real-life published so far, with the highest rate of patients with partial response and one of the lowest drug discontinuation rate for AEs. The correct timing of treatment start, the tailoring of the dose, and a proper management of the AEs may have a significant impact on the treatment response to LEN.
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http://dx.doi.org/10.1007/s12020-020-02477-0DOI Listing
May 2021

Three months of COVID-19 in a pediatric setting in the center of Milan.

Pediatr Res 2021 05 27;89(6):1572-1577. Epub 2020 Aug 27.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, De Marchi Clinic, 20122, Milan, Italy.

The second epicenter of the global COVID-19 epidemic following Wuhan, and the first in the Western world, occurred unexpectedly in the Lombardy region of Italy, whose capital city is Milan. The aggressive nature of the outbreak in the region was dramatic, leading to a 2-month period of lockdown. Within the Policlinico, the historic hospital in the center of Milan, many units were rapidly converted into intensive care units or semi-intensive units for adult patients. During lockdown, the pediatric inpatient units had to face daily reorganization caused by the necessary logistic and structural transformations, thus restricting routine care pathways for chronic patients, while the Pediatric Emergency Unit had to develop a system able to effectively separate the children and caregivers infected with COVID-19 from those who were not affected. These 2 months enhanced resilience among both doctors and nurses, and facilitated the transversal transmission of data aimed at helping colleagues and patients in any way possible, in spite of the restrictive measures limiting the rate of activity in pediatric care. The reorganization of the current phase of decreasing epidemic activity still leaves us with unanswered questions regarding the further possible changes to implement in the event of a potential reoccurrence of epidemic peaks.
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http://dx.doi.org/10.1038/s41390-020-01108-8DOI Listing
May 2021

Molecular characterization of Mycobacterium abscessus subspecies isolated from patients attending an Italian Cystic Fibrosis Centre.

New Microbiol 2020 Jul 13;43(3):127-132. Epub 2020 Jun 13.

UOS Microbiology and Cystic Fibrosis Microbiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Mycobacterium abscessus (MABS) infection represents significant management challenge in cystic fibrosis (CF) patients. This retrospective study (2005-2016) aims to determine the prevalence of the subspecies of MABS isolated from CF patients, to evaluate the persistence over the years of a single subspecies of MABS and to correlate mutations responsible for macrolides and amikacin resistance with MIC values. We investigated 314 strains (1 isolate/patient/year) isolated from the lower respiratory tract of 51 chronically infected CF patients. Sequencing of rpoB gene was performed to identify the MABS subspecies. The erm(41) gene was sequenced to differentiate the strains with and without inducible macrolide resistance. Regions of 23S and 16S rRNA were sequenced to investigate mutations responsible for constitutive resistance to macrolides and aminoglycosides, respectively. Antibiotic susceptibility, using commercial microdilution plates, was evaluated according to CLSI. M. abscessus subsp. abscessus accounted for 64% of the isolates, bolletii subspecies for 16% and massiliense subspecies for 20%. All the massiliense strains presented truncated erm(41) gene while 12 abscessus strains presented the mutation T28->C in the erm(41) gene, which makes it inactive. The 23S rRNA analysis did not show constitutive resistance to macrolides in any strain. Mutation of the 16S rRNA gene was highlighted in 2 strains out of 314, in agreement with high MIC values. The correct identification at the subspecies level and the molecular analysis of 23S rRNA, 16S rRNA and erm gene is useful to guide the treatment strategy in patients with M. abscessus lung infection.
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July 2020

Impact of COVID-19 on people with cystic fibrosis.

Lancet Respir Med 2020 05 15;8(5):e35-e36. Epub 2020 Apr 15.

Department of Women's and Children's Health, University of Liverpool, Institute in the Park, Alder Hey Children's Hospital, Liverpool, UK.

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http://dx.doi.org/10.1016/S2213-2600(20)30177-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159857PMC
May 2020