Rheumatology (Oxford). 2021 Jun 17;60(Supplement_3):iii47-iii49. doi: 10.1093/rheumatology/keab041.

NO ABSTRACT

PMID:34137874 | DOI:10.1093/rheumatology/keab041

Adv Mater. 2021 Jun 17:e2006619. doi: 10.1002/adma.202006619. Online ahead of print.

ABSTRACT

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) protein gene editing is poised to transform the treatment of genetic diseases. However, limited progress has been made toward precise editing of DNA via homology-directed repair (HDR) that requires careful orchestration of complex steps. Herein, dendrimer-based lipid nanoparticles (dLNPs) are engineered to co-encapsulate and deliver multiple components for in vivo HDR correction. BFP/GFP switchable HEK293 cells with a single Y66H amino acid mutation are employed to assess HDR-mediated gene editing following simultaneous, one-pot delivery of Cas9 mRNA, single-guide RNA, and donor DNA. Molar ratios of individual LNP components and weight ratios of the three nucleic acids are systematically optimized to increase HDR efficiency. Using flow cytometry, fluorescence imaging, and DNA sequencing to quantify editing, optimized 4A3-SC8 dLNPs edit >91% of all cells with 56% HDR efficiency in vitro and >20% HDR efficiency in xenograft tumors in vivo. Due to the all-in-one simplicity and high efficacy, the developed dLNPs offer a promising route toward the gene correction of disease-causing mutations.

PMID:34137093 | DOI:10.1002/adma.202006619

JAAD Case Rep. 2021 Apr 29;13:17-19. doi: 10.1016/j.jdcr.2021.04.023. eCollection 2021 Jul.

NO ABSTRACT

PMID:34136618 | PMC:PMC8181521 | DOI:10.1016/j.jdcr.2021.04.023

Front Pediatr. 2021 May 31;9:665022. doi: 10.3389/fped.2021.665022. eCollection 2021.

ABSTRACT

Purpose: Jejunoileal atresia (JIA) is a rare disease. We aimed to determine the overall incidence of this malformation and associated malformations in a national cohort. Furthermore, we compared the treatment results of this cohort with the current literature. Methods: Data from the major health insurance company, which covers ~30% of the German population, were analyzed. All patients with ICD-10-Code Q41.1-9 (atresia of jejunum, ileum, other parts and not designated parts of the small bowel) who underwent any surgical procedure for small bowel were analyzed in a 10-year period between 2007 and 2016. Results: A total of 435 patients were included in the study. The incidence was 2.1 per 10,000 live births. The male:female ratio was 1:2. Sixty-four percent were premature, 21% had associated cardiac anomalies, 16% had abdominal wall defects, 7% had urogenital malformations, and 7% had cystic fibrosis. Sixty percent of all patients with jejunoileal atresia, 57% of patients with accompanying abdominal wall defects and 72% of patients with associated cystic fibrosis required ostomy as the initial procedure. In 25% of all patients, only one intestinal operation was coded. In 39% of patients, two operations were coded. Twelve percent of all patients required feeding gastrostomy or jejunostomy. Sixteen percent of all patients presented with liver-related complications, i.e., cholestasis or liver insufficiency. Six patients underwent an intestinal lengthening procedure (2 Bianchi, 4 STEP). In five patients, initial lengthening was performed within 1 year after the first intestinal operation. Mortality until 1 year after initial surgery was 5%. Of those who died, 88% were premature, 34% had cardiac anomalies and 16% had abdominal wall defects. None had cystic fibrosis. Patients with ostomy significantly more often needed operative central venous line or operative feeding tube. Short bowel was coded significantly more often in these patients. Conclusion: Patients with JIA present with low mortality. The rate of ostomies is higher than in literature. To give clinical recommendations for the initial surgical approach, further clinical research is needed.

PMID:34136442 | PMC:PMC8200531 | DOI:10.3389/fped.2021.665022

J Cyst Fibros. 2021 Jun 13:S1569-1993(21)00124-7. doi: 10.1016/j.jcf.2021.04.014. Online ahead of print.

ABSTRACT

BACKGROUND: Being able to function cognitively is imperative for successful achievement in school, working life, and disease self-management. Diabetes is known to cause changes in brain structure and long-term cognitive dysfunction. This work investigated cystic fibrosis-related diabetes (CFRD) as a mechanism for cognitive impairment in people with CF. It was hypothesised that cognition would be poorer in adults with CFRD than in those with CF without diabetes (CFND) or in healthy controls.

METHODS: Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery which provides a comprehensive cognitive assessment with tests mapping onto specific brain regions. Demographic, clinical and self-reported health data were documented for all participants. CF specific clinical variables were recorded for the two CF groups.

RESULTS: Ninety-eight people with CF (49CFRD,49CFND) and 49 healthy controls were recruited. People with CF demonstrated deficits in aspects of verbal and spatial memory, processing speed and cognitive flexibility compared with healthy controls, with all areas of the brain implicated. Those with CFRD had additional difficulties with higher-level processes known collectively as 'executive function', which demand greater cognitive load and recruit the prefrontal cortex. Compared with healthy controls, those with CFND and CFRD had an estimated 20% and up to 40% reduction in processing speed respectively.

CONCLUSION: Managing CF requires higher order executive function. Impairments may be sufficient to interfere with self-care and the ability to perform everyday tasks efficiently. At which point in the CF disease trajectory these difficulties begin, and what may attenuate them, has yet to be determined.

PMID:34134937 | DOI:10.1016/j.jcf.2021.04.014

Popul Health Manag. 2021 Jun 16. doi: 10.1089/pop.2021.0040. Online ahead of print.

ABSTRACT

Multiple sclerosis (MS) is a "3C" (complex, chronic, costly) condition that is a common and disabling neurological illness affecting approximately 1 million adults in the United States. MS has been studied at the basic science, individual, and population levels, but not at the system level to assess small-area variation effects on MS population health outcomes. System-level effects have been observed in other 3C conditions including cystic fibrosis, rheumatoid arthritis, and inflammatory bowel disease. The authors report here on system-level variation findings from the baseline period during the first year of the Multiple Sclerosis Continuous Quality Improvement (MS-CQI) study. Stepwise binary logistic regression analyses were conducted to investigate system-level (small-area variation) effects on MS relapses (exacerbations), disease-modifying therapy (DMT) utilization, and brain MRI utilization, controlling for demographics (age and sex) and other potential confounders. Significant differences were observed in people with MS (PwMS) between centers for a number of demographic and disease characteristics, including sex, age, and MS subtype. Controlling for these factors, significant system-level effects were observed on outcomes, including DMT utilization, MRI utilization, and relapses. Significant relationships also were observed between outcomes and urgent care utilization, including emergency department visits and hospitalizations. This initial study provides evidence establishing the presence of system-level variation effects on MS outcomes in a multicenter population study - where PwMS get their care can influence their outcomes. Results support continued systems-level research and improvement initiatives to optimize MS population health outcomes in this challenging and costly complex chronic condition.

PMID:34134513 | DOI:10.1089/pop.2021.0040

mSphere. 2021 Jun 16:e0040121. doi: 10.1128/mSphere.00401-21. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a multidrug-resistant, opportunistic pathogen that frequently causes ventilator-associated pneumonia in intensive care units and chronic lung infections in cystic fibrosis patients. The rising prevalence of drug-resistant bacteria demands the exploration of new therapeutic avenues for treating P. aeruginosa infections. Perhaps the most thoroughly explored alternative is to use novel treatments to target pathogen virulence factors, like biofilm or toxin production. Gallium(III) nitrate is one such agent. It has been recognized for its ability to inhibit pathogen growth and biofilm formation in P. aeruginosa by disrupting bacterial iron homeostasis. However, irreversible sequestration by pyoverdine substantially limits its effectiveness. In this report, we show that disrupting pyoverdine production (genetically or chemically) potentiates the efficacy of gallium nitrate. Interestingly, we report that the pyoverdine inhibitor 5-fluorocytosine primarily functions as an antivirulent, even when it indirectly affects bacterial growth in the presence of gallium, and that low selective pressure for resistance occurs. We also demonstrate that the antibiotic tetracycline inhibits pyoverdine at concentrations below those required to prevent bacterial growth, and this activity allows it to synergize with gallium to inhibit bacterial growth and rescue Caenorhabditis elegans during P. aeruginosa pathogenesis. IMPORTANCE P. aeruginosa is one of the most common causative agents for ventilator-associated pneumonia and nosocomial bacteremia and is a leading cause of death in patients with cystic fibrosis. Pandrug-resistant strains of P. aeruginosa are increasingly identified in clinical samples and show resistance to virtually all major classes of antibiotics, including aminoglycosides, cephalosporins, and carbapenems. Gallium(III) nitrate has received considerable attention as an antipseudomonal agent that inhibits P. aeruginosa growth and biofilm formation by disrupting bacterial iron homeostasis. This report demonstrates that biosynthetic inhibitors of pyoverdine, such as 5-fluorocytosine and tetracycline, synergize with gallium nitrate to inhibit P. aeruginosa growth and biofilm formation, rescuing C. elegans hosts during pathogenesis.

PMID:34133200 | DOI:10.1128/mSphere.00401-21

Wien Klin Wochenschr. 2021 Jun 16. doi: 10.1007/s00508-021-01896-x. Online ahead of print.

ABSTRACT

Chronic inflammation induces proinflammatory cytokine cascades. In addition to systemic inflammation, hypoxemia, hypercapnia, a catabolic metabolism, gonadal or thyroid dysfunction, musculoskeletal dysfunction and inactivity as well as vitamin D deficiency contribute to an increased risk of fragility fractures. Iatrogenic causes of osteoporosis are long-term use of inhaled or systemic glucocorticoids (GC). Inhalative GC application in asthma is often indicated in childhood and adolescence, but interstitial lung diseases such as chronic organizing pneumonia, COPD, sarcoid or rheumatic diseases with lung involvement are also treated with inhalative or oral GC. In patients with cystic fibrosis, malabsorption in the context of pancreatic insufficiency, hypogonadism and chronic inflammation with increased bone resorption lead to a decrease in bone structure. After lung transplantation, immunosuppression with GC is a risk factor.The underlying pneumological diseases lead to a change in the trabecular and cortical bone microarchitecture and to a reduction in osteological formation and resorption markers. Hypercapnia, acidosis and vitamin D deficiency can accelerate this process and thus increase the individual risk of osteoporotic fragility fractures.A bone mineral density measurement with a T‑Score < -2.5 is a threshold value for the diagnosis of osteoporosis; in contrast the vast majority of all osteoporotic fractures occur with a T‑Score > -2.5. A history of low-trauma fracture indicates osteological therapy.All antiresorptive or anabolic drugs approved in Austria for the treatment of osteoporosis are also indicated for pneumological patients with an increased fragility fracture risk of bone fractures in accordance with the national reimbursement criteria.

PMID:34132916 | DOI:10.1007/s00508-021-01896-x

J Clin Endocrinol Metab. 2021 Jun 16:dgab384. doi: 10.1210/clinem/dgab384. Online ahead of print.

ABSTRACT

BACKGROUND: Indeterminate (INDET) and impaired glucose tolerance (IGT) are independently associated with CFRD risk. We determined whether patients meeting both criteria have increased risk of diabetes in two separate adult cohorts.

METHODS: The Montreal CF (MCFC; n=293 baseline & 198 for prospective analysis excluding subjects identified with incident CFRD at baseline) and Lyon CF (DIAMUCO; n=144/105) are prospective observational cohorts.

RESULTS: In the MCFC and DIAMUCO, mean age was (25.5 ± 7.7 & 25.0 ± 8.6 years), BMI (21.7 ± 3.0 & 20.2 ± 2.2 kg/m 2), FEV1% of (73.2 ± 22.1 & 62.5 ± 21.9%) and follow-up (6.9 ± 3.8 & 2.4 ± 1.2 years), respectively. In the MCFC cohort, the IGT only and INDET+IGT groups had greater risk of CFRD (p = 0.0109). In the DIAMUCO cohort, there was lower diabetes-free survival in the INDET+IGT group (p = 0.0105). In both cohorts, CFRD risk ranged from 17% in NGT patients up to 42 to 56% in patients with combined INDET and IGT.

CONCLUSION: Conclusion: Patients who meet combined criteria have a higher risk of developing diabetes probably justifying closer follow-up.

PMID:34132785 | DOI:10.1210/clinem/dgab384

Am J Dermatopathol. 2021 Jun 15. doi: 10.1097/DAD.0000000000001987. Online ahead of print.

ABSTRACT

Basaloid follicular hamartoma (BFH) is a rare, benign follicular neoplasm which typically presents as brown to skin-colored papules on the face, scalp, and trunk. Histologically, BFH consists of cords and strands of basaloid cells forming cystic structures with scant stroma and should be distinguished from infundibulocystic basal cell carcinoma to avoid overly aggressive treatment. Although BFH has been found to be associated with distinct syndromes, including alopecia, myasthenia gravis, and cystic fibrosis, there is often clinical, histopathologic, and genetic overlap with nevoid basal cell carcinoma syndrome (NBCCS). In this article, we describe a case of a 13-year-old patient with NBCCS who presented with multiple BFHs and propose that it its inclusion into the diagnostic criteria for NBCCS be considered.

PMID:34132667 | DOI:10.1097/DAD.0000000000001987

Microbiol Spectr. 2021 Jun 16:e0012721. doi: 10.1128/Spectrum.00127-21. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex (Bcc) comprises several species of closely related, versatile bacteria. Some Bcc strains produce 4-hydroxy-3-methyl-2-alkylquinolines (HMAQs), analogous to the 4-hydroxy-2-alkylquinolines of Pseudomonas aeruginosa. Using in silico analyses, we previously estimated that the hmqABCDEFG operon, which encodes enzymes involved in the biosynthesis of HMAQs, is carried by about one-third of Bcc strains, with considerable inter- and intraspecies variability. In the present study, we investigated by PCR, using consensus primers, the distribution of hmqABCDEFG in a collection of 312 Bcc strains (222 of clinical and 90 of environmental origins) belonging to 18 Bcc species. We confirmed that this operon is not distributed evenly among Bcc species. Among the 30% of strains bearing the hmqABCDEFG operon, we found that 92% of environmental isolates and 82% of clinically isolated Bcc strains produce levels of HMAQs detectable by liquid chromatography-mass spectrometry in at least one of the tested culture conditions. Among the hmqABCDEFG-positive but HMAQ-negative strains, none expressed the hmqA gene under the specified culture conditions. Interestingly, the hmqABCDEFG operon is more prevalent among plant root environment species (e.g., Burkholderia ambifaria and Burkholderia cepacia) and absent in species commonly found in chronically colonized individuals with cystic fibrosis (e.g., Burkholderia cenocepacia and Burkholderia multivorans), suggesting a role for the Hmq system in niche adaptation. We investigated the impact of the Hmq system on plant growth promotion and found that Pisum sativum root development by B. ambifaria required a functional HMAQ system. IMPORTANCE Environmental bacteria belonging to the various closely related species forming the Burkholderia cepacia complex (Bcc) can infect plants and animals, including humans. Their pathogenicity is regulated by intercellular communication, or quorum sensing, allowing them to collaborate instead of acting individually. Bcc organisms generally exploit interacting quorum sensing systems based on N-acyl-homoserine lactones as signaling molecules. Several Bcc strains also carry an hmqABCDEFG operon responsible for the biosynthesis of 4-hydroxy-3-methyl-2-alkylquinolines (HMAQs), molecules analogous to the Pseudomonas quinolone signal (PQS) system of P. aeruginosa. Our finding that the prevalences of the Hmq system and HMAQ production are very different between various Bcc species suggests a key role in niche adaptation or pathogenicity. This is supported by a significant reduction in plant growth promotion in the absence of HMAQ production for a beneficial Bcc strain.

PMID:34132614 | DOI:10.1128/Spectrum.00127-21

Epidemiol Prev. 2021 May-Jun;45(3 Suppl 1):1-37. doi: 10.19191/EP21.3.S1.050.

ABSTRACT

INTRODUCTION: On the 15th of November 2020, the National Centre for Rare Diseases of the Italian National Health Institute, clinicians of the Italian National Referral and Support Centres for Cystic Fibrosis, Children's Hospital "Bambino Gesù", Italian Cystic Fibrosis Society, Italian League for Cystic Fibrosis renewed the agreement about CF data flow for a 3-year period. The possibility to access data by third parties is among the most important innovation introduced within the agreement.

OBJECTIVES: Aim of the present Report is to improve the know-how of cystic fibrosis (CF) through a better characterization of Italian patients. Furthermore, the present Report aims at improving the care of CF patient. In particular, this Report should contribute to the following objectives: • to analyse the medium- and long-term clinical and epidemiological trends of the disease; • to identify the main healthcare needs at regional and national level, in order to contribute to the healthcare programmes and to the distribution of resources; • to compare Italian data with international ones.

DESIGN: Analyses and results described in the present Report are referred to patients currently followed at the Italian National Referral and Support Centres for Cystic Fibrosis in the 2017-2018 period. Data were sent by clinical Centres through a new-committed software. Data underwent a double quality control (QC): the first is automatically performed by the software (quantitative QC), the second is performed at a European level (before the inclusion of the Italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and the accuracy of data as well as their consistency with the European core data.

SETTING AND PARTICIPANTS: The present Report has been organized into 10 sections. 1. Demography: in the ICFR, 5,565 CF patients were registered in 2017 and 5,501 in 2018; median age was 21.4 years in 2017 and 21.2 years in 2018. Prevalence was 9.20/100,000 residents in Italy in 2017 and in 2018. Male percentage was 51.65% in 2017 and 2018, CF distribution by age range showed higher frequency in patients aged 7 to 35 years. Adult patients (aged more than 18 years) were 56.4% on average in 2017 and 2018. 2. Diagnoses: most of the CF patients were diagnosed before two years of age (median value 66.4%); a significant percentage of patients (21.6% in 2017 and 18.3% in 2018) was diagnosed in adult age. 3. New diagnoses: new diagnoses were 162 in 2017 and 142 in 2018. Estimated incidence was 1/5.214 living births in 2017 and 1/5.442 in 2018. 4. Genetics: 99.8% of patients underwent genetic analyses and in 97.1% of these patients a mutation in Cystic Fibrosis Transmembrane Regulator (CFTR) gene was identified. The F508del mutation was the most frequent (44.6% in 2018). Furthermore, 16.3% of patients in 2017 and 16.9% of patients in 2018 had at least one 'residual function' mutation. At least one gating mutation is present in 3.3% of Italian patients. Finally, 20.5% of patients had at least one stop codon mutation (class 1). 5. Lung function: percent predicted FEV1 (Forced Expiratory Volume in the first second) progressively declined before adult age, in accordance with the natural history of the disease. The majority of paediatric patients (6-17 years of age), i.e., 86.70% in 2017 and 90.50% in 2018, had percent predicted FEV1 ≥70%; whereas paediatric patients with a FEV1% ≤40% are less than 2% in the 2017-2018 period. 6. Nutrition: the two most critical periods are the first 6 months of life and adolescence. Prevalence of malnourished adolescent males (12-17 years of age) is higher than the prevalence observed in females. Increasing percentages of adult female patients with a suboptimal BMI value (39.1% and 36.1%, respectively, in 2017 and 2018) are observed. 7.

COMPLICATIONS: in 2018, CF-related liver disease without cirrhosis was the main complication both in patients aged less than 18 years (17.0% on average) and in adults (31.5%). CF-related diabetes was also frequent in CF adults (23.4%). 8. Transplantation: in 2017-2018, 83 patients received a double-lung transplantation. Median and range of age were 29.3 years (11.8-60.2) in 2017 and 29.1 (7.8-45.6) years in 2018. Median waiting times for lung transplantation in the two considered years were 8.6 and 7.7, respectively. 9. Microbiology: percentage of adult patients with chronic Pseudomonas aeruginosa infection was 51.3% in 2017 and 46.3% in 2018 vs 15.6% in 2017 and 10.2% in 2018 in paediatric age. Staphylococcus aureus infection is present in 53.4% and 53.5% of adult patients in 2017 and in 41.6% and 37.5% of paediatric patients in 2018. 10. Mortality: a total of 89 patients died in the 2017-2018 period (49 females); median age at death was 33.9 years in 2017 and 35.8 years in 2018 (transplanted patients are not included).

CONCLUSIONS: The present report shows that the Italian CF population is growing (4,159 in 2010 vs 5,501 in 2018; +1,342). Quality of data collected has been improved by the drastic reduction of missing data, thanks to the new software for data collection. Median age of patients increased in the 2010-2018 period (17 years in 2010 vs 21.2 years in 2018). Paediatric death is a very rare event. A very low percentage of paediatric population was characterized by severe lung disease (FEV1% <40). Prevalence of adult patients is increasing (56.4% in 2018). Age at diagnosis is decreasing (4.2 months in 2017 vs 3.8 months in 2018). Median age at death (transplanted patients not included) was 33.9 in 2017 and 35.8 in 2018. RIFC is completely compliant with the GDPR (UE 2016/679 regulation) and its role in national and international CF communities is confirmed.

PMID:34132083 | DOI:10.19191/EP21.3.S1.050

Pediatr Int. 2021 Jun 16. doi: 10.1111/ped.14888. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a lethal recessive genetic disease caused by loss of function associated with mutations in the CF trans-membrane conductance regulator (CFTR). CF is highly prevalent (approximately 1 in 3500) in Caucasians. The aim of this study was to compare demographic and clinical features, diagnostic tests, treatments, and complications of patients with CF whose newborn screening (NBS) with twice-repeated immune reactive trypsinogen (IRT/IRT) testing was positive, normal, and not performed.

METHODS: In this study, 359 of all 1,488 CF patients recorded in the CF Registry of Turkey in 2018, who had been born through the process of NBS, were evaluated. Demographic and clinical features were compared in patients diagnosed with positive NBS (Group 1), normal (Group 2), or without NBS (Group 3).

RESULTS: In Group 1, there were 299 patients, in Group 2, there were 40 patients, and in Group 3, there were 20 patients. Among all patients, the median age at diagnosis was 0.17 years. The median age at diagnosis was higher in Groups 2 and 3 than in Group 1 (p=0.001). Fecal elastase results were higher in Group 2 (p=0.033). Weight z-score was lower and chronic S. aureus infection was more common in Group 3 (p=0.017, p=0.004, respectively).

CONCLUSIONS: Frequency of growth retardation and chronic S. aureus infection can be reduced with an early diagnosis with NBS. In the presence of clinical suspicion in patients with normal NBS, further analyses such as genetic testing should be performed, especially to prevent missing patients with severe mutations.

PMID:34131975 | DOI:10.1111/ped.14888

J Cyst Fibros. 2021 Jun 12:S1569-1993(21)00159-4. doi: 10.1016/j.jcf.2021.05.008. Online ahead of print.

ABSTRACT

The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate. The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus.

PMID:34130909 | DOI:10.1016/j.jcf.2021.05.008

J Zoo Wildl Med. 2021 Jun;52(2):470-478. doi: 10.1638/2020-0128.

ABSTRACT

Orangutans are noteworthy among great apes in their predilection for chronic, insidious, and ultimately fatal respiratory disease. Termed Orangutan Respiratory Disease Syndrome (ORDS), this cystic fibrosis-like disease is characterized by comorbid conditions of sinusitis, mastoiditis, airsacculitis, bronchiectasis, and recurrent pneumonia. The aim of this retrospective study was to determine the sensitivity of clinical signs in the diagnosis of ORDS in Bornean orangutans (Pongo pygmaeus) compared with the gold standard for diagnosis via computed tomography (CT). We retrospectively compared observed clinical signs with CT imaging in a population of clinically affected animals at an orangutan rescue center in southeastern Borneo. From August 2017 to 2019, this center housed 21 ORDS-affected animals, all of which underwent CT imaging to delineate which areas of the respiratory tract were affected. We reviewed clinical signs recorded in medical records and keeper observation notes for each individual for the period of 2 years prior to the date of the CT scan. A chi-square test of association was used to assess whether the observed clinical signs could predict the results of CT imaging. Results show that clinical signs may not be sensitive indicators in predicting respiratory disease identified by CT imaging. Based on the results of this study, clinical signs appear to be very poor predictors of underlying respiratory pathology in orangutans, based on high P-values, low sensitivity, and low specificity. This result is observed even with clinical signs data gathered over a full 24-mo period prior to CT scan performance. The findings of this study suggest the need for advanced imaging to properly diagnose and manage the most common health issue of captive orangutans.

PMID:34130389 | DOI:10.1638/2020-0128

J Pediatr Gastroenterol Nutr. 2021 Jun 11. doi: 10.1097/MPG.0000000000003202. Online ahead of print.

ABSTRACT

BACKGROUND: Constipation is prevalent in pediatric cystic fibrosis patients and colonic motility has not been studied in this population. In this study, we aimed to evaluate the total and segmental colonic transit time in children and adolescents with cystic fibrosis based on the presence of constipation and radiological fecal impaction.

METHODS: In this case series, all patients aged 3 to 20 years of a cystic fibrosis reference center were invited to participate. Cystic fibrosis-associated constipation was diagnosed based on the European Society for Paediatric Gastroenterology Hepatology and Nutrition criteria. Total and segmental colonic transit time was determined using radiopaque markers. Fecal impaction on plain abdominal radiography was assessed based on the Barr score.

RESULTS: Of the 43 eligible patients, 34 (79%) agreed to participate. Constipation was found in 44.1% of children and adolescents, predominantly in females. The total colonic transit time (medians of 42 and 24 hours, respectively, p = 0.028) and the segmental right colon transit time (medians of 8 and 2 hours, respectively, p = 0.012) were significantly longer in cystic fibrosis-associated constipation group than in the group of patients without constipation. The frequency of radiological fecal impaction was similar in patients with (50.0%) and without (64.2%) cystic fibrosis-associated constipation (p = 0.70). There was no relationship between radiological fecal impaction and the total and segmental colonic transit time.

CONCLUSIONS: Children and adolescents with cystic fibrosis-associated constipation had a longer total and segmental right colon transit time. Colonic transit time was similar in patients with and without radiological fecal impaction.

PMID:34128499 | DOI:10.1097/MPG.0000000000003202

Interact Cardiovasc Thorac Surg. 2021 Jun 13:ivab093. doi: 10.1093/icvts/ivab093. Online ahead of print.

ABSTRACT

OBJECTIVES: The Ross procedure is an attractive option for the management of aortic valve disease in paediatric patients. We reviewed our experience with the paediatric Ross procedure to determine survival and freedom from reoperation in the third decade after surgery.

METHODS: We reviewed the data of 124 paediatric patients [71% male, median age at time of surgery 11.1 years (interquartile range 6-14.8 years); 63.7% bicuspid aortic valve], who underwent the Ross procedure at 2 tertiary centres from April 1991 to April 2020. The Ross-Konno procedures were performed on 14 (11.3%) patients. Deaths were cross-checked with the national health insurance database, and survival status was available for 96.8% of the patients. The median follow-up time was 12.1 years (interquartile range 3-18 years).

RESULTS: There were 3 early and 6 late deaths. All early deaths occurred in patients aged <1 year at the time of surgery. The 25-year survival was 90.3%. Actuarial freedom from reoperation (linearized rates in parentheses) was as follows: Autograft reoperation was 90.8% (0.48%/patient-year) and right ventricular outflow tract (RVOT) reoperation was 67% (2.07%/patient year) at 25 years. The univariable Cox-proportional hazard analysis revealed younger age at time of surgery (P < 0.001), smaller implanted valve size (P < 0.001) and the use of a xenograft rather than a homograft (P < 0.001) as predictors of RVOT reoperation. At multivariable Cox-proportional hazard analysis, only age was an independent risk factor for RVOT reoperation (P = 0.041).

CONCLUSIONS: The Ross and the Ross-Konno procedures are associated with good outcomes in paediatric patients. Reoperation of the RVOT is frequent and associated with younger age.

PMID:34128047 | DOI:10.1093/icvts/ivab093

Can Fam Physician. 2021 Jun;67(6):e144-e152. doi: 10.46747/cfp.6706e144.

ABSTRACT

OBJECTIVE: To explore primary care providers' (PCPs') preferred roles and confidence in caring for infants receiving a positive cystic fibrosis (CF) newborn screening (NBS) result, as well as management of CF family planning issues, given that expanded NBS has resulted in an increase in positive results.

DESIGN: Mailed questionnaire.

SETTING: Ontario.

PARTICIPANTS: Ontario FPs, pediatricians, and midwives identified by Newborn Screening Ontario as having had an infant with a positive CF NBS result in their practice in the previous 6 months.

MAIN OUTCOME MEASURE: Primary care providers' preferred roles in providing well-baby care for infants with positive CF screening results.

RESULTS: Overall, 321 of 628 (51%) completed surveys (208 FPs, 68 pediatricians, 45 midwives). For well-baby care for infants confirmed to have CF, 77% of PCPs indicated they would not provide total care (ie, 68% would share care with other specialists and 9% would refer to specialists completely); for infants with an inconclusive CF diagnosis, 50% of PCPs would provide total care, 45% would provide shared care, and 5% would refer to a specialist; for CF carriers, 89% of PCPs would provide total care, 9% would provide shared care, and 2% would refer. Half (54%) of PCPs were extremely or very confident in providing reassurance about CF carriers' health. Only 25% knew how to order parents' CF carrier testing; 67% knew how to refer for prenatal diagnosis. Confidence in reassuring parents about the health of CF carrier children was associated with providing total well-baby care for CF carriers (risk ratio of 1.50; 95% CI 1.14 to 1.97) and infants with an inconclusive diagnosis (risk ratio of 3.30; 95% CI 1.34 to 8.16).

CONCLUSION: Most PCPs indicated willingness to treat infants with a range of CF NBS results in some capacity. It is concerning that some indicated CF carriers should have specialist involvement and only half were extremely or very confident about reassuring families about carrier status. This raises issues about possible medicalization of those with carrier status, prompting the need for PCP education about genetic disorders and the meaning of genetic test results.

PMID:34127476 | DOI:10.46747/cfp.6706e144

Can Fam Physician. 2021 Jun;67(6):439-448. doi: 10.46747/cfp.6706439.

ABSTRACT

OBJECTIVE: To explore primary care providers' (PCPs') role in result notification for newborn screening (NBS) for cystic fibrosis (CF), given that expanded NBS has increased the number of positive screening test results, drawing attention to the role of PCPs in supporting families.

DESIGN: Cross-sectional survey and qualitative interviews.

SETTING: Ontario.

PARTICIPANTS: Primary care providers (FPs, pediatricians, and midwives) who received a positive CF NBS result for an infant in their practice in the 6 months before the study.

MAIN OUTCOME MEASURES: Whether the PCP notified the family of the initial positive CF screening result.

RESULTS: Data from 321 PCP surveys (response rate of 51%) are reported, including 208 FPs, 68 pediatricians, and 45 midwives. Interviews were completed with 34 PCPs. Most (65%) surveyed PCPs reported notifying the infant's family of the initial positive screening result; 81% agreed that they have an important role to play in NBS; and 88% said it was important for PCPs, rather than the NBS centre, to notify families of initial positive results. With support and information from NBS centres, 68% would be extremely or very confident in doing so; this dropped to 54% when reflecting on their recent reporting experience. More than half (58%) of all PCPs said written point-of-care information from the NBS centre was the most helpful format. Adjusted for relevant factors, written educational information was associated with a lower rate of notifying families than written plus verbal information (risk ratio of 0.79; 95% CI 0.69 to 0.92). In the interviews, PCPs emphasized the challenge of balancing required content knowledge with the desire for the news to come from a familiar provider.

CONCLUSION: Most PCPs notify families of NBS results and value this role. These data are relevant as NBS programs and other genomic services expand and consider ways of keeping PCPs confident and actively involved.

PMID:34127469 | DOI:10.46747/cfp.6706439

Prog Mol Biol Transl Sci. 2021;181:165-183. doi: 10.1016/bs.pmbts.2021.01.017. Epub 2021 Feb 24.

ABSTRACT

This chapter analyzes to use of the genome editing tool to the treatment of various genetic diseases. The genome editing method could be used to change the DNA in cells or organisms to understand their physiological response. Therefore, a key objective is to present general information about the use of the genome editing tool in a pertinent way. An emerging genome editing technology like a clustered regularly short palindromic repeats (CRISPR) is an extensively expended in biological sciences. CRISPR and CRISPR-associated protein 9 (CRISPR-Cas9) technique is being utilized to edit any DNA mutations associated with hereditary diseases to study in cells (in vitro) and animals (in vivo). Interestingly, CRISPR-Cas9 could be used to the investigation of treatments of various human hereditary diseases such as hemophila, β-thalassemia, cystic fibrosis, Alzheimer's, Huntington's, Parkinson's, tyrosinemia, Duchnene muscular dystrophy, Tay-Sachs, and fragile X syndrome disorders. Furthermore, CRISPR-Cas9 could also be used in other diseases to the improvement of human health. Finally, this chapter discuss current progress to treatment for hereditary diseases using CRISPR-Cas9 technology and highlights associated challenges and future prospects.

PMID:34127193 | DOI:10.1016/bs.pmbts.2021.01.017