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Anne Yoder

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Germline mutations are the raw material for natural selection, driving species evolution and the creation of earth’s biodiversity. Life on earth would stagnate without this driver of genetic diversity. Yet, it is a double-edged sword. An excess of mutations can have devastating effects on fitness and population viability. It is therefore one of the great challenges of molecular ecology to determine the rate and spectrum by which these mutations accrue across the tree of life. Advances in high-throughput sequencing are providing new opportunities for characterizing these rates and patterns within species and populations, thus informing essential evolutionary parameters such as the timing of speciation events, the intricacies of historical demography, and the degree to which lineages are subject to the burdens of mutational load. Here, we will focus on the applications and limitations of whole-genome comparisons among closely related individuals in what are typically described as “trio” analyses for the detection of germline mutations as they arise in real time. By sequencing and comparing whole-genomes generated for individuals of known relatedness – typically, parent to offspring – investigators can ideally count and characterize mutations as they appear per generation. The promise for gaining insight into classic hypotheses of molecular evolution is high, though so too is the cost. Namely, the technical challenges are daunting given that pedigree-based studies are essentially searching for needles in a haystack. Even so, the opportunities are so enticing, and the field so young, we can say with confidence that fundamental insights have only just begun to emerge.

Gaëlle Magliocco

and 7 more

Background and Purpose: Individualized assessment of the activity of cytochrome P450 2D6 (CYP2D6), a highly variable drug-metabolizing enzyme, is performed through phenotyping during which a probe drug is administered to measure the enzyme’s activity. In order to avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-invasive tools for real-time phenotyping of CYP2D6 could significantly contribute to the expansion of precision medicine in clinical practice. This study focuses on the identification of endogenous markers of the CYP2D6 enzyme in human biofluids using a liquid chromatography (LC)-high-resolution mass spectrometry (HRMS)-based metabolomics approach. Experimental Approach: Data from a control session were compared to data from an inhibition session. Before the latter, healthy volunteers (extensive and ultrarapid metabolizers) received a daily dose of paroxetine 20 mg over seven days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. Key Results: In CYP2D6 extensive and ultrarapid metabolizers (n = 37), mean relative intensities of five features were significantly reduced during the inhibition session compared to the control session (fold changes ≤ 0.67, FDR-adjusted P < 0.0001). Furthermore, mean relative intensities of these candidates were significantly higher in the CYP2D6 extensive-ultrarapid metabolizer group (n = 37) compared to the poor metabolizer group (n = 6) (fold changes ≤ 0.67, P < 0.0001). Conclusion and Implications: The applied untargeted metabolomics strategy was able to identify five CYP2D6 endogenous metabolites, a promising discovery for non-invasive phenotyping and personalised medicine.

Oguz Ozden Cebeci

and 4 more

Introduction Residual stone fragments remain a challenging topic for urologists following retrograde intrarenal surgery (RIRS). This study investigates the effectiveness of second-look flexible ureterorenoscopy (URS) to achieve a true stone-free status and decrease stone-related events. Material and Method A total of 176 consecutive patients treated with RIRS for kidney stones were included in the study. Patients were divided into two groups, group 1 receiving the standard of care (n=51) and group 2 receiving second-look flexible URS (n=125). In all cases, one or more calyceal stones of 1 to 4 mm were extracted with a basket at the time of stent removal. Unless earlier intervention was necessary, patients were followed up every six months to determine if they had experienced SREs. Results The mean follow-up time for the whole group was 21±11.1 months. The mean number of stones in group 1 and group 2 was 1.25±0.11 and 1.56±0.19, respectively. Postoperative stone-free rate after RIRS for group 1 and group 2 were 37.25% (n=19/51) and 40.8% (n=51/125), respectively. The SFR improved to 93.6% (n=117/125) in group 2. Multivariable analysis showed that type of intervention, stone size, and body mass index were independent prognostic factors for SREs. When group 2 was taken as a reference, the odds ratio for SREs was 8.48 (95% CI: 2.95–24.42) in group 1. Conclusion This study found that second-look flexible URS increased the SFRs and diminished the number of SREs. We propose performing second-look flexible URS following RIRS in the presence or suspicion of RSFs to provide better treatment results, less radiation exposure, and greater patient satisfaction. Key Words Retrograde Intrarenal Surgery, Flexible Ureteroscopy, Stone-free Rate, Residual stone Fragments, Stone-Related Event, Second-look Flexible Ureteroscopy.
Objective: To present an alternative surgical technique in treating cases of Chiari I Malformation with mild-to-moderate syringomyelia after decompressive suboccipital craniectomy: incising only the outer layer of the dura mater, then dissecting it from the inner layer without opening the latter. Methods and Results: We utilized this technique in a short series of three cases who were admitted in our department for mild symptoms such as intermittent headache and dissociated sensory loss in the upper limbs, caused by a Chiari Malformation Type I. The patients were placed in the sitting position. We performed a reduced median suboccipital craniectomy and resection of the posterior arch of C1 adapted to the level of tonsil descent, from a limited superior half to a complete resection. Afterwards, we incised the outer dural layer, while sparing the inner one. Using a fine dissector, we then split apart the outer and inner layers to the margin of the craniectomy. Through the transparency of the inner layer and the arachnoid, the cerebellum and the medulla were visible and pulsating. An autologous fascia duraplasty was then performed. The postoperative course was favorable in all cases, patients being discharged without any deficits and with complete symptom resolution. Conclusions: Interlayer dural split technique can be used effectively in treating symptomatic cases of type I Chiari malformation in adults, with mild-to-moderate syringomyelia. It is less invasive than opening the dura and possibly more effective than decompressive craniectomy and C1 laminectomy alone. This technique must be validated in a larger case-control series.
Background: Muscle wasting and limitation in physical activity have been reported in patients with hemodialysis; this leads to poor quality of life at the end. Objective: To develop the respiratory training device and to determine the efficiency of the prototype on respiratory muscle strength, functional capacity and dyspnea perception in hemodialysis patients. Design, setting and participants: the development of respiratory device was created and then effects of respiratory device were examined in hemodialysis patients. A total of 25 patients with quasi experimental study was recruited in the present study with aged ≥ 35 years old. All participants had a history of hemodialysis 3 days per week. Outcome measurements and statistical analysis: The protocol was conducted 15 inhales, three set per day with 40% of maximal inspiratory pressure; totally 45 inhales. The participants were asked to perform for three times per week during on hemodialysis. Respiratory muscle strength, the 6minute walk test and rate of dyspnea scores were assessed before and after 8-week intervention program. Paired t-tests was used to compare between initial values and follow-up values in respiratory prototype. Results: Of 25 patients at initially was enrolled, 22 individuals (88%) completed in the 8-week program. Significant improve in inspiratory muscle strength, 6minite walk distance and rate of dyspnea was observed after 8-week intervention (12.44± 3.55 cmH2O, 24.78 ± 8.89 meters, and 0.50 ± 0.19, respectively). Conclusion: Using porotype of respiratory device can effectively improve cardiorespiratory performance which is marked by increasing inspiratory muscle functional capacity and rate of dyspnea in hemodialysis patients after 8-week training program.

Esra Yazarlı

and 5 more

Objective: This study aimed to investigate the association between carotid intima-media changes that play a part in the atherosclerotic process in childhood obesity and fibrin monomers as an important indicator of fibrin plaque. Methods: This is a cross-sectional study of obese children and non-obese healthy control subjects. Height, weight, body mass index, waist/hip ratio, systolic/diastolic blood pressures were recorded, in addition, biochemistry, hemogram, fibrin monomers and d-dimer were measured in both groups. Right and left common carotid intima-media thicknesses were measured by ultrasonography and mean carotid intima-media thickness was calculated. Results: Obese children (n=89, 46.1% girls, median age: 12.6±2.3 years) and healthy control group (n=40, 52.5% girls, median age: 13.2±2.2 years) were comparable in terms of gender, age and puberty stage. Mean carotid intima-media thickness was higher in obese children than the healthy control group (p=0.002). There was no difference between the two groups in terms of fibrin monomers and D-dimer levels. In obese children, there was a weak negative correlation between mean carotid intima-media thickness and fibrin monomers (p=0.030, r=-0.233). Conclusion: In obese children, mean carotid intima-media thickness was determined higher, as an early indicator of atherosclerosis. We want to emphasize that obese children are at risk for cardiovascular disease and should be evaluated in terms of atherosclerosis. This study investigates the relation between increased carotid intima-media thickness and fibrin monomers, in children, the first time in Literature. What’s already known about this topic? It is possible to reveal the early period of the atherosclerosis process by showing carotid intima medial thickness. Fibrin is a major component of many atherosclerotic plaques. What does this article add? Our study investigated the relationship between mean carotid intima-media thickness in childhood obesity and fibrin monomers. But no positive correlation was found between fibrin monomers and the carotid intima-media thickness.

Supakit Paosen

and 5 more

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Oktay Ucer

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Semih Ak

and 1 more

Background: Hookah is a tobacco product of Middle Eastern origin; however, its popularity increases in Europe and the US. Despite its frequent use, hookah’s potentially detrimental effects are underestimated due to the scarcity of the relevant research. Since septoplasty is one of the most commonly performed procedures of otolaryngology practice, we aimed to investigate the impact of hookah consumption on recovery after septoplasty. Methods: Patients who underwent septoplasty in Sanliurfa Training and Research Hospital Department of Otolaryngology between January 2017 and December 2019 were divided into four groups based on their history of hookah and cigarette smoking. The patients’ prospectively collected data, including demographic features, healing time, and presence or absence of septal perforation during follow-up, were compared between these four groups. Results: The entire cohort included 270 patients. The mean patient age was 29.2±5.8 years. One hundred and thirty-two (48.9%) patients were non-smokers, 96 (35.5%) were cigarette smokers, 27 (10%) were hookah smokers, and 15 (5.6%) consumed both tobacco products regularly. Mean healing time was 10 days, and septal perforation was encountered in 10 patients (3.7%). A comparison of the groups revealed that cigarette smoking did not impact septal perforation rates (p=0.326) but prolonged the healing time. However, hookah smoking with or without cigarette smoking significantly influenced septal perforation rates and healing times. Conclusion: Patients should be questioned about hookah smoking in addition to cigarette smoking before the septoplasty procedure. Patients with a positive history of hookah smoking should be followed closely in terms of delayed healing and increased septal perforation rates.

George Angelidis

and 3 more

COVID-19 and nuclear cardiology: Introducing the ‘’forward” virtual visit Angelidis G, Valotassiou V, Psimadas D, Georgoulias PNuclear Medicine Laboratory, University of Thessaly, Larissa, GreeceWe read with great interest the recent review article by Kaushik A, et al. concerning the potential role of digital health applications in the present pandemic situation [1]. As the authors noted, alternative tools are needed for the optimal management of cardiovascular patients, avoiding unnecessary visits to health care facilities. The severe acute respiratory syndrome – coronavirus – 2 (SARS-CoV-2) can invade the cardiovascular cells, potentially causing life-threatening cardiac impairment [2]. In particular, patients with pre-existing cardiovascular diseases are characterized by a higher risk of adverse cardiovascular events. Therefore, most of those referred for nuclear cardiology techniques are expected to be at higher risk of developing serious coronavirus disease 2019 (COVID-19) complications. However, the performance of the individually required diagnostic and follow-up procedures is important [3].Telemedicine applications have been used in public health emergencies, leading to several advantages in terms of safety and efficacy. In the field of nuclear cardiology, the initial evaluation of patients’ history and clinical features can take place remotely (‘’forward” virtual visit). This approach seems to be patient-centred (permitting an adequate case assessment) and conducive to self-quarantine (protecting patients, healthcare professionals, and the community from viral exposure). Importantly, possible clinical presentations of COVID-19 may be evaluated during the ‘’forward” virtual visit, as well as information regarding travel and exposure histories. Moreover, local epidemiological information may be used to adjust screening pattern, and special measures could be developed (such as isolation in dedicated ‘’hot” rooms) for patients with high-risk features. After the performance of the examination, telemedicine applications could be also used for the consultation with the patients.Telemedicine applications may contribute to a better adjustment of nuclear cardiology services under the current demanding circumstances. Of course, no telemedicine programme can be created overnight, but this approach may be of value not only during the next months but also after the end of COVID-19 pandemic [4]. For example, our nuclear medicine laboratory is located in central Greece providing services to inhabitants of mountain villages, and nearby small islands. Consequently, the use of telemedicine applications could aid our practice in the future as well, particularly during the winter months when travelling by car or sea travels may be extremely demanding.

Attila Mokánszki

and 8 more

Background Retinoblastoma (Rb) is a malignant tumor of the developing retina that affects children before the age of five years in association with inherited or early germline mutations of the RB1 gene. The genetic predisposition is also related with second primary malignancies arising de novo, or following radiotherapy which have become the leading cause of death in retinoblastoma survivors. Procedure We describe a retinoblastoma case with a novel RB1 and a synchronous MET aberration. Our goal was to identify all germline and somatic genetic alterations in available tissue samples from different time periods and to reconstruct their clonal relations using next generation sequencing (NGS). We also used structural and functional prediction of the mutant RB and MET proteins to find interactions between the defected proteins with potential causative role in the development of this uniqe form of retinoblastoma. Results In this study we detected a retinoblastoma case of non-parental origin with a novel RB1 c.2548C>T;p.(Gln850Ter) and a synchronous MET c.3029C>T;p.(Thr1010Ile) germline mutations. Following bilateral retinoblastoma the boy further developed at least four different manifestations of two independent osteosarcomas. Both histopathology and NGS findings supported the independent nature of a chondroblastic osteosarcoma of the irradiated facial bone followed by an osteoblastic sarcoma of the leg (tibia). Conclusions Because of the expanding number of registered Rb cases, the novel rare cases publication is very important to understand the molecular mechanism of this malignancy. We reported a novel form of Rb and consequential chondroblastic and osteoblastic osteosarcoma, the latter one developing pulmonary metastatses.

Ugur Balkanci

and 2 more

An Unusual Case of Necrotizing Pneumonia Presenting with Acute Kidney InjuryUgur Berkay Balkanci, MDSchool of Public Health, University of Minnesota, Minneapolis, MNDavid J. Sas, DODivision of Pediatric Nephrology and Hypertension, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MinnesotaNadir Demirel, MDDivision of Pediatric Pulmonology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MinnesotaCorresponding Author:Nadir Demirel, MDDivision of Pediatric Pulmonology200 First Street SWRochester, MN 55906Tel. No.: 5075380754Fax No.: 5072840727Demirel.nadir@mayo.eduKey words: postinfectious glomerulonephritis, pneumothorax, complications, complicated pneumoniaFinancial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.Funding: No external funding.Short title: “An unusual case of necrotizing pneumonia”To the Editor:Lower respiratory tract infections are the most common reason for hospitalization in the pediatric age group in the United States. Although pneumonia is prevalent, complicated pneumonia such as empyema, lung abscess and necrotizing pneumonia (NP) is uncommon in children1. The prevalence of complicated pneumococcal pneumonia decreased significantly after the introduction of the thirteen-valent pneumococcal vaccine in 20101. NP in the pediatric population is a severe disease characterized by extensive destruction and liquefaction of the lung tissue resulting in loss of the pulmonary parenchymal architecture, cavitation of the lung, and pleural involvement. Renal complications of complicated pneumonia are rare and mostly reported as atypical hemolytic uremic syndrome (HUS)2. Post-infectious glomerulonephritis (PIGN) is an unexpected complication of bacterial pneumonia3.We report a six-year-old otherwise healthy fully vaccinated girl with a 4-day history of fever, abdominal pain, vomiting, non-bloody diarrhea, and poor oral intake. Parents reported decreased urine output and dark-colored urine on the day of admission. Initial evaluation revealed serum creatinine of 5.01 mg/dL and blood urea nitrogen of 86 mg/dL, elevated acute phase reactants suggesting acute kidney injury (AKI) in the setting of an undiagnosed acute infectious process. The patient was admitted with decreased effective circulatory volume. Urinalysis revealed hematuria with <25% dysmorphic red blood cells (RBCs), proteinuria, pyuria, and RBC casts and granular casts, suggestive of acute glomerulonephritis.She was started on intermittent hemodialysis at day 2 of admission to address uremia, fluid overload, and hyperphosphatemia. A renal biopsy revealed diffuse exudative glomerulonephritis, consistent with infection-related glomerulonephritis. ASO, Anti-DNase B were negative; C3, C4 levels were low. She was treated with pulse IV methylprednisolone 10mg/kg/day for three days. The first 5 days in the hospital, the patient remained afebrile and her lung exam was normal without respiratory symptoms.On day six of admission, she developed acute right-sided chest pain and shortness of breath during hemodialysis. Chest x-ray (CXR) revealed a large right-sided tension pneumothorax, prompting therapeutic chest tube placement. Repeat CXR revealed reexpansion of the right lung and a significant right upper lobe consolidation with an ovoid hyperlucency and an air-fluid level. A chest CT scan confirmed the diagnosis of NP with multiple cavities (Image).Flexible bronchoscopy was performed with bronchoalveolar lavage revealing 42% neutrophils and negative cultures. She was treated with broad spectrum intravenous antibiotics.During admission, she developed hypertension, well-controlled with scheduled enalapril and amlodipine, as well as isradipine as needed. On day 14 of admission, hemodialysis was discontinued as kidney function improved, and chest tube was removed. She was discharged at day 26 of admission on intravenous ceftriaxone and oral metronidazole to complete 30 days of treatment. A repeat chest CT at end of treatment showed complete resolution of NP. Renal functions and blood pressure normalized on follow up.NP is characterized by persistent high fevers and prolonged hospitalizations even with appropriate antibiotic treatment1. Most often, NP affects immunocompetent children with no underlying risk factors4. The pathophysiology of this complication is acute liquefactive necrosis of the lung parenchyma which results in the development of pneumatoceles4. The most common pathogen causing NP is Streptococcus pneumoniae followed by Staphylococcus aureus and Streptococcus pyogenes. Other rarer bacterial and viral pathogens are Mycoplasma pneumonia, Influenza, and Adenovirus1. Identifying the microbiologic pathogen can be challenging and is only made in 50% of cases1. In our case, we did not isolate the causative microorganism. NP typically resolves without residual morbidity, even after a protracted course1,4.Pleural involvement is almost universal in NP, and the course of pleural disease often determines duration and outcome, particularly as it relates to the complication of bronchopleural fistula (BPF)1. BPF is most likely due to the necrotic development of a connection between bronchial space and pleural space4. BPF formation is associated with a significantly longer hospital stay in children with NP4. Yet, most cases heal without surgical intervention4. Tension pneumothorax has been observed as a rare complication of NP1.Renal involvement in complicated pneumonia is rare. Atypical HUS has been reported as a complication of pneumonia, particularly associated with empyema. (most commonly due to invasive Streptococcus pneumoniae)2. In a case series of 37 cases of atypical HUS, 34 patients (92%) had pneumonia with 10 patients (29%) with NP5. Less commonly, pneumonia can be associated with PIGN. PIGN is the most common glomerulonephritis in children worldwide. Pneumonia-associated PIGN is rare. In a case series from the US, PIGN accounted for 0.15% of admissions for pneumonia and 0.39% of admissions for glomerulonephritis6. Pneumonia-associated PIGN is known to be caused by various bacterial pathogens including Streptococcus pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, Nocardia, and Coxiella burnetii3. Different from the usual presentation of the PIGN (in which the time interval between a pharyngeal group A Streptococcal infection and PIGN is 6 to 10 days), pneumonia-associated PIGN is usually concomitant with the pulmonary disease3,6.Our case is unusual in several ways: pneumonia-associated PIGN typically presents with respiratory symptoms first, and acute kidney injury developing during the course of pneumonia3. More surprisingly, the patient developed NP which is characterized by even more severe respiratory symptoms1. Yet, our patient presented without respiratory complaints and pneumonia became apparent only after the development of pneumothorax. We could only identify 2 cases of pneumonia-associated PIGN who presented with renal involvement before pulmonary complaints6,7. Also, previous cases in the literature of pneumonia-associated PIGN report mostly a non-complicated course of pulmonary disease3,6. In a case series of 11 children with pneumonia-associated PIGN, only one case developed a small empyema6. Similarly, the majority of the reported cases of pneumonia-associated PIGN describe a benign course of renal disease3,6. Our patient’s kidney failure progressed rapidly, and she required 2 weeks of intermittent hemodialysis and a three-day course of pulse steroid therapy. At present, systemic corticosteroids are not recommended for patients with complicated pneumonia. A Cochrane review including 17 randomized controlled trials, of which four were conducted on children, found that corticosteroid therapy reduced mortality and morbidity in adults with severe CAP, and morbidity, but not mortality, in adults and children with non-severe CAP1. We speculate that pulse steroid treatment may have modified the course of NP in our patient.This case suggests an atypical presentation of NP with predominant renal complications is possible. Pediatricians should be aware of renal complications of respiratory diseases. Systemic steroids should be considered in the treatment of NP.References:1. de Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, Bush A. Complicated pneumonia in children. Lancet 2020;396:786-798.2. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr 2013;25:203-208.3. Carceller Lechón F, de la Torre Espí M, Porto Abal R, Écija Peiró JL. Acute glomerulonephritis associated with pneumonia: a review of three cases. Pediatr Nephrol 2010;25:161-164.4. Sawicki GS, Lu FL, Valim C, Cleveland RH, Colin AA. Necrotising pneumonia is an increasingly detected complication of pneumonia in children. Eur Respir J 2008;31:1285-1291.5. Banerjee R, Hersh AL, Newland J, Beekmann SE, Polgreen PM, Bender J, Shaw J, Copelovitch L, Kaplan BS, Shah SS. Streptococcus pneumoniae-associated Hemolytic Uremic Syndrome Among Children in North America. Pediatr Infect Dis J 2011;30:736-739.6. Srivastava T, Warady BA, Alon US. Pneumonia-associated acute glomerulonephritis. Clin Nephrol 2002;57:175-182.7. Schachter J, Pomeranz A, Berger I, Wolach B. Acute glomerulonephritis secondary to lobar pneumonia. Int J Pediatr Nephrol 1987;8:211-214.

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