Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

BACKGROUND: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. PATIENTS AND METHODS: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). RESULTS: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. CONCLUSIONS: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

The Olfactory Cleft Endoscopy Scale: a multi-institutional validation study in chronic rhinosinusitis.

BACKGROUND: Olfactory dysfunction (OD) associated with chronic rhinosinusitis (CRS) remains quite challenging. Instruments to precisely assess olfactory cleft anatomy and their association with olfaction are needed. METHODS: The olfactory cleft endoscopy scale (OCES) was used to assess the olfactory cleft in healthy control subjects and a cohort of patients with CRS. Psychophysical and psychosocial olfactory function were assessed and correlations with OCES scores were measured. RESULTS: Control subjects and subjects with CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) were enrol- led. OCES correlated with both psychophysical and psychosocial olfaction, as measured by threshold, discrimination and identi- fication (TDI) scores and Questionnaire on Olfactory Disorders (QOD-NS) scores for all case and control subjects combined. OCES improved in both CRS groups postoperatively with the highest correlation seen in postoperative olfaction in CRSwNP patients. CRS patients who achieve near perfect OCES and sinus endoscopy scores after surgery have olfactory metrics that are indistin- guishable from controls regardless of polyp status. CONCLUSIONS: The OCES is a valid olfactory-specific measure that demonstrates strong validity and provides complimentary infor- mation to traditional sinus endoscopy to aid in our understanding of OD associated with CRS.

[Intramedullary injection with tethered cord : Case report of a rare complication during spinal anesthesia]. / Intramedulläre Injektion bei "tethered cord" : Fallbericht einer seltenen Komplikation bei Spinalanästhesie.

Although very rare, severe neurological complications can occur when undergoing spinal anesthesia. This report describes and analyses a case of spinal injury due to an undiagnosed tethered cord (TC) during spinal anesthesia for a cesarean section of a 31-year-old woman expecting twins. As a consequence of spinal dysraphism during embryogenesis, an atypically low conus level can occur and increase the risk of injury during neuraxial anesthesia, especially in the absence of symptoms. Injuries can be caused by mechanical trauma from direct needle injury, hematoma or neurotoxicity from local anesthetics. Special attention should therefore be paid to frequent symptoms, such as a hairy nevus on the back, deformities of the feet or bladder and bowels, voiding and micturition dysfunction in order to reduce the risk of complications.

[Epidemiological Study of the Effects of Gender, Age, Mobility and Time of Injury on Proximal Femoral Fractures]. / Epidemiologická studie vlivu pohlaví, veku, mobility a doby úrazu na zlomeniny proximálního femuru.

PURPOSE OF STUDY Based on the selected criteria the study presents the evaluation of data of patients who underwent a surgery for proximal femoral fracture at the Department of Orthopaedic Trauma of the 1 st Faculty of Medicine and Military University Hospital Prague in the period 2013-2016. The paper aimed to determine whether there are any differences in proximal femoral fractures depending on the selected criteria. MATERIAL AND METHODS The study comprised 805 patients (562 women and 243 men) older than 21 years with proximal femoral fractures who were treated between January 1, 2013 and December 31, 2016. In the study, the patient s data on gender, age, a type of fracture (according to the AO classification), a level of mobility, time of injury and month of injury were analysed. The data was evaluated using the methods of descriptive statistics, one-way analysis of variance, two-way analysis by ANOVA and by following select POST-HOC test (Fisher LSD test) were utilized, 95% confidence interval was selected . RESULTS In the group of treated patients, the men were outnumbered by women (70% vs. 30%). In women the fractures occurred at a significantly (p < 0.001) older age (82 years) compared to men (77 years). Until the 8 th decade the fractures in men dominated, while from the 9th decade the fractures were more frequent in women. A sharp increase in the number of fractures in women was reported exactly in the 9th decade (56% of the total number of fractures in women). The group of women showed a significant difference (p = 0.027) between the age of femoral neck fractures and the age of trochanteric femoral fractures (80 years vs. 84 years). In both genders intracapsular and pertrochanteric fractures prevailed. In women and men with a limited mobility, fractures were sustained at the highest mean age (85 years in women, 84 years in men) compared to the other levels of mobility. In mobile patients, a significant difference (p < 0.001) was found between the age of women and men at which the fracture was sustained (79 years vs. 71 years). The largest significant difference (p < 0.001) in the age of fracture is seen in night time (84 years in women, 71 years in men). The highest number of injuries was suffered in the months of October to January, whereas the lowest number was reported in the period from June to July. DISCUSSION The epidemiological studies underline a notably higher incidence of proximal femoral fractures in women than in men, which was also confirmed by our study. The mean age of women with proximal femoral fracture was significantly higher compared to men. Similar conclusions have been drawn also by other studies. The incidence of fractures in dependence on the age group was the highest in women and men in their 9th decade, which compared to the previous studies was at a later age. This finding can be justified by aging of the Czech population, with the growing number of persons in the 9 th decade age group between 2012 and 2017 by 40,000. Nonetheless, men prevailed in fractures until the 9 th decade, while from the 9 th decade there is a marked growth in the number of these fractures sustained by women. This corresponds with the findings of other authors. As to the individual types of fractures (neck, trochanteric fracture) no difference was revealed in the percentage of women and men. In both genders intracapsular and petrochanteric fractures prevailed. Neither the level of pre-fracture mobility, nor the time of injury have been sufficiently monitored and evaluated with regard to the age of patients, therefore there is no adequate data to compare our results with. The lowest mean age at the time of injury was achieved by fully mobile men (71 years), which can be attributable to their sports and social activities performed at this age. The highest number of proximal femoral fractures was reported in the period from October to January, whereas their lowest number was reported in the period from June to July, which corresponds with the majority of other conducted studies in this area of research. CONCLUSIONS A considerably higher incidence of proximal femoral fractures in women was confirmed. The mean age of women with proximal femoral fracture was significantly higher than in men (82 vs. 77 years). Men prevailed in the number of fractures up to the 9 th decade, whereas from the 9 th decade the number of proximal femoral fractures in women significantly grew. In individual types of fractures (neck, trochanteric fractures), no difference in percentage of women and men was found. In both the genders intracapsular and pertrochanteric fractures significantly prevailed. The lowest mean age (71 years) at the time of injury was achieved by fully mobile men. The same age was identified in men also with respect to injuries sustained at night. The highest number of proximal femoral fractures was reported in the period from October to January, the lowest in the period from June to July. The knowledge of these seasonal variations can help plan the health care in the medical facility concerned. Key words: proximal femur, fracture, gender, mobility, day-time, seasonality.

Evolutionary diversification of the auditory organ sensilla in Neoconocephalus katydids (Orthoptera: Tettigoniidae) correlates with acoustic signal diversification over phylogenetic relatedness and life history.

Neoconocephalus Tettigoniidae are a model for the evolution of acoustic signals as male calls have diversified in temporal structure during the radiation of the genus. The call divergence and phylogeny in Neoconocephalus are established, but in tettigoniids in general, accompanying evolutionary changes in hearing organs are not studied. We investigated anatomical changes of the tympanal hearing organs during the evolutionary radiation and divergence of intraspecific acoustic signals. We compared the neuroanatomy of auditory sensilla (crista acustica) from nine Neoconocephalus species for the number of auditory sensilla and the crista acustica length. These parameters were correlated with differences in temporal call features, body size, life histories and different phylogenetic positions. By this, adaptive responses to shifting frequencies of male calls and changes in their temporal patterns can be evaluated against phylogenetic constraints and allometry. All species showed well-developed auditory sensilla, on average 32-35 between species. Crista acustica length and sensillum numbers correlated with body size, but not with phylogenetic position or life history. Statistically significant correlations existed also with specific call patterns: a higher number of auditory sensilla occurred in species with continuous calls or slow pulse rates, and a longer crista acustica occurred in species with double pulses or slow pulse rates. The auditory sensilla show significant differences between species despite their recent radiation, and morphological and ecological similarities. This indicates the responses to natural and sexual selection, including divergence of temporal and spectral signal properties. Phylogenetic constraints are unlikely to limit these changes of the auditory systems.

Development and validation of technologies suitable for the decontamination and re-use of contaminated N95 filtering facepiece respirators in response to the COVID-19 pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has brought significant challenges to society globally, particularly in the area of healthcare provision. A pressing need existed in protecting those tasked with delivering healthcare solutions during the COVID-19 crisis by providing solutions for preserving adequate supplies of effective personal protective equipment (PPE). AIM: To evaluate and validate available methods for the decontamination of N95 filtering facepiece respirators (FFRs) while maintaining functionality during re-use. METHODS: Multiple low-temperature steam and vaporized hydrogen peroxide (VHP) technologies were assessed for inactivation of Mycobacterium spp. and feline calicivirus (employed as representatives of the contamination challenge). FINDINGS: Virus (≥3log10) and Mycobacterium spp. (≥6log10) inactivation was achieved on various types of N95 FFRs using an array of heat (65-71oC), humidity (>50% relative humidity) and VHP without affecting the performance of the PPE. CONCLUSION: The methods have been validated and were authorized by the US Food and Drug Administration under a temporary emergency use authorization. Based on the findings, opportunities exist for development and deployment of decontamination methods made from simple, general purpose materials and equipment should a future need arise.

Clinical Impact of Ventilation Duration in Patients with Stroke Undergoing Interventional Treatment under General Anesthesia: The Shorter the Better?

BACKGROUND AND PURPOSE: Whether general anesthesia for neurothrombectomy in patients with ischemic stroke has a negative impact on clinical outcome is currently under discussion. We investigated the impact of early extubation and ventilation duration in a cohort that underwent thrombectomy under general anesthesia. MATERIALS AND METHODS: We analyzed 103 consecutive patients from a prospective stroke registry. They met the following criteria: CTA-proved large-vessel occlusion in the anterior circulation, ASPECTS above 6 on presenting cranial CT, revascularization by thrombectomy with the patient under general anesthesia within 6 hours after onset of symptoms, and available functional outcome (mRS) 90 days after onset. RESULTS: The mean ventilation time was 128.07 ± 265.51 hours (median, 18.5 hours; range, 1-1244.7 hours). Prolonged ventilation was associated with pneumonia during hospitalization and unfavorable functional outcome (mRS ≥3) and death at follow-up (Mann-Whitney U test; P ≤ .001). According to receiver operating characteristic analysis, a cutoff after 24 hours predicted unfavorable functional outcome with a sensitivity and specificity of 60% and 78%, respectively. Our results imply that delayed extubation was not associated with a less favorable clinical outcome compared with immediate extubation after the procedure. CONCLUSIONS: Short ventilation times are associated with a lower pneumonia rate and more favorable clinical outcome. Cautious interpretation of our data implies that whether patients are extubated immediately after the procedure is irrelevant for clinical outcome as long as ventilation does not exceed 24 hours.

Interleukin-1beta stimulates growth hormone-releasing hormone receptor mRNA expression in the rat hypothalamus in vitro and in vivo.

Changes in growth hormone-releasing hormone (GHRH), GHRH-receptor (R), somatostatin and interleukin (IL)-1beta mRNA levels were determined in fetal rat hypothalamic cultures after administration of IL-1beta (1, 10, 100 ng/ml, 2 h incubation), and in adult rat hypothalamus 5 h after intracerebroventricular injection of IL-1beta (2.5 and 25 ng). IL-1beta stimulated GHRH-R mRNA expression both in vitro (10 and 100 ng/ml) and in vivo (2.5 and 25 ng). Somatostatin mRNA was significantly stimulated and GHRH mRNA slightly reduced in vitro, while these mRNA species were not altered in vivo in response to IL-1beta. IL-1beta stimulated its own expression both in vitro (10 and 100 ng/ml) and in vivo (25 ng). IL-1beta-induced mRNA responses occurred 2 h after treatment in vitro (incubation times, 30 min to 6 h). IL-1beta also elicited slight GHRH releases in vitro. Up-regulation of hypothalamic GHRH-R by IL-1beta may explain previous findings suggesting that IL-1beta stimulates GHRH activity.

[Value of endoanal sonography in the assessment of faecal incontinence]. / Wertigkeit der Endoanalsonographie in der Abklärung bei fäkaler Inkontinenz.

PURPOSE: The aim of this study was to assess the value of endoanal ultrasound (EUS) in comparison to anal manometry and operative findings in patients suffering from faecal incontinence. Patient history, localisation of sphincter defects and therapeutic modalities were analysed. METHODS: Over a 3-years period, 92 patients with faecal incontinence were investigated by endoanal ultrasound. Results were compared with anal manometry in 81 cases. RESULTS: At EUS, 27 patients (29 %) showed no sphincter defect, 18 (20 %) had an isolated internal sphincter defect, 13 (14 %) an isolated defect of the external sphincter and 34 (37 %) presented with a combined internal/external sphincter defect. Manometry correlated in 30 % with endoanal ultrasound. Compared with surgery, endoanal ultrasound was correct in 100 % and manometry in only 54 %. An obstetric trauma was most frequently related to faecal incontinence. CONCLUSION: Endoanal ultrasound is a very sensitive method for localizing anal sphincter defects and is mandatory in the assessment of patients with faecal incontinence.

Proteinuria in rats in relation to age-dependent renal changes.

A variety of sex-dependent urinary proteins of low molecular weight, absent in females and in castrated males, can be identified in male rats by disc electrophoresis. In the urine of male rats of age 5.5 months, albumin comprises only 1-2% of the total protein. Albumin excretion increases greatly with age and associated kidney disease. Total protein excretion, however, stays the same or even decreases slightly as the rat ages, due to a loss of low molecular weight, sex-dependent, proteins. These are virtually absent in senescent rats (38 months of age), although total protein excretion rises tenfold in these animals due to high molecular weight plasma proteins passing into the urine; the glomerular filtration rate decreases to 70% of the value measured at 5.5 months of age.

Traumatic hyphema in an intercollegiate baseball player: a case report.

OBJECTIVE: To present the case of a collegiate baseball player struck in the right eye. BACKGROUND: While attempting a bunt, a 20-year-old collegiate baseball player was hit in the right eye when the ball was deflected off the bat. The athlete bled from the nose, and the right eye swelled shut from eyelid edema. Initial nasal hemorrhage was controlled, and the athlete was referred to the emergency room for further care due to pain in the inferior orbit. DIFFERENTIAL DIAGNOSIS: Eyelid contusion, traumatic iritis, or traumatic microhyphema to the right eye secondary to blunt trauma. TREATMENT: Immediate treatment consisted of controlling the nasal bleeding with sterile gauze pads. Because of palpable tenderness over the inferior orbit, the athlete was immediately transported to the emergency room. UNIQUENESS: Hyphema is one of the most common sport-related eye injuries: the incidence is 12.2 cases per 100,000 population, with approximately 37% resulting from sports injury. Racquet sports, baseball, and softball account for more than half of all hyphema injuries in athletics. Individuals with traumatic hyphema rarely require surgery; however, proper initial care, treatment, and referral are imperative to a good prognosis. CONCLUSIONS: Athletic trainers need to be able to recognize the signs and symptoms of hyphema and seek medical evaluation immediately in order to avoid secondary complications. With proper recognition, initial care and referral, and appropriate, well-fitted protective eyewear as needed, hyphema can have minimal complications, and the athlete may be able to compete again within 1 to 2 weeks.

Isolation of an inducible amidase from Pseudomonas acidovorans AE1.

A bacterial strain, AEI, which hydrolysed acetanilide, was isolated from soil and identified as Pseudomonas acidovorans. Numerous amides, esters and enzyme inhibitors were tested as amidase inducers. Phenacetin was chosen as inducer for the large scale cultivation of these organisms because it was less toxic to the bacteria than acetanilide. The induction increased the enzymic activity 250-fold. In comparison, the type culture strain of P. acidovorans, ATTCCI5668, had no amidase activity which could be induced by phenacetin. Optimal growth conditions were established with respect to the concentration of carbon source and inducer so that about 10% of the extractable bacterial protein consisted of the amidase. The organisms were lysed with lysozyme in the presence of EDTA and the enzyme was isolated mainly by column chromatography procedures. A preparation form 60 g (wet wt) bacteria yielded about 100 mg highly purified amidase with a specific activity of 137 mugmol substrate hydrolysed/min/mg protien. In addition to acetanilide, the purified enzyme hydrolysed several other amides and esters. As standard substrate, p-nitroacetanilide was chosen.

Nucleotide sequence of the gene for pre-apocytochrome f in the spinach plastid chromosome.

We have characterized a cloned fragment of the spinach plastid chromosome encoding the gene for apocytochrome f. Northern blot analysis and hybrid selection translation discloses that the gene is expressed. From the nucleotide sequence, we deduce that the protein contains 285 amino acids and an amino-terminal signal sequence of 35 amino acid residues. The calculated molecular mass of pre-apocytochrome f is 35.3 kd. The clustering of hydrophobic residues indicates that the processed protein (31.3 kd) possesses only a single anchoring transmembrane domain close to the C terminus, and that 75% of the polypeptide chain including the heme-binding site protrudes into the thylakoid lumen. This topology resembles that reported for beef heart mitochondrial cytochrome c1.

Effect of albumin on the function of perfused rat kidney.

The effect of different albumin concentrations on whole kidney function has been studied in the isolated perfused rat kidney. When a dialyzer was included in the perfusion circuit, GFR and sodium transport remained nearly constant for 2 h. Perfusion flow rate was directly correlated with albumin concentration. GFR was low (0.56 ml.min-1.g-1) at high albumin concentration (7.6 g/100 ml) and highest (1.38 ml.min-1.g-1) when albumin was omitted. The latter observation differed from earlier findings by other investigators who found a reduced GFR in the absence of albumin. This reduced GFR could be explained by ureteral backpressure, which results from the use of narrow ureter catheters. Fractional sodium reabsorption was approximately 50% irrespective of load when albumin was absent, and reached 90% at a GFR of 0.95 ml.min-1.g-1 when 5-6 g/100 ml albumin was used. At reduced load, fractional sodium reabsorption approached in vivo values of 98%. Potassium secretion was observed at high urinary flow rates when albumin concentration was low; low urinary flow rates at high protein concentration were associated with net potassium reabsorption.