Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment

Introduction: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822.Methods: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression.Results: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to –11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was –26 [–29, –23]. Odds of –26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041).Conclusions: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.     

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.     

Genomic landscape of inverted urothelial papilloma and urothelial papilloma of the bladder

Inverted urothelial papilloma (IUP) and urothelial papilloma (UP) are rare urothelial neoplasms that typically follow a benign clinical course. Oncogenic mutations in FGFR3, HRAS, and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed. We sought to characterize the genomic landscape of IUP and UP using whole-exome and targeted next-generation sequencing. In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation. None of the IUP tumors harbored TERT promoter or FGFR3 mutations. In UP, 8 of 11 tumors had oncogenic KRAS mutations and two had oncogenic HRAS mutations. One UP tumor had oncogenic mutations in FGFR3, PIK3CA, and the TERT promoter, and arose in a patient with recurrent non-invasive papillary urothelial carcinomas. In contrast to urothelial carcinoma, the APOBEC mutational signature was not present in any IUP and UP tumors, and oncogenic alterations in chromatin remodeling genes were uncommon in both IUP and UP. The current study suggests that IUP and UP are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial cancers. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

瞬时性受体电位通道香草酸受体5、6与骨代谢的关系

目的:探讨瞬时性受体电位通道香草酸受体5、6与骨代谢的关系。资料来源:应用计算机检索PubMed数据库1999-01/2006-07相关瞬时性受体电位通道方面的文献,检索词“TRPV”,限定文献语言种类为English。资料选择:对资料进行初审,选取包括瞬时性受体电位通道香草酸受体5、6的文献,开始查找全文。纳入标准:对两者及瞬时性受体电位通道家族进行研究的文章。排除标准:研究内容局限于瞬时性受体电位通道香草酸受体1～4的文章。资料提炼:共检索到106篇关于瞬时性受体电位通道香草酸受体的文献,最终纳入30篇符合标准的文献。资料综合:瞬时性受体电位通道香草酸受体5、6是瞬时性受体电位通道超家族中的成员,是专门的上皮样钙离子通道。目前研究已经证明它们在肠道和肾脏等组织中有表达,并对跨细胞钙离子转运起着关键性调控作用。但在骨组织中表达情况相关报道较少,在骨代谢机制上的研究更少,本文针对目前两者与骨代谢的关系进行综述。结论:深入研究瞬时性受体电位通道香草酸受体5、6钙离子通道在骨代谢中的作用,对于那些与骨代谢相关疾病的治疗将能从分子水平上找到解决的方法。     

创伤与复苏:治疗创伤性凝血病需要特殊血液制品

民用创伤中心和部队战斗支持医院正在收治越来越多的严重损伤,他们常规挽救那些在二十年前无法医治的病人。最重要的进展是发展了“紧急”外科学———由于发生凝血病阻碍了正常解剖的恢复,这项技术的发展超越了常规的血库支持治疗。失控的凝血紊乱性出血是创伤后可预防的导致死亡的主要原因。在美国每年大约有1/10的人由于创伤需要医疗处理,其中1/100的人住院,大约1/1000由于创伤后紧急处理而输注了血液制品。2000年,美国马里兰的大学创伤性休克中心(UMSTC),5649人中8%的受伤病人入院后直接根据创伤情况输注红细胞,5%的输注血浆,3%的输注…     

Prevalence and risk factors for hepatitis C antibodies in volunteer blood donors in Brazil

BACKGROUND: Little is known about the prevalence, risk factors, and transmission of hepatitis C virus (HCV) in a nontransfused population, particularly in developing countries. STUDY DESIGN AND METHODS: To investigate the association between HCV seropositivity and some demographic variables, a case-control study was conducted on 138 seropositive donors among 4762 consecutive volunteer blood donors and 1101 seronegative controls in Rio de Janeiro, Brazil. Donors were initially screened by interview for male homosexuality, use of illicit drugs, tattoos, previous transfusions, venereal diseases, and jaundice. Eligible donors were then tested for HCV antibodies by enzyme-linked immunosorbent assay. A multivariate analysis was performed on age, ethnic group, gender, and prior donation. RESULTS: The overall prevalence of HCV seropositivity was 2.89 percent. An increased risk of seropositivity was demonstrated for nonwhite donors at an odds ratio of 2.11 (95% CI, 1.43-3.13), for males at 2.39 (95% CI, 1.01-5.7), and for prior donors at 1.66 (95% CI, 1.09-2.52). The risk of anti-HCV positivity increased markedly with age. Those at highest risk were the group 40 to 49 years old, with an odds ratio of 4.37 (95% CI, 2.39- 7.99) versus the group 20 to 29 years old. The group under 20 years old showed an odds ratio of 0.50 (95% CI, 0.06-3.87) compared to the group 20 to 29 years old. These findings were equally significant in a univariate analysis. CONCLUSION: Our results suggest that HCV seropositivity is strongly associated with male sex, nonwhite ethnicity, and greater age. A significant number of seropositive donors were not detected by screening interview.     

The functional expression of tissue factor by fibroblasts and endothelial cells under flow conditions

The expression of tissue factor (TF) by a variety of vascular cell types under physiologic flow conditions is critical to factor X activation and in vivo clotting. Therefore, in a parallel-plate flow chamber (volume 40 microL) we mounted monolayers of human embryonic fibroblasts (FBs) or interleukin-1 alpha (IL-1 alpha) (5 U/mL x 4 hours)-stimulated human umbilical vein endothelial cells (ECs). Inflow buffer contained 10 nmol/L factor VIIa, 100 nmol/L factor X, and 2.0 mmol/L CaCl. With FBs, production of factor Xa (product of outflow concentration of factor Xa-and flow rate) increased 200-fold over the range of shear stress from 0 to 2.7 dynes/cm2. Production values (mean +/- SE (N)) were 7.93 +/- 0.024 (6), 312 +/- 7.3 (6), 688 +/- 33.1 (8), 1,033 +/- 119 (6), and 1,601 +/- 183 (7) fmol/cm2.minute at shear stresses of 0, 0.27, 0.68, 1.35, and 2.7 dynes/cm2, respectively. Further experiments at 0.68 dynes/cm2 indicated that factor Xa production increased with factor X concentration over the range from 3 to 100 nmol/L, but changed little from 300 to 1,000 nmol/L. With ECs, production was 0.13 +/- 0.86 (6), 8.17 +/- 1.65 (13), and 1.66 +/- 1.66 (5) fmol/cm2.minute at 0, 0.68, and 2.7 dynes/cm2, respectively. However, in the presence of an antibody directed against tissue factor pathway inhibitor (TFPI) production with ECs was augmented to 16.46 +/- 0.80 (8), 149.8 +/- 18.6 (8), and 48.9 +/- 10.3 (10), respectively, at these same shear stresses. Control experiments with factor VIIa, factor X, or both absent confirm for both cell types the specificity of the reaction for the TF pathway. Similarly, specificity for TF itself is shown by the virtual absence of factor Xa generation in the presence of the monoclonal antibody HTF1-7B8 directed against human TF. We conclude that ECs, even when activated, are normally unable to generate significant quantities of factor Xa in the presence of factors X and VIIa. However, significant quantities of factor Xa are possible in the presence of an inhibitor of TFPI. On the other hand, production of factor Xa by fibroblasts is markedly augmented by shear stress, yet independent of the availability of substrate factor X above an inflow concentration of 100 nmol/L. The latter suggests a direct effect of flow on the fibroblast monolayers, not substrate limitation by convective diffusion.     

Mediastinal bronchogenic cyst. A cause of upper airway obstruction.

Although bronchogenic cysts may involve the mediastinum, they have rarely been responsible for significant upper airway obstruction. We describe a young man who had a rapidly expanding cervical mass due to the migration of a mediastinal bronchogenic cyst. Flow-volume loops confirmed the presence of a variable intrathoracic obstruction. The patient rapidly developed respiratory failure requiring urgent intubation and surgical resection.     

Design and interpretation of clinical research studies in oral medicine: a brief review

The objective of this short review is to help researchers improve the designs of their clinical studies. Also included is a discussion of the level of evidence provided by the various clinical research study designs.     

Serological investigation of pneumonia as it presents to the physician��s office

Purpose:

To define the etiology of pneumonia, using a battery of serological tests, among patients presenting to physicians’ offices in Cumberland County, Nova Scotia from July 2, 1989 to July 1, 1990.

Methods:

Patients presenting to their physician’s office with symptoms suggestive of pneumonia were invited to participate in the study by completing a questionnaire, having a chest radiograph and providing acute and convalescent phase serum samples. These serum samples were tested for antibodies to Mycoplasma pneumoniae, Coxiella burnetii, Legionella pneumophila, adenovirus, and influenza viruses A and B. Some of the samples were tested for antibodies to Chlamydia pneumoniae.

Results:

Seventy-five of the inception cohort of 203 patients had a chest radiograph compatible with pneumonia, a completed questionnaire and acute and convalescent phase serum samples. There were 39 females and 36 males with a mean age of 41.7 years. Twenty-six (35%) were admitted to hospital. The mortality rate was 3%. Forty-five per cent had a diagnosis made by serology: M pneumoniae, 22 (29%); influenza A virus, five (7%); C burnetii, L pneumophila, adenovirus, two (3%) each.

Conclusions:

While it is not possible to generalize about these findings because of ascertainment bias, the data suggest that M pneumoniae is a common cause of pneumonia presenting to a physician’s office and that mortality is low in this group of patients.