Soil microbial community succession and interactions during combined plant/white-rot fungus remediation of polycyclic aromatic hydrocarbons.
Despite combined plant/white-rot fungus remediation being effective for remediating polycyclic aromatic hydrocarbon (PAH)-contaminated soil, the complex organismal interactions and their effects on soil PAH degradation remain unclear. Here, we used quantitative PCR, analysis of soil enzyme activities, and sequencing of representative genes to characterize the ecological dynamics of natural attenuation, mycoremediation (MR, using Crucibulum laeve), phytoremediation (PR, using Salix viminalis), and plant-microbial remediation (PMR, using both species) for PAHs in soil for 60 days. On day 60, PMR achieved the highest removal efficiency of all three representative PAHs (65.5%, 47.5%, and 62.4% for phenanthrene, pyrene, and benzo(a)pyrene, respectively) when compared with the other treatments. MR significantly increased the relative abundance of Rhizobium and Bacillus but antagonized the other putative indigenous PAH-degrading bacteria, which were enriched by PR. PR significantly reduced soil nutrients, such as NO3- and NH4+, and available potassium (AK), thereby changing the microbial community composition as reflected by redundancy analysis, significantly reducing the soil bacterial biomass relative to that in other treatments. These disadvantages hampered phenanthrene and pyrene removal. MR provided additional nutrients, which counteracted the nutrient consumption associated with PR, thereby maintaining the microbial community diversity and bacterial biomass of PMR at a level achieved in the NA treatment. Combination remediation therefore overcame the disadvantages of using PR alone. These results indicated that inoculation with the combination of S. viminalis and C. laeve synergistically stimulated the growth of indigenous PAH-degrading microorganisms and maintained bacterial biomass, thus accelerating the dissipation of soil PAHs.


A continuous flow microfluidic calorimeter: 3-D numerical modeling with aqueous reactants.
A computational analysis of the reacting flow field, species diffusion and heat transfer processes with thermal boundary layer effects in a microchannel reactor with a coflow configuration was performed. Two parallel adjacent streams of aqueous reactants flow along a wide, shallow, enclosed channel in contact with a substrate, which is affixed to a temperature controlled plate. The Fluent computational fluid dynamics package solved the Navier-Stokes, mass transport and energy equations. The energy model, including the enthalpy of reaction as a nonuniform heat source, was validated by calculating the energy balance at several control volumes in the microchannel. Analysis reveals that the temperature is nearly uniform across the channel thickness, in the direction normal to the substrate surface; hence, measurements made by sensors at or near the surface are representative of the average temperature. Additionally, modeling the channel with a glass substrate and a silicone cover shows that heat transfer is predominantly due to the glass substrate. Finally, using the numerical results, we suggest that a microcalorimeter could be based on this configuration, and that temperature sensors such as optical nanohole array sensors could have sufficient spatial resolution to determine enthalpy of reaction.


Left fronto-temporal dynamics during agreement processing: evidence for feature-specific computations.
Grammatical agreement is a widespread language phenomenon that indicates formal syntactic relations between words; however, it also conveys basic lexical (e.g. grammatical gender) or semantic (e.g. numerosity) information about a discourse referent. In this study, we focus on the reading of Spanish noun phrases, violating either number or gender determiner-noun agreement compared to grammatical controls. Magnetoencephalographic activity time-locked to the onset of the noun in both types of violation revealed a left-lateralized brain network involving anterior temporal regions (~220 ms) and, later in time, ventro-lateral prefrontal regions (>300 ms). These activations coexist with dependency-specific effects: in an initial step (~170 ms), occipito-temporal regions are employed for fine-grained analysis of the number marking (in Spanish, presence or absence of the suffix '-s'), while anterior temporal regions show increased activation for gender mismatches compared to grammatical controls. The semantic relevance of number agreement dependencies was mainly reflected by left superior temporal increased activity around 340 ms. These findings offer a detailed perspective on the multi-level analyses involved in the initial computation of agreement dependencies, and theoretically support a derivational approach to agreement computation.


AAV-mediated conversion of human pluripotent stem cell-derived pacemaker.
Malfunction of nodal pacemaker (Pm) cardiomyocytes (CMs) due to diseases or aging leads to rhythm generation disorders, necessitating electronic Pm implantation. We functionally reprogrammed human pluripotent stem cell (hPSC) derived-ventricular (V) CMs into -PmCMs via recombinant adeno-associated virus serotype 9 (rAAV9)-mediated overexpression of engineered HCN1 channel (HCN1ΔΔΔ) whose S3-S4 linker has been strategically deleted by design to promote cardiac pacemaking. rAAV9-HCN1ΔΔΔ-reprogrammed hPSC-PmCMs converted from -VCMs showed automaticity and action potential parameters typical of native nodal PmCMs. Implantation of rAAV9-HCN1ΔΔΔ-based BPm in a preclinical porcine model of complete heart block significantly reduced the dependence on device-supported pacing and generated spontaneous heart rhythms from the BPm. Collectively, these results have further laid the groundwork on BPm for future translation.


Effect of Behavior Change Techniques Targeting Clinicians to Improve Advance Care Planning in Heart Failure: A Systematic Review and Meta-Analysis.
National and international guidelines recommend advance care planning (ACP) for patients with heart failure. But clinicians seem hesitant to engage with ACP. Our aim was to identify behavioral interventions with the greatest potential to engage clinicians with ACP in heart failure. A systematic review and meta-analysis. We searched CINAHL, Cochrane Central Register of Controlled Trials, Database of Systematic Reviews, Embase, ERIC, Ovid MEDLINE, Science Citation Index, and PsycINFO for randomized controlled trials (RCTs) from inception to August 2018. Three reviewers independently extracted data, assessed risk of bias (Cochrane risk of bias tool), the quality of evidence (Grading of Recommendation Assessment, Development, and Evaluation), and intervention synergy according to the behavior change wheel and behavior change techniques (BCTs). Odds ratios (ORs) were calculated for pooled effects. Of 14,483 articles screened, we assessed the full text of 131 studies. Thirteen RCTs including 3,709 participants met all of the inclusion criteria. The BCTs of prompts/cues (OR: 4.18; 95% confidence interval [CI]: 2.03-8.59), credible source (OR: 3.24; 95% CI: 1.44-7.28), goal setting (outcome; OR: 2.67; 95% CI: 1.56-4.57), behavioral practice/rehearsal (OR: 2.64; 95% CI: 1.50-4.67), instruction on behavior performance (OR: 2.49; 95% CI: 1.63-3.79), goal setting (behavior; OR: 2.12; 95% CI: 1.57-2.87), and information about consequences (OR: 2.06; 95% CI: 1.40-3.05) showed statistically significant effects to engage clinicians with ACP. Certain BCTs seem to improve clinicians' practice with ACP in heart failure and merit consideration for implementation into routine clinical practice.


Matrix metalloproteinases and tissue inhibitors of metalloproteinases in nasal lavage after an inhalation challenge with flour.
The existence of nasal mucosa remodeling in allergic rhinitis is controversial. Few data are available on the dynamics of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in nasal fluid after an allergen challenge. We examined whether an immediate allergic reaction that induces nasal congestion and inflammation is able to also induce changes in remodeling parameters in nasal fluid. Controlled experimental study. Ten patients with allergic occupational rhinitis due to flour underwent a control and active inhalation challenge with serial monitoring of nasal congestion and nasal symptoms with acoustic rhinometry and a visual analogue scale. Levels of remodeling markers (MMP-2, MMP-7, MMP-9, MMP-13, TIMP-1, TIMP-2) and inflammatory cells in nasal fluid were measured before the challenge and at 30 minutes, 6 hours, and 24 hours following the challenge. In contrast to the control challenge, the flour challenge induced nasal symptoms and significant decreases in nasal volume in all subjects. After the flour challenge, a significant increase in nasal levels of TIMP-2 and a nonsignificant increase in TIMP-1 levels were observed, whereas no significant changes in nasal levels of MMPs were documented. This study showed that after an inhalation challenge with an occupational allergen, the nasal mucosa displayed an imbalance in favor of TIMPs enzymes activity as compared to MMPs enzymes activity, represented in an increase in nasal levels of TIMP-2 during the course of the early reaction following the allergen challenge.


Taking or creating control: A qualitative study of uncertainty among novice nurses in ambulance care.
In emergency nursing situations, uncertainty may lead to delays, or block a decision which can have devastating consequences for a patient. The ambulance service is a complex clinical environment that often challenges the decision-making capabilities of the professionals, especially novice nurses. Novice nurses' uncertainty may also lead to unhealthy transitions and turnover. To increase the understanding of how uncertainty affects novice nurses, this study explores novice nurses' uncertainty during the first year of professional practice in the ambulance service. A qualitative descriptive design was applied using qualitative content analysis of thirteen individual face-to-face semi-structured deep interviews. From nine subcategories, three generic categories were derived: Reflections on contextual understanding, Strategies to create control, and Actions to take control. These were combined to form the main category Understanding what and dealing with how, while becoming a confident professional. Uncertainty is exacerbated by situations that demand rapid decisions or actions. This is especially true of newcomers to a profession. Preparing novices through study programs and encouraging continuous reflection in professional practice may increase resilience and tolerance of uncertainty, as well as benefiting professional development.


Doppler echocardiographic assessment of the effect of varying atrioventricular delay and pacemaker mode on left ventricular filling.
Pulsed Doppler echocardiography was used to study the timing and dynamics of left ventricular filling in 14 patients with permanent dual-chamber programmable pacemakers. Pacemakers were programmed to atrial sensed (VDD) mode and atrial-ventricular sequential paced mode at low (DVI-L) and high (DVI-H) heart rates, and pulsed Doppler recordings of transmitral flow were analyzed at atrioventricular delays of 50 to 300 msec in each mode. There was a significant decrease in the one-third filling fraction in both VDD and DVI-L modes and a significant increase in DVI-H modes with increasing atrioventricular delay. The ratio of early filling area to atrial filling area was significantly lower at longer atrioventricular delays in both VDD and DVI-L modes. The time from pacemaker spike to mitral valve closure was highly significantly correlated with atrioventricular delay in VDD, DVI-L, and DVI-H modes (r = -0.92, p = 0.0001; r = -0.90, p = 0.0001; and r = -0.85, p = 0.0001, respectively) as was the diastolic filling time to a lesser extent (r = -0.73, p = 0.0001; r = -0.69, p = 0.0001; r = -0.61, p = 0.0001, respectively). Events reflecting atrial systole occurred at a later time in the cardiac cycle in the atrial paced vs the atrial sensed mode. Thus changes in atrioventricular delay and pacemaker mode in this group of patients are a strong determinant of the timing and dynamics of left ventricular filling.


Sex differences in long-term outcomes following acute heart failure hospitalization: Findings from the Get With The Guidelines-Heart Failure registry.
Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event. Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85-0.89; pinteraction [sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5-year follow-up (aHR 1.06, 95% CI 1.04-1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07-1.14; pinteraction [sex*HF subtype] = 0.001). While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age- and sex-matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization.


The relationship of hyperuricemia and blood pressure in the Thai army population.
Previous studies have demonstrated a strong association of hypertension and renal disease with gout. Nevertheless, controversy remains concerning serum uric acid concentration as an independent factor of hypertension. To explore the relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) with serum uric acid levels. An observational study. A total of 5,564 subjects from the Armed Forces Research Institute of Medical Sciences were included in the study. ANOVA tests, Chi-square test, correlation coefficients, and multiple regression analysis were performed. Of the total subjects, 4,099 (73.7%) were male. Mean SBP and DBP were 128.73+/-17.06 and 81.62 +/- 11.58 mm Hg, respectively. The mean serum uric acid level was 6.54 +/- 1.71 mg/dL. A significant and positive correlation was found both between serum uric acid and SBP (r=0.186, P P CONCLUSIONS: In this study, we suggest that serum uric acid be used to correlate with levels of blood pressure in the general population. Further investigation is required to establish the treatment for hyperuricemia in hypertensive patients.


Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia.
The congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of genetic disorders of red cell production. They are characterized by ineffective erythropoiesis and dyserythropoiesis. Here, we present the clinical description and mutation analysis of a Japanese female with CDA type 1. She has long been diagnosed with unclassified congenital hemolytic anemia from the neonatal period. However, bone marrow morphology and genetic testing of the CDAN1 gene at the age of 12 years confirmed the afore-mentioned diagnosis. Thus, we should be aware of the possibility of CDA if the etiology of congenital anemia or jaundice cannot be clearly elucidated.


Inactivated SARS-CoV-2 vaccination does not disturb the clinical course of Graves' disease: An observational cohort study.
SARS-CoV-2 vaccination has been reported to be associated with the induction of thyroid disorders. To investigate the influence of SARS-CoV-2 vaccination on the disease course of patients who were undergoing treatment for Graves' disease (GD), a total of 651 consecutive GD patients who attended follow-up visits in Jiangyuan Hospital were enrolled in this retrospective study, including 443 inactivated SARS-CoV-2 vaccine recipients and 208 unvaccinated participants. The changes in serum levels of free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH) and TSH receptor antibody (TRAb) were analyzed. Crude and adjusted hazard ratios (HRs) were estimated using Cox regression models to investigate the risks in incident TRAb positivity and hyperthyroidism recurrence following vaccination. The median levels of TRAb and fT3 significantly decreased in both vaccinated and unvaccinated groups during the GD hyperthyroidism treatment. The fT4 levels of both groups were well within normal limits and presented downward trends simultaneously. Although the present study observed an increasing trend of TSH level during follow-up, significant difference was not seen in both vaccinated and unvaccinated groups. Except for newly diagnosed GD patients, vaccinated participants had significantly lower risks of incident TRAb positivity (adjusted HR = 0.22; 95%CI: 0.10-0.48, P < 0.001) after adjusted for sex, age, disease duration and MMI dose at baseline. Besides, vaccination was unlikely to serve as a risk factor for hyperthyroidism recurrence (adjusted HR = 1.20; 95%CI: 0.51-2.83, P = 0.678). Notably, newly diagnosed patients who received vaccination were just as likely to achieve remission of thyrotoxicosis as those not receiving the vaccination at any time. Our results concluded that inactivated SARS-CoV-2 vaccination would not disturb the treatment course among GD hyperthyroidism patients.


Preparation of monoclonal antibody and identification of two novel B cell epitopes to VP1 protein of porcine sapelovirus.
Porcine sapelovirus (PSV) is an important emerging swine pathogen that causes diarrhoea, respiratory distress, severe reproductive system and neurological disorders in pigs, posing huge threat to swine industry. However, there are no effective serological diagnostic products and the epitope characterization of PSV VP1 protein is still largely unknown. In current study, we successfully expressed recombinant His-VP1 protein by prokaryotic expression system and the recombinant VP1 protein had good immunogenicity. BALB/C mice were then selected and immunized with purified recombinant VP1 protein, and two monoclonal antibodies (Mabs) 9F10 and 15E4 against VP1 were successfully prepared by hybrioma technology. The isotype of these two Mabs were identified and showed that Mab 9F10 with the heavy chain subtype was IgG1 and the light chain subtype was kappa. Mab 15E4 was identified as IgG2 for the heavy chain subtype and Kappa for the light chain subtype. The antigen epitopes of prepared two VP1 Mabs were clearly identified. The minimal unit of B cell specific epitope recognized by Mab 15E4 was 203YDGDG207 and conserved in different strain genotypes of PSV, indicating this epitope may be a good target for serological detection of PSV. However, the epitope recognized by Mab 9F10 was 8QAIVNRT14 and varied greatly among different PSV strains. Structural modeling analysis showed that the identified two novel B cell epitopes were located on the surface of VP1. Our study provides useful tool for the establishment the serological detection methods of PSV and may support the study of VP1 protein function.


Waveguide devices with homogeneous complementary media.
We report the design of microwave waveguide devices based on complementary media. Various kinds of waveguide devices that possess nearly 100% transmission efficiency are proposed, such as waveguide bends, splitters, connectors, and shifters. Compared with previous work on waveguide devices of low reflection and minimized distortion based on transformation optics, our transform media are homogeneous metamaterials. Electromagnetic simulations by a finite-element method on detailed examples have been performed to validate the designs and these functionalities can be close to the practical.


Exploring a peer-based physical activity program in the community for adults with moderate-to-severe traumatic brain injury.
To explore the experiences of program mentors, participants, and employees involved in a peer-based physical activity (PA) program for adults with moderate-to-severe TBI, being piloted by a community fitness center, to develop the program as a measurable intervention. We adopted an exploratory case study approach through an interpretivist paradigm, which focused on discovering realities about the peer-based PA program across the study participants' views, backgrounds, and experiences. Semi-structured focus groups and individual interviews were conducted with nine adult program participants (3 peer mentors, 6 participants), and three program employees. Inductive content analysis was used to develop themes about their perceived experiences. 44 open-codes were grouped into 10 subthemes and three final themes: 1) program impacts identified the importance of the program in daily life and resulting psychological, physical, and social outcomes; 2) program characteristics highlighted program leaders, accessibility, and social inclusion; 3) program sustainability included program adherence, benefits for the center, and the program's future. Perceptions of program experiences and outcomes identified how peer-based PA for adults with moderate-to-severe TBI can lead to meaningful activities, functioning better, and buy-in from all parties. Implications for research and practice related to supporting health-related behaviors after TBI through group-based, autonomy-supporting approaches are discussed.


Steroidogenic acute regulatory protein transcription is regulated by estrogen receptor signaling in largemouth bass ovary.
Estrogenic contaminants in the environment are linked to the occurrence of reproductive abnormalities in many aquatic species, including largemouth bass (Micropterus salmoides; LMB). Previous work has shown that many different types of xenoestrogens regulate expression of the Steroidogenic Acute Regulatory protein (StAR), a cholesterol-transporting protein vital to steroid hormone biosynthesis; however, the regulatory mechanisms of StAR are incompletely characterized in fish. To learn more about endogenous expression patterns of StAR in the ovary, LMB were collected from the St. John's River (Florida, USA) over an entire breeding season to investigate StAR expression. Plasma 17β-estradiol (E2) and StAR mRNA levels were positively correlated in females, and StAR mRNA levels displayed ~ 100-fold increase between primary oocyte growth stages and final maturation. To further study the regulation of StAR, female LMB in the laboratory were fed at ≃2% of their weight on a diet laden with 17α-ethinylestradiol (EE2, 70 or 200 ng EE2 per gram feed). Diets were designed to achieve a physiologically-relevant exposure to EE2, and StAR expression was assessed in vivo. We observed a dose-dependent suppression of StAR mRNA levels, however both diets led to high, pharmacological levels in the blood and do not represent normal physiological ranges of estrogens. In the 200 ng EE2/gm feed group, ovarian StAR mRNA levels were suppressed to approximately 5% of that of the LMB control group. These investigations suggest that LMB StAR increases in expression during oocyte maturation and that it is suppressed by E2 feedback when estrogen levels are high, through the HPG axis. A 2.9 kb segment of the LMB StAR promoter was examined for putative E2 response elements using in silico software, and a putative estrogen receptor binding element (ERE/-1745) was predicted in the promoter. The functionality of the ERE was examined using MA-10 mouse Leydig cells transfected with the LMB StAR promoter. Estrogen receptor (ER) interaction with ERE/-1745 was evaluated under basal and human chorionic gonadotropin (hCG)-treated conditions in the presence and absence of E2. Chromatin immunoprecipitation (ChIP) experiments revealed that ESR1 binding to the promoter was enriched under basal conditions and E2 exposure elicited an increase in enrichment (4-fold) above that observed under basal conditions. ESR2 was not strongly enriched at the ERE/-1745 site, suggesting that StAR may be preferentially regulated by LMB estrogen receptor 1 (esr1). Taken together, these different experiments provide evidence that LMB StAR is under the control of estrogens and that ESR1 binds directly to the LMB StAR promoter in an E2-responsive manner.


Partial sequence conservation of SARS-CoV-2 NSP-2, NSP-12, and Spike in stool samples from Abadan, Iran.
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the clinical manifestations of the virus have undergone many changes. Recently, there have been many reports on gastrointestinal symptoms in COVID-19 patients. This study is aimed to perform a detailed phylogenetic study and assessment of different SNVs in the RNA genome of viruses isolated from fecal samples of patients with COVID-19 who have gastrointestinal symptoms, which can help better understand viral pathogenesis. In the present study, 20 fecal samples were collected by written consent from COVID-19 patients. According to the manufacturer's protocol, virus nucleic acid was extracted from stool samples and the SARS-CoV-2 genome presence in stool samples was confirmed by RT-PCR assay. Three viral genes, S, nsp12, and nsp2, were amplified using the reverse transcription polymerase chain reaction (RT-PCR) method and specific primers. Multiple sequencing alignment (MSA) was performed in the CLC word bench, and a phylogenetic tree was generated by MEGA X based on the neighbor-joining method. Of all cases, 11 (55%) were males. The mean age of the patients was 33.6 years. Diabetes (70%) and blood pressure (55%) were the most prevalent comorbidities. All 20 patients were positive for SARS-CoV-2 infection in respiratory samples. Molecular analysis investigation among 20 stool samples revealed that the SARS-CoV-2 genome was found among 10 stool samples; only three samples were used for sequencing. The polymorphism and phylogenetic analysis in SARS-CoV-2 showed great similarity among all of the evaluated genes with the Wuhan reference sequence and all of the current variants of concern (VOCs). The current study represents a great similarity in polymorphism and phylogenetic analysis of the SARS-CoV-2 isolates with the Wuhan reference sequence and all of the current VOC in the particular evaluated partial sequences of S, nsp12, and nsp2.


The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach.
Mitochondria are critical to multiple cellular processes, from the production of adenosine triphosphate (ATP), maintenance of calcium homeostasis, synthesis of key metabolites, and production of reactive oxygen species (ROS) to maintain necrosis, apoptosis, and autophagy. Therefore, proper clearance and regulation are essential to maintain various physiological processes carried out by the cellular mechanism, including mitophagy and autophagy, by breaking down the damaged intracellular connections under the influence of various genes and proteins and protecting against various neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), and Huntington disease (HD). In this review, we will discuss the role of autophagy, selective macroautophagy, or mitophagy, and its role in neurodegenerative diseases along with normal physiology. In addition, this review will provide a better understanding of the pathways involved in neuron autophagy and mitophagy and how mutations affect these pathways in the various genes involved in neurodegenerative diseases. Various new findings indicate that the pathways that remove dysfunctional mitochondria are impaired in these diseases, leading to the deposition of damaged mitochondria. Apart from that, we have also discussed the therapeutic strategies targeting autophagy and mitophagy in neurodegenerative diseases. The mitophagy cycle results in the degradation of damaged mitochondria and the biogenesis of new healthy mitochondria, also highlighting different stages at which a particular neurodegenerative disease could occur.


Efficacy assessment of acid mine drainage treatment with coal mining waste using Allium cepa L. as a bioindicator.
The aim of this study was to evaluate the efficacy of the treatment of acid mine drainage (AMD) with calcinated coal mining waste using Allium cepa L. as a bioindicator. The pH values and the concentrations of aluminum, iron, manganese, zinc, copper, lead and sulfate were determined before and after the treatment of the AMD with calcinated coal mining waste. Allium cepa L. was exposed to untreated and treated AMD, as well as to mineral water as a negative control (NC). At the end of the exposure period, the inhibition of root growth was measured and the mean effective concentration (EC(50)) was determined. Oxidative stress biomarkers such as lipid peroxidation (TBARS), protein carbonyls (PC), catalase activity (CAT) and reduced glutathione levels (GSH) in the fleshy leaves of the bulb, as well as the DNA damage index (ID) in meristematic cells, were evaluated. The results indicated that the AMD treatment with calcinated coal mining waste resulted in an increase in the pH and an expressive removal of aluminum, iron, manganese and zinc. A high sub-chronic toxicity was observed when Allium cepa L. was exposed to the untreated AMD. However, after the treatment no toxicity was detected. Levels of TBARS and PC, CAT activity and the DNA damage index were significantly increased (P<0.05) in Allium cepa L. exposed to untreated AMD when compared to treated AMD and also to negative controls. No significant alteration in the GSH content was observed. In conclusion, the use of calcinated coal mining waste associated with toxicological tests on Allium cepa L. represents an alternative system for the treatment and biomonitoring of these types of environmental contaminants.


Differential involvement of reactive oxygen species and myeloperoxidase in oxygen-dependent killing of urinary tract bacterial isolates by polymorphonuclear leukocytes.
We examined the involvement of reactive oxygen species (ROS) and myeloperoxidase (MPO) in bacterial killing by human polymorphonuclear leukocytes (PMN) by means of a chemiluminescence assay. Using four bacterial strains, including Pseudomonas aeruginosa strain ATCC 27853 and three other strains of P. aeruginosa that were isolated from patients with urinary tract infections, we examined whether the production of ROS and changes in MPO activity altered the numbers of bacteria in contact with PMN. For three strains (P. aeruginosa strain ATCC 27853, strain 40, and strain 64), a decrease in number of viable bacteria was observed with PMN addition over three 20-min intervals that differed significantly from observations in these strains without the addition of PMN, and residual MPO activity of these three strains correlated significantly with decreases in numbers of viable bacteria. We concluded that MPO-dependent processes are strongly favored by human PMN for the oxidative killing of bacteria.


Survival, behaviour and spatial distribution of shell morphs in a population of the snail Brephulopsis bidens (Pulmonata).
Microspatial variation of banded and unbanded shell morphs frequencies as well as number of individuals per m2, mortality, migration and burrowing into the ground were examined in a population of snail Brephulopsis bidens found in South Crimea mountains (USSR). Differential values of relative survival of morphs were determined by their thermotolerance. The relative survival of the banded morph was lower at the west sites of population area (W=0.273), and increased gradually up to 1 at the east sites. Survival of the banded morph was dependent on its burrowing activity. Differences in relative survival of morphs decreased parallel with increasing general mortality of snails.Burrowing activity and intensity of migration of the banded morph were significantly higher than that in unbanded. In experiments with artificial shaded sections, the banded morph preferred shaded sections, whereas unbanded chose illuminated sites. All these differences in behaviour probably form the main factors for microspatial variation of morph frequencies.


Importance of β2AR elevation for re-endothelialization capacity mediated by late endothelial progenitor cells in hypertensive patients.
Dysfunction of late endothelial progenitor cells (EPCs) has been suggested to be associated with hypertension. β2-Adrenergic receptor (β2AR) is a novel and key target for EPC homing. Here, we proposed that attenuated β2AR signaling contributes to EPCs dysfunction, whereas enhanced β2AR signaling restores EPCs' functions in hypertension. EPCs derived from hypertensive patients exhibited reduced cell number, impaired in vitro migratory and adhesion abilities, and impaired re-endothelialization after transplantation in nude mice with carotid artery injury. β2AR expression of EPCs from hypertensive patients was markedly downregulated, whereas the phosphorylation of the p38 mitogen-activated protein kinase (p38-MAPK) was elevated. The cleaved caspase-3 levels were elevated in EPCs. The overexpression of β2AR in EPCs from hypertensive patients inhibited p38-MAPK signaling, whereas it enhanced in vitro EPC proliferation, migration, and adhesion and in vivo re-endothelialization. The β2AR-mediated effects were attenuated by treating the EPCs with a neutralizing monoclonal antibody against β2AR, which could be partially antagonized by the p38-MAPK inhibitor SB203580. Moreover, shear stress stimulation, a classic nonpharmacological intervention, increased the phosphorylation levels of β2AR and enhanced the in vitro and in vivo functions of EPCs from hypertensive patients. Collectively, the current investigation demonstrated that impaired β2AR/p38-MAPK/caspase-3 signaling at least partially reduced the re-endothelialization capacity of EPCs from hypertensive patients. Restoration of β2AR expression and shear stress treatment could improve their endothelial repair capacity by regulating the p38-MAPK/caspase-3 signaling pathway. The clinical significance of β2AR in endothelium repair still requires further investigation.NEW & NOTEWORTHY Impaired β2-adrenergic receptor (β2AR) expression with an elevation of p38-MAPK/caspase-3 signaling at least partially contributes to the decline of re-endothelialization capacity of late endothelial progenitor cells (EPCs) from hypertensive patients. β2AR gene transfer and shear stress treatment improve the late EPC-mediated enhancement of the re-endothelialization capacity in hypertensive patients through activating β2AR/p38-MAPK/caspase-3 signaling. The present study is the first to reveal the potential molecular mechanism of the impaired endothelium-reparative capacity of late EPCs in hypertension after vascular injury and strongly suggests that β2AR is a novel and crucial therapeutic target for increasing EPC-mediated re-endothelialization capacity in hypertension.


The natural history of papillary transitional cell carcinoma of the bladder and its treatment in an unselected population on the basis of histologic grading.
Between 1950 and 1965, 365 patients were treated for transitional cancer of the bladder at our hospitals. A retrospective study was done, using clinical records and a histopathologic review to determine the long-term natural history of this population when treated conservatively. The natural history of 3 separate patient populations was discovered, based solely on the grading of the transurethrally resected fragments. Based on the grade on initial presentation these patients were divided into grades I, II and III. Of the patients 5 per cent in grade I, 16 per cent in grade II, 28 to 35 per cent in grade III not involving muscle and 83 per cent in grade III involving muscle died of bladder cancer. Ninety-seven patients (26 per cent) died of bladder cancer, 110 (31 per cent) died of other causes and 158 (43 per cent) have been alive more than 5 years (104 more than 10 years). Grade I tumors that progressed to a higher grade did so within 2 years of the initial diagnosis. Of the bladder cancer deaths 83 per cent occurred within 2 years of the initial diagnosis. Of 64 patients dying more than 5 years after presentation only 7 died of bladder cancer.


Purification and primary structure of pituitary adenylate cyclase activating polypeptide (PACAP) from the brain of an elasmobranch, stingray, Dasyatis akajei.
Pituitary adenylate cyclase activating polypeptide (PACAP) was isolated from ovine hypothalami and found to exist as two amidated forms with 38 (PACAP 38) and 27 (PACAP 27) residues. The amino acid sequences of PACAPs isolated from the vertebrates, such as a bird, a frog and teleost fish, appear to be well conserved. In the present study, we attempted to isolate PACAP from the brain of an elasmobranch fish, Dasyatis akajei (stingray), which belongs to the Chondrichthyes (cartilaginous fish), by extraction of the acetone-dried powder with acetic acid, followed by successive high-performance liquid chromatography (HPLC) on a gel-filtration, a cation-exchange and two reverse-phase columns. Purification was monitored by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) and Western blotting analysis using an anti-PACAP 27 serum. The PACAP thus obtained consisted of 44 residues. The amino acid sequence of the comparable portion of its N-terminal 38 residues showed 92%, 89%, 89%, and 82% identity with those of mammalian, chicken, frog and teleost PACAPs with 38 residues, respectively. The extra six C-terminal residues of the stingray resembled those of tetrapod and teleost PACAP precursors which were deduced from the respective cDNAs. These results indicate that PACAP, which has an amino acid sequence showing high similarity with those of tetrapod and teleost PACAPs, is present in the elasmobranch brain.


Predicting vaccine effectiveness against invasive pneumococcal disease in children using immunogenicity data.
The strength of the immune response, as measured by antibody concentrations, varies between pneumococcal conjugate vaccines (PCVs). Linking immunogenicity and effectiveness is necessary to assess whether changes in immune response from currently recommended PCVs to next-generation vaccines could impact effectiveness. Simulated reverse cumulative distribution curves were generated using published serotype-specific IgG concentrations with placebo or PCV7. This was combined with the published estimates of serotype-specific vaccine effectiveness of PCV7 against invasive pneumococcal disease to estimate the protective antibody concentration for each serotype in PCV7. Then, based on the published serotype-specific IgG concentrations in PCV13 recipients, reverse cumulative distribution curves were generated for the serotypes shared between PCV13 and PCV7. These estimated protective antibody concentration values were then used to predict the vaccine effectiveness of PCV13. The results were compared to published aggregate values for vaccine effectiveness. The aggregate median predicted vaccine effectiveness values were similar to previously reported observed values for the United Kingdom (93% versus 90%), Australia (71% versus 70%), and Germany (91% versus 90%). These results demonstrate that IgG concentrations of next-generation PCVs can be used to generate reliable estimates of vaccine effectiveness for serotypes shared with established PCVs.


Explaining Discrepancies Between Total and Segmental DXA and BIA Body Composition Estimates Using Bayesian Regression.
Few investigations have sought to explain discrepancies between dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) body composition estimates. The purpose of this analysis was to explore physiological and anthropometric predictors of discrepancies between DXA and BIA total and segmental body composition estimates. Assessments via DXA (GE Lunar Prodigy) and single-frequency BIA (RJL Systems Quantum V) were performed in 179 adults (103 F, 76 M, age: 33.6 ± 15.3 yr; BMI: 24.9 ± 4.3 kg/m2). Potential predictor variables for differences between DXA and BIA total and segmental fat mass (FM) and lean soft tissue (LST) estimates were obtained from demographics and laboratory techniques, including DXA, BIA, bioimpedance spectroscopy, air displacement plethysmography, and 3-dimensional optical scanning. To determine meaningful predictors, Bayesian robust regression models were fit using a t-distribution and regularized hierarchical shrinkage "horseshoe" prior. Standardized model coefficients (β) were generated, and leave-one-out cross validation was used to assess model predictive performance. LST hydration (i.e., total body water:LST) was a predictor of discrepancies in all FM and LST variables (|β|: 0.20-0.82). Additionally, extracellular fluid percentage was a predictor for nearly all outcomes (|β|: 0.19-0.40). Height influenced the agreement between whole-body estimates (|β|: 0.74-0.77), while the mass, length, and composition of body segments were predictors for segmental LST estimates (|β|: 0.23-3.04). Predictors of segmental FM errors were less consistent. Select sex-, race-, or age-based differences between methods were observed. The accuracy of whole-body models was superior to segmental models (leave-one-out cross-validation-adjusted R2 of 0.83-0.85 for FMTOTAL and LSTTOTAL vs. 0.20-0.76 for segmental estimates). For segmental models, predictive performance decreased in the order of: appendicular lean soft tissue, LSTLEGS, LSTTRUNK and FMLEGS, FMARMS, FMTRUNK, and LSTARMS. These findings indicate the importance of LST hydration, extracellular fluid content, and height for explaining discrepancies between DXA and BIA body composition estimates. These general findings and quantitative interpretation based on the presented data allow for a better understanding of sources of error between 2 popular segmental body composition techniques and facilitate interpretation of estimates from these technologies.


[Radiotherapy of exudative senile macular degeneration. A prospective controlled study].
Despite the successful therapy of subretinal neovascular membranes by laserphotocoagulation there are many problems to be overcome. In the case of subfoveolar neovascularization, photocoagulation leads to a sudden decrease in visual acuity. Recently radiotherapy is considered as an alternative. Complications and effectivity were evaluated in this prospective and randomized trial. The initial results are presented. There are 76 patients (51 women, 25 men, average age 77.7 +/- 8.6 years) included in the prospective randomized study. All of them show subfoveolar neovascular membranes in FLA and a decrease in visual acuity between 0.05 and 0.5. They were randomly assigned to either the radiotherapy or the control group. Radiotherapy was done within 6 days by 6 x 2 Gy (6 MV photons). The follow-up was at 4 weeks, after 3 months, after 6 months and then every 6 months after the end of radiotherapy. On average the follow-up is at 15.1 months. Concerning age and visual acuity before therapy, the control group and the radiotherapy group were not significantly different. At 4 weeks after radiotherapy, visual acuity was 0.13 +/- 0.46 (LogMAR). After 12 months, visual acuity at a distance was 0.11 +/- 0.30 in the therapy group and 0.09 +/- 0.13 (P = 0.838) in the control group. Patients with a preoperative visual acuity better than 0.2 improved more after radiotherapy. Metamorphopsy improved in 75% of the therapy group. The following complications could be observed: In the control group 3 patients suffered subretinal bleeding, in the radiotherapy group 3 patients, respectively. At present, the follow-up is too short to recommend radiotherapy as a standard procedure in the case of subfoveolar neovascularization. The results in patients with a better preoperative visual acuity encourage us to continue this study.


Pseudarthrosis presenting as a late complication of meningococcal septicaemia and disseminated intravascular coagulation.
Late skeletal complications of meningococcal septicaemia and disseminated intravascular coagulation are well recognised in children and are largely centred on the growing epimetaphyseal region of long bones. In this article we describe a case of pseudarthrosis of the mid-ulna presenting 18 months following a devastating episode of meningococcal septicaemia in a 3-year-old boy. Radiographs and MRI demonstrated the ulna abnormality. We briefly review the late skeletal complications of the disease and other causes of pseudarthrosis.


Meeting the wellness needs of emergency department clinicians: A scoping review of interventions.
Emergency Departments are stressful work environments that can adversely affect clinicians' wellbeing. The purpose of this scoping review was to report wellness interventions evaluated in Emergency Departments and clinicians' experience of these interventions. Five data bases were searched using a modification of Arksey and O'Malley's framework. PRISMA guidelines for scoping reviews were employed to report the findings. The review included only peer-reviewed articles and had no date or language restrictions applied. Nine studies met inclusion criteria. Interventions included tactile massage, hypnosis, mindfulness, happiness practice, resiliency, meditation, and video-based debriefing. Three key themes emerged following data extraction and analysis: The value of mindfulness; One size doesn't fit all; and Enablers and Barriers. Successful wellness programs must be relevant to Emergency Departments and staff need to be involved in the development and application of these programs to achieve maximum benefit. For long term benefits and sustainability, the strategies must be supported by senior hospital management.


Determining key clinical predictors for chronic ankle instability and return to sports with cost of illness analysis: protocol of a prospective cohort study.
Ankle sprains are common in sports and the general population. Although considered innocuous, a large proportion has residual complaints such as recurrent ankle sprains and develop chronic ankle instability. Although some predicting factors are identified, there is no unequivocality regarding the development of chronic ankle instability, nor about the optimal rehabilitation for an acute ankle sprain. Alongside the biomechanical impairments, ankle sprains are a burden on society due to substantial economic costs. Therefore, we aim to identify key clinical predictors of chronic ankle instability or recovery after acute lateral ankle sprain. Additionally, we aim to determine cost-of-illness of patients who developed chronic ankle instability. This prospective cohort study (Clinicaltrials.gov: NCT05637008 - pre-results) aims to recruit adult (18-55 years) patients with an acute lateral ankle sprain who are active in sports. Clinical assessments and patient-reported outcome measures will be used to collect data at 7-14 days, 6 weeks, 12 weeks and 12 months after enrolment in the study. The primary outcome will be chronic ankle instability at 12-month follow-up. Salient outcomes will be analysed by logistic regression to determine association with the development of chronic ankle instability. Participants will fill in a cost diary containing direct and indirect costs related to their injury. The ethical committee of the Antwerp University Hospital (B3002022000138) has given approval of the protocol and consent forms on 10 October 2022. We perform this study according to the Helsinki Declaration. We will present results at conferences or webinars and publish in peer-reviewed articles.NCT05637008.


Antigenic and biological characterization of influenza virus neuraminidase (N2) with monoclonal antibodies.
Competitive radioimmunoassays using monoclonal antibodies established that the neuraminidase of A/RI/5+/57 (H2N2) influenza can be divided into four overlapping antigenic regions. Antigenic regions 1 and 4 are sufficiently far apart so that there was no competition between antibodies for these sites. Region 1 is conserved in neuraminidases from N2 viruses over a 10-year period, while the other regions changed antigenically during this time. The antibodies belonging to groups 2 and 3 completely inhibited catalytic activity on fetuin substrate, whereas antibodies in groups 1 and 4 inhibited weakly or not at all. Antigenic region 2 can be further divided into four overlapping areas (2a, 2b, 2c, and 2d) based on the reactivity patterns of monoclonal antibodies with antigenic variants, chemically modified neuraminidase, and the ability of the antibodies to inhibit enzyme activity of different molecular weight substrates. Previous studies [R. G. Webster, V. S. Hinshaw , and W. G. Laver (1982) Virology 117, 93-104; D. C. Jackson and R. G. Webster (1982) Virology 123, 69-77] characterized only region 2 of the neuraminidase molecule. Each of the monoclonal antibodies inhibited virus release from MDCK cells when incorporated in an agar overlay, and some antibodies in each group inhibited hemagglutination by intact virus, but only antibodies in group 2 neutralized virus in embryonated eggs and permitted selection of antigenic variants. The results indicate that antibodies to some antigenic sites on the neuraminidase may inhibit virus release more efficiently than others, depending on their relation to the enzyme active center. None of the monoclonal antibodies inhibited the hemolytic activity of viruses possessing N2. Based on antigenic mapping and biological properties of the monoclonal antibodies, a topographical map of the neuraminidase can be constructed. It is proposed that antigenic regions 1 and 4 are spacially separated and, based on their failure to inhibit biological activity, may be located on the bottom surface of the molecule; region 3 may be on the top surface of the molecule but at some distance from the catalytic center. Antigenic region 2 probably encompasses most of the top surface of the molecule; region 2d being closest to the enzyme center, with subregions 2a and 2b adjacent to it on the top surface. Chemical treatment of the neuraminidase with trinitrobenzenesulfonic acid (TNBS) causes modification of the 2b region, confirming the antigenic mapping results.


Clonal evolution in hematological malignancies and therapeutic implications.
The ability of cancer to evolve and adapt is a principal challenge to therapy in general and to the paradigm of targeted therapy in particular. This ability is fueled by the co-existence of multiple, genetically heterogeneous subpopulations within the cancer cell population. Increasing evidence has supported the idea that these subpopulations are selected in a Darwinian fashion, by which the genetic landscape of the tumor is continuously reshaped. Massively parallel sequencing has enabled a recent surge in our ability to study this process, adding to previous efforts using cytogenetic methods and targeted sequencing. Altogether, these studies reveal the complex evolutionary trajectories occurring across individual hematological malignancies. They also suggest that while clonal evolution may contribute to resistance to therapy, treatment may also hasten the evolutionary process. New insights into this process challenge us to understand the impact of treatment on clonal evolution and inspire the development of novel prognostic and therapeutic strategies.


Mixed-effects variance components models for biometric family analyses.
Recent substantive research on biometric analyses of twin and family data has used both a biometric path analysis model (PAM) and a biometric variance components model (VCM). Methodological research on these same topics have suggested benefits of using linear structural equation model algorithms (SEMA) as well as mixed effect multilevel algorithms (MEMA). To better understand the potential similarities and differences among these approaches we first highlight the algebraic equivalence between the standard biometric PAM and the corresponding biometric VCM models for family data. Second, we demonstrate how several SEMA programs based on either the PAM or VCM approach produce equivalent estimates for all phenotypic and biometric parameters. Third, we show how the biometric VCM approach (but not the PAM approach) can be easily programmed using current MEMA programs (e.g., SAS PROC MIXED). We then expand the scope of these different approaches to include measured covariates, observed variable interactions and multiple relatives within each family. MEMA software is compared to SEMA software for programming complex models, including the flexibility of data input, treatment of missing data, inclusion of covariates, and ease of accommodating varying numbers of observations (per family or individual).


Isoelectric focusing with immobilized pH gradients for the analysis of transferrin (Tf) subtypes and variants.
The human serum transferrin (Tf) system was analyzed by isoelectric focusing (IEF) with immobilized pH gradients. For the demonstration of the genetic variability the Fe1-Tf region was chosen. The pH range suitable for analysis of the Tf system was pH 5.20 to pH 5.75. The phenotypes of the common six TfC subtypes are described. No further heterogeneity among TfC1, TfC2, and TfC3 was noted. Aslo presented are the phenotypes of the TfC6 subtype, and of three different TfB and three different TfD variants. IEF with immobilized pH gradients appears to be a suitable method for the analysis of the inherited transferrin polymorphism.


Catalytic efficiencies of directly evolved phosphotriesterase variants with structurally different organophosphorus compounds in vitro.
The nearly 200,000 fatalities following exposure to organophosphorus (OP) pesticides each year and the omnipresent danger of a terroristic attack with OP nerve agents emphasize the demand for the development of effective OP antidotes. Standard treatments for intoxicated patients with a combination of atropine and an oxime are limited in their efficacy. Thus, research focuses on developing catalytic bioscavengers as an alternative approach using OP-hydrolyzing enzymes such as Brevundimonas diminuta phosphotriesterase (PTE). Recently, a PTE mutant dubbed C23 was engineered, exhibiting reversed stereoselectivity and high catalytic efficiency (k cat/K M) for the hydrolysis of the toxic enantiomers of VX, CVX, and VR. Additionally, C23's ability to prevent systemic toxicity of VX using a low protein dose has been shown in vivo. In this study, the catalytic efficiencies of V-agent hydrolysis by two newly selected PTE variants were determined. Moreover, in order to establish trends in sequence-activity relationships along the pathway of PTE's laboratory evolution, we examined k cat/K M values of several variants with a number of V-type and G-type nerve agents as well as with different OP pesticides. Although none of the new PTE variants exhibited k cat/K M values >107 M-1 min-1 with V-type nerve agents, which is required for effective prophylaxis, they were improved with VR relative to previously evolved variants. The new variants detoxify a broad spectrum of OPs and provide insight into OP hydrolysis and sequence-activity relationships.


In vitro fertilization and embryo transfer as a treatment for male factor infertility.
In vitro fertilization was attempted in 25 consecutive cycles as a treatment for male factor infertility. These cycles were compared with 25 control cycles in which a male factor was not present. The fertilization rates for mature oocytes in male factor cases and controls were 17% and 70%, respectively (P less than 0.001). For immature oocytes, the fertilization rates for study patients and controls, respectively, were 16% and 57% (P less than 0.001). Embryos were available for transfer in 36% of study cycles and in 88% of control cycles (P less than 0.01). The pregnancy per transfer rate for study cycles was 33% and for control cycles was 32%. The hamster ova penetration assay was 100% specific and 50% sensitive in predicting fertilization in vitro among male factor patients.


Destination therapy: does progress depend on left ventricular assist device development?
The role of therapy using mechanical circulatory support devices has evolved rapidly over the last two decades. New developments in the field achieved smaller adverse events, but, currently, only minor improvements in survival were observed in published observational data. The authors discuss the development of mechanical circulatory support devices as a "destination therapy" option for patients who have end-stage heart failure and are ineligible for heart transplantation as it relates to left ventricular assist device development.


[Application of liquid biopsy in clinical practice: the importance of a scientific network for effective use of the biomolecular markers in NSCLC patient..]
The therapeutic approach to the patient with non-small cell lung cancer (NSCLC) has undergone, in the last decade, a profound revolution following the marketing of molecularly targeted drugs. The launch of a vast research activity with the use of next generation sequencing (NGS) applied to liquid biopsy should be underlined. This last methodology, which allows to identify the correct biomolecular structure of the neoplastic population, has achieved significant progress in the effective implementation of personalized medicine. Nevertheless, the liquid biopsy represents a useful diagnostic strategy in those patients in whom a rebiopsia is difficult for technical reasons or for the patient's health conditions. The liquid biopsy represents a substantial cultural revolution opening a scenario in the identification of molecular drivers in the treatment of lung neoplasms.


DNA binding and mutagenicity of ethyl methanesulfonate in wild-type and uvrB cells of Salmonella typhimurium.
The extent of DNA ethylation and the influence of excision repair on ethyl methanesulfonate (EMS) mutagenesis of Salmonella typhimurium were examined. The relationship between the dose to DNA and the exposure concentration of EMS was linear. EMS induction of his+ revertants followed exponential kinetics and did not parallel the increase in total DNA ethylation. Mutant induction was influenced by the cells' nucleotide excision repair ability. Although mutagenized to a larger extent than the wild-type (uvr+) strain at high doses, the uvrB strain was more resistant to the mutagenic effect of low doses of EMS.


Association Between Life's Simple 7 and Biomarkers of Cardiovascular Disease: Aldosterone, Interleukin-6, C-Reactive Protein.
Background To promote ideal cardiovascular health, the American Heart Association recommends adhering to Life's Simple 7 (LS7)-achieving healthy targets for body mass index, physical activity, dietary intake, blood pressure, fasting plasma glucose, and cholesterol, along with smoking abstinence. Poorer achievement of LS7 (lower score) has been associated with the development of hypertension and cardiovascular disease. However, less is known about the associations between LS7 and specific biomarkers linked to cardiovascular health: aldosterone, CRP (C-reactive protein), and IL-6 (interleukin-6). Methods and Results We analyzed 379 individuals (age 18-66 years) from the HyperPATH (International Hypertensive Pathotype), who were maintained on ≥200 mEq of sodium daily for 1 week. We calculated a 14-point summative LS7 score according to participants' baseline data. Based on the range of LS7 score in this population (3-14), we classified participants as "inadequate" (3-6), "average" (7-10), and "optimal" (11-14). Regression analyses found that a higher LS7 score group was associated with lower levels of serum and urinary aldosterone (Ptrend<0.001 and Ptrend=0.001, respectively), lower plasma renin activity (Ptrend<0.001), and a blunted increase in serum aldosterone with angiotensin II infusion (Ptrend=0.023). Being in the "optimal" LS7 score group was associated with lower serum CRP (Ptrend=0.001) and IL-6 (Ptrend=0.001). Conclusions A higher LS7 score was associated with a lower activity of the renin-angiotensin-aldosterone system and lower levels of the inflammatory markers CRP and IL-6. These findings offer a possible link between ideal cardiovascular health targets and biomarkers known to play a central role in the development of cardiovascular disease.


Heart valve prostheses: who protects our patients, and from what?
Phenomenal advances in the development of cardiac valve prostheses have taken place in less than two decades. However, the currently prevailing atmosphere of consumer protectionism in existence 20 years ago probably would have made such developments impossible. Recent passage of the Medical Device Amendments of 1976 (P.L. 94-295) will not only make future development extremely difficult, but also may force the field of cardiac valve replacement back into the era of the 1950s. Regulations implementing this legislation may be even more disastrous. It is time for someone to protect patients from their so-called protectors.


Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment.
More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody-drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.


Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway.
Estrogen regulates a plethora of biological processes, under physiological and pathological conditions, by affecting key pathways involved in the regulation of cell proliferation, fate, survival and metabolism. The Notch receptors are mediators of communication between adjacent cells and are key determinants of cell fate during development and in postnatal life. Crosstalk between estrogen and the Notch pathway intervenes in many processes underlying the development and maintenance of the cardiovascular system. The identification of molecular mechanisms underlying the interaction between these types of endocrine and juxtacrine signaling are leading to a deeper understanding of physiological conditions regulated by these steroid hormones and, potentially, to novel therapeutic approaches to prevent pathologies linked to reduced levels of estrogen, such as coronary heart disease, and cardiotoxicity caused by hormone therapy for estrogen-receptor-positive breast cancer.


Thoracoscopic diaphragmatic hernia repair in a warmblood mare.
To describe successful repair of a diaphragmatic hernia in a standing sedated horse using a minimally invasive thoracoscopic technique. Clinical report. Warmblood mare with a diaphragmatic hernia. An 18-year-old Warmblood mare with severe colic was referred for surgical treatment of small intestinal strangulation in a diaphragmatic defect. Twelve days after initial conventional colic surgery, left-sided laparoscopy in the standing sedated mare for diaphragmatic herniorrhaphy failed because the spleen obscured the hernia. One week later, a left-sided thoracoscopy was performed in the standing sedated horse and the hernia repaired by an intrathoracic suture technique. No long-term complications occurred (up to 4 years) and the mare returned to her previous athletic activity, followed by use as a broodmare. To avoid the high risks associated with general anesthesia, and to reduce surgical trauma and postoperative recovery, central diaphragmatic hernias are amenable to repair using a minimally invasive thoracoscopic technique in the standing sedated horse.


Mental health problems and marital disruption: is it the combination of husbands and wives' mental health problems that predicts later divorce?
Divorce has been established as an adverse social consequence of mental illness. There is, however, little research that has considered how the mental health of both spouses may interact to predict relationship disruption. The aim of the current study was to use data from a large population-based survey to examine whether the combination of spouses' mental health problems predicts subsequent marital dissolution. Prospective analysis of data from a longitudinal national household survey. 3,230 couples were tracked over 36 months, with logistic regression models used to determine whether the mental health problems of both spouses at wave 1 (determined by the SF36 mental health subscale) predicted subsequent relationship dissolution. Couples in which either men or women reported mental health problems had higher rates of marital disruption than couples in which neither spouse experienced mental health problems. For couples in which both spouses reported mental health problems, rates of marital disruption reflected the additive combination of each spouse's separate risk. Importantly, these couples showed no evidence of a multiplicative effect of mental illness on rates of subsequent divorce or separation. The results do not support the notion that a combination of mental health problems in both spouses uniquely predicts marital dissolution. Rather, there is an additive effect of individual mental health problems on the risk of dissolution.


Cell cycle regulation in NAFLD: when imbalanced metabolism limits cell division.
Cell division is essential for organismal growth and tissue homeostasis. It is exceptionally significant in tissues chronically exposed to intrinsic and external damage, like the liver. After decades of studying the regulation of cell cycle by extracellular signals, there are still gaps in our knowledge on how these two interact with metabolic pathways in vivo. Studying the cross-talk of these pathways has direct clinical implications as defects in cell division, signaling pathways, and metabolic homeostasis are frequently observed in liver diseases. In this review, we will focus on recent reports which describe various functions of cell cycle regulators in hepatic homeostasis. We will describe the interplay between the cell cycle and metabolism during liver regeneration after acute and chronic damage. We will focus our attention on non-alcoholic fatty liver disease, especially non-alcoholic steatohepatitis. The global incidence of non-alcoholic fatty liver disease is increasing exponentially. Therefore, understanding the interplay between cell cycle regulators and metabolism may lead to the discovery of novel therapeutic targets amenable to intervention.


Evaluation of immune response to Hepatitis B vaccine in health care workers at a tertiary care hospital in Pakistan: an observational prospective study.
Seroconversion rates reported after Hepatitis B virus (HBV) vaccination globally ranges from 85-90%. Health care workers (HCWs) are at high risk of acquiring HBV and non responders' rates after HBV vaccination were not reported previously in Pakistani HCWs. Therefore we evaluated immune response to HBV vaccine in HCWs at a tertiary care hospital in Karachi, Pakistan. Descriptive observational study conducted at Aga Khan University from April 2003 to July 2004. Newly HBV vaccinated HCWs were evaluated for immune response by measuring serum Hepatitis B surface antibody (HBsAb) levels, 6 weeks post vaccination. Initially 666 employees were included in the study. 14 participants were excluded due to incomplete records. 271 (41%) participants were females and 381(59%) were males. Majority of the participants were young (<25-39 years old), regardless of gender. Out of 652 HCWs, 90 (14%) remained seronegative after six weeks of post vaccination. The percentage of non responders increased gradually from 9% in participants of <25, 13% in 25-34, 26% in 35-49, and 63% in >50 years of age. Male non responders were more frequent (18%) than female (8%). Seroconversion rate after HBV vaccination in Pakistani HCWs was similar to that reported in western and neighboring population. HCWs with reduced immune response to HBV vaccine in a high disease prevalent population are at great risk. Therefore, it is crucial to check post vaccination HBsAb in all HCWs. This strategy will ensure safety at work by reducing nosocomial transmission and will have a cost effective impact at an individual as well as at national level, which is very much desired in a resource limited country.


Short-term effects of naloxone on hemodynamics and baroreflex function in conscious dogs with pacing-induced congestive heart failure.
The purpose of this study was to determine the effects of naloxone on systemic hemodynamics and reflex function in dogs with congestive heart failure induced by rapid pacing. We have shown previously that naloxone, an opiate receptor antagonist, improves cardiac output, aortic blood pressure, systolic performance and the baroreflex function in conscious dogs with chronic right-sided congestive heart failure. However, whether endogenous opioids also play a role n mediating the reduction of myocardial and baroreflex function in animals with left heart failure remains controversial. We administered naloxone (1 mg/kg body weight) and normal saline solution to 15 dogs with pacing-induced congestive heart failure (225 beats/min for 8 weeks) and 11 control dogs. In addition to systemic hemodynamic measurements, the slope of pressure-area relation obtained from echocardiography with intravenous bolus injection of phenylephrine was taken as a load-independent index of myocardial contractility. Baroreflex function was estimated by the slope of the regression line relating systolic aortic pressure and RR interval. Plasma beta-endorphin levels were elevated in dogs with congestive heart failure. Naloxone administration increased heart rate, mean aortic pressure, first derivative of left ventricular pressure, cardiac output and myocardial contractility in pacing-induced congestive heart failure. These changes correlated significantly with basal plasma beta-endorphin levels and were accompanied by increases in plasma beta-endorphin and catecholamines after naloxone administration. However, unlike the hemodynamic and cardiac effects of naloxone, baroreflex function did not change after naloxone in dogs with congestive heart failure. The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in left-sided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.


Mapping the patient safety footprint: The RADICAL framework.
Numerous interventions to promote patient safety have been proposed. For these to produce demonstrable and positive change, appropriate metrics should be available. Measurements must, however, be comprehensive enough to cover all domains of patient safety. In this paper, I introduce the term 'patient safety footprint' to encapsulate the totality of attributes and domains that define or describe the degree of protection accorded to patient safety by a healthcare provider (individual or organisation). A framework, identified by the acronym RADICAL, is presented. It specifies and captures all domains required for mapping the patient safety footprint: (R)aise (A)wareness, (D)esign for safety, (I)nvolve users, (C)ollect and (A)nalyse patient safety data, and (L)earn from patient safety incidents. In addition to providing a schema, the RADICAL framework describes a worldview of the concept of patient safety. Examples are given of its application in obstetrics and gynaecology.


Prognostic value of serum alkaline phosphatase in the survival of prostate cancer: evidence from a meta-analysis.
Many studies have evaluated the relationship between alkaline phosphatase (ALP) and the prognosis for prostate cancer (PCa). But they have not reached a widespread consensus yet. Therefore, we completed a meta-analysis to ascertain the significance of ALP and the prognosis for PCa. A literature search was performed in the PubMed, Embase, and Web of Science databases. HRs concerning overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CSS) were extracted to evaluate the impacts of ALP on the prognosis for PCa. Subgroup analyses were conducted on different study types, regions, sample sizes, and cutoff values. Sensitivity analysis was performed by removing one study in sequence. A total of 63 studies from 54 articles with 16,135 patients were included in this meta-analysis. The pooled results indicated that high baseline ALP was associated with obviously poor OS (HR=1.74, 95% CI: 1.47-2.06) and PFS (HR=1.60, 95% CI: 1.13-2.26) in patients with PCa. The pooled HR for bone-specific ALP and OS was 1.76 (95% CI: 1.45-2.15). However, no association between ALP and CSS (HR=1.002, 95% CI: 0.998-1.005) was found for PCa. The results of subgroup analyses were all in accordance with the main findings. Sensitivity analysis suggested that no single study could affect the stability of the results. High serum ALP is significantly associated with poor OS and PFS except for CSS in PCa. ALP is an efficient and convenient biomarker for PCa prognosis.


Estimation of secular trends in adult height, and childhood socioeconomic circumstances in three Eastern European populations.
The objective of these analyses was to estimate the strength and direction of secular trends in adult height and childhood socioeconomic circumstances in eight towns in three Eastern European countries in the mid-20th century, and to assess the extent to which childhood conditions might explain the height differences. We used cross-sectional data from the baseline survey of the Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study, conducted in 2002-2005. The study examined 24,012 men and women born between 1933 and 1957, randomly selected from the general populations of Novosibirsk (Russia), Krakow (Poland) and six towns of the Czech Republic. To allow for age-related height loss we estimated maximum attained height. Parental education and household item ownership at age 10 were used as markers of childhood socioeconomic conditions. In all 5-year birth cohorts, Novosibirsk men and women were shortest. There were positive and statistically significant secular trends in childhood conditions and in maximum adult height. Adjustment for childhood conditions explained about one third of the trend in height. There appeared to be a small reduction in height of persons born during the Second World War which was, however, only significant in Novosibirsk. These results suggest that secular trends in height mirror, but are not wholly explained by, trends in socioeconomic circumstances in early life.


Comparing steady counterflow separation with differential chromatography.
Separation of closely related solutes by steady solid-fluid counterflow is compared with differential separation in a fixed chromatographic bed. Analogous expressions for exit concentration and mean residence time in the two systems are presented. A counterpart to chromatographic resolution is derived for binary steady counterflow separations. Estimated counterflow savings in product-concentration dilution, solvent volume requirement and solid-phase volume requirement obtained with these expressions relative to comparable chromatographic operations are compared with experimental results from adsorptive, simulated moving beds. Analysis of a size-exclusion protein separation suggests counterflow substantially decreases solvent and resin usage relative to conventional, batch operation.


Delirium prevalence point: an observational monocentric study in a tertiary university hospital.
Delirium is a serious and common condition that needs an upgrade of the scientific and clinical attention. To assess the delirium prevalence in an Italian university hospital. The monocentric 1-day observational study cohort has been conducted on March 15, 2018; the population was composed of adult hospitalized patients. All the eligible patients have been evaluated for the presence of delirium with the 4AT. We enrolled 596 patients. Twenty-nine Acute and 3 Rehabilitation Units were involved in the study. The median age of the sample was 60 (IQR 48-74) and 52% (n = 313) were male. Patients from medical units were 42% (n = 252), from surgery units 41% (n = 249), and from rehabilitation units 15% (n = 95). Results of 4AT showed that 5.4% (n = 32) had delirium (4AT = 4), 12% (n = 73) had cognitive impairment (4AT = 1-3), and 82% (n = 491) had no delirium or cognitive impairment (4AT = 0). We found association between delirium and age, BMI, mortality at 30 days, and hospital mortality. Delirium was related with Barthel Index, dementia, and anticholinesterase inhibitors. About devices in use, we observed a correlation of delirium with central venous catheter, feeding tube, and urinary catheter. Physical restraints were also correlated to delirium. We confirmed the presence of delirium across the hospital units, more in medical than in surgical ones. We found associations of delirium with conditions that limit movement, such as dementia, physical restraints, or devices. The development of delirium initiates a cascade of events culminating in the loss of independence and increased morbidity.


The larval head of Exechia (Mycetophilidae) and Bibio (Bibionidae) (Diptera).
Exechia and Bibio have retained several plesiomorphic groundplan features of Diptera and Bibionomorpha, including a fully exposed and sclerotized head capsule, the transverse undivided labrum, the absence of movable premandibles, and undivided mandibles without combs. The fusion of the hypostomal bridge with the head capsule and largely reduced antennae are derived features shared by both taxa. The absence of teeth at the anterior hypostomal margin is a potential autapomorphy of Bibionomorpha. A basal position of Anisopodidae is suggested by a number of plesiomorphies retained in this family. Apomorphies of Bibionomorpha excluding Anisopodidae are the reduction of tentorial elements, the partial fusion of the labrum and clypeus, one-segmented antennae, the absence of a separate submental sclerite, the loss of the labial palpus, and the reduction of the pharyngeal filter apparatus. Head structures of Bibio are largely unmodified. The subprognathous orientation is one of few autapomorphic features. In contrast, the mouthparts of Exechia are highly modified in correlation with the specialized food uptake. The rasping counterrotating movements of maxillae and mandibles with teeth oriented in opposite directions are carried out by strongly developed extensors and flexors of the paired mouthparts. The modified labium mechanically supports the "drill head" formed by the mandibles und maxillae. The necessary stability of the head capsule is provided by the hypostomal bridge which also compensates the far-reaching reduction of the tentorium.


Obstructive sleep apnea syndrome. A review.
Obstructive sleep apnea syndrome (OSAS) is a complex disorder characterized by a sleep-related collapse of the upper airway. The most likely candidate for the common pathway linking various abnormalities casually associated with OSAS (such as adenotonsillar hypertrophy, obesity, retro- or micrognathia, acromegaly, or more subtle structural anomalies) is an abnormally small upper airway lumen. Symptoms of OSAS that appear during sleep include snoring, abnormal motor activity, disturbed nocturnal sleep, a sensation of choking, heartburn, nocturia, nocturnal enuresis, and heavy sweating. Daytime waking symptoms are dominated by often profound sleepiness, which may secondarily be associated with automatic behavior, retrograde amnesia, hypnagogic hallucinations, personality changes, sexual difficulties, and headaches. Careful evaluation, both sleeping and waking, are essential to select appropriate treatment. Treatments include nasal continuous positive airway pressure, tracheostomy, weight loss, uvulopalatopharyngoplasty, mandibular advancement, and so forth.


Readability of educational materials for endodontic patients.
Vocabulary and writing style have been shown to affect the readability of patient-education materials. Readability is generally defined as the ease of understanding or comprehension because of the style of writing. Microsoft Word software (Microsoft Corporation, Bellevue, WA) can quantify and report readability statistics, providing both the Flesch Reading Ease score and the Flesch-Kincaid Grade Level score of selected documents. This study evaluated the readability of 22 endodontic patient education web sites and 15 endodontic patient education brochures. The web sites and brochures were arbitrarily selected based on availability, reputation of the source, and relevance to endodontic patients. The Flesch Reading Ease score and the Flesch-Kincaid Grade Level score were determined for the 37 selected materials. The Flesch Reading Ease scores varied between 44.4 and 76.6, and the Flesch-Kincaid Grade Level scores ranged between 4.5 and 10.6. These findings remind practitioners that some patients may have difficulty reading some endodontic educational materials.


Utilizing novel recurrent laryngeal motor nerve conduction studies to characterize the aging larynx: A pilot study.
Age-related changes to the larynx are associated with dysphonia and contribute to reduced quality of life. This study utilizes recurrent laryngeal motor nerve conduction studies (rlMNCS) to determine if neurophysiologic changes occur in the aging larynx using an aging rat model. Animal study. In vivo rlMNCS were performed in 10 young hemi-larynges (3-4 months) and 10 aged hemi-larynges (18-19 months) rats (Fischer 344 × Brown Norway F344BN). Recording electrodes were placed into the thyroarytenoid (TA) muscle through direct laryngoscopy. Recurrent laryngeal nerves (RLNs) were directly stimulated with bipolar electrodes. Compound motor action potentials (CMAPs) were obtained. RLN cross-sections were stained with toluidine blue. Axon count, myelination, and g-ratio were quantified utilizing AxonDeepSeg analysis software. rlMNCS were successfully obtained in all animals. Mean CMAP amplitude and negative durations in young rats were 3.58 ± 2.20 mV and 0.93 ± 0.14 mS (mean dif: 0.17; 95% CI: -2.21 to 2.54), respectively, and 3.74 ± 2.81 mV and 0.98 ± 0.11 mS (mean dif: 0.050; 95% CI: -0.07 to 0.17). No significant differences in onset latency or negative area were observed. Mean axon count in young rats (176 ± 35) was comparable to that in old rats (173 ± 31). Myelin thickness and g-ratio did not differ between groups. There were no statistically significant differences in RLN conduction or axon histology between young and aged rats in this pilot study. This work provides a basis for future, adequately powered studies, and may lead to a tractable animal model to study the aging larynx. 5.


Lepromatous leprosy with a suspected 30-year incubation period: A case report of a practically eradicated area.
This report aims to demonstrate and remind healthcare providers that, despite being considered eradicated in a specific area, leprosy can still be found due to its unusually long incubation period. A case of leprosy has been reported in a 48-year-old Thai woman who presented classic dermatological and neurological symptoms. A physical examination and slit smear preparation with acid-fast staining was performed to fulfil the diagnostic criteria of the World Health Organization (WHO). Therapeutic regimens were prescribed according to WHO recommendations. A patient was diagnosed with leprosy given that all cardinal signs of WHO diagnostic criteria were met after both physical and microscopic examinations. Physical examination of the skin lesions revealed the lepromatous type. Slit smear preparation of the lesions revealed abundant acid-fast bacilli. The patient has been living solely in an area where leprosy has been practically eradicated, with no new cases reported. The most likely cause of her infection is her close contact with a leprosy-infected family member 30 years ago, with whom she shared a house for a week. This report describes a rare case of leprosy with a long incubation period in a non-endemic area. Only non-human primates have had such an unusually long incubation period, which is extremely rare in humans. This information reminds healthcare providers that leprosy is not a disease of the past, and a careful surveillance program for leprosy remains necessary, even in eradicated areas.


LONG-TERM OUTCOMES OF INTRAVITREAL BEVACIZUMAB THERAPY FOR SUBRETINAL NEOVASCULARIZATION SECONDARY TO IDIOPATHIC MACULAR TELANGIECTASIA TYPE 2.
To assess the long-term visual acuity results for intravitreal bevacizumab therapy in the treatment of subretinal neovascular membrane (SRNVM) secondary to idiopathic macular telangiectasia (Mactel) Type 2. This retrospective review of a consecutive, interventional case series includes patients with SRNVM secondary to Mactel Type 2 who were seen at Cincinnati Eye Institute from February 2006 to December 2014. Best-corrected visual acuity, fluorescein angiography, and optical coherence tomography measurements were performed. Exclusion criteria were the following: Mactel Type 2 patients without SRNVM, Mactel Type 1 patients, patients who had SRNVM or macular edema related to other maculopathies, and patients who had pars plana vitrectomy or laser treatment to the macula during the course of care or before their first visit. Twenty-five eyes of 20 patients with SRNVM secondary to Mactel Type 2 were included in the study. The mean baseline best-corrected visual acuity was 20/91 (median: 20/69) and the mean final best-corrected visual acuity was 20/62 (median: 20/60) at the last visit (P < 0.0001). The mean number of injections was 8.4 ± 11.1 (range: 2-53, median: 4). The mean pretreatment central macular thickness of 254 μm improved to 205 μm at the final visit (P = 0.011). No complications related to intravitreal bevacizumab injection were noted during the mean follow-up time of 40.8 ± 33.7 months (range: 4-108 months, median: 24 months). Intravitreal bevacizumab therapy is an effective long-term treatment modality for SRNVM secondary to Mactel Type 2 based on improvement in best-corrected visual acuity and associated reduction in central macular thickness.


Hand-held dynamometer testing of the internal and external rotator musculature based on selected positions to establish normative data and unilateral ratios.
Objective documentation is needed of shoulder internal and external rotator strength using hand-held dynamometry in selected positions commonly used in a clinic. We compared strength measures and unilateral ratios between gender, limbs (dominant, nondominant), and 3 testing positions. We hypothesized that men would be stronger than women, the dominant shoulder would be stronger than the nondominant shoulder, and the seated neutral (0° adduction) and seated 30° abduction, 30° scaption, 30° diagonal (30°-30°-30°) positions would be stronger than the prone at 90°-90° position. Three positions (prone at 90°, seated at neutral, and seated at 30°-30°-30°) were evaluated in 181 individuals using hand-held dynamometry. Three separate 3-factor (limb by position by gender) analyses of variance were conducted on internal rotation, external rotation, and unilateral ratios. Although the dominant limb was significantly stronger (P < .001) than the nondominant for internal rotation, there was no difference for external rotation. The external rotators demonstrated significantly greater strength in the prone at 90° position compared with the seated at neutral (P = .001) and seated at 30°-30°-30° (P = .002) positions. The internal rotators demonstrated significantly greater (P = .036) strength in the neutral position than in the prone at 90° position for the women. The unilateral ratio of external rotators/internal rotators ranged from 86% to 99%. For the women, the prone at 90° ratio was significantly greater than seated at neutral (P = .001) and seated at 30°-30°-30° (P = .001) positions. Moderate strength relationships (r = 0.506 to 0.572) were revealed between body mass and all strength measures. The results of this study provide evidence to interpret normative data, bilateral comparisons and unilateral ratios of the internal/external rotators in the 3 selected positions. Because there are no differences between the seated at neutral and 30°-30°-30° positions and the advantages it offers, we recommend the 30°-30°-30° position for testing and the initiation of rehabilitation.


Pelvic organ prolapse after 3 modes of hysterectomy: long-term follow-up.
There are various indications and approaches for hysterectomy; yet, the difference in long-term risk of subsequent prolapse after surgery is not well studied. To assess the risk of prolapse after abdominal, vaginal, and laparoscopic or robotic hysterectomy for up to 17 years from surgery. A retrospective chart review study of women undergoing hysterectomy across all indications (benign and malignant) between 2001 and 2008 was conducted. An equivalent random sample of hysterectomy patients was selected each year. We compared demographic and other surgical characteristics data including age, race, parity, body mass index, indication and year of hysterectomy, blood loss, cervix removal, cuff suspension, and complications using chi-square, Kruskal-Wallis test, and Fisher's exact across the 3 groups. Presence and treatment of subsequent prolapse (based on patient symptoms, pelvic exam, International Classification of Diseases, Ninth Revision diagnosis, and current procedural terminology pessary or surgical codes) were compared with Kaplan-Meier survival analysis and Cox proportional hazards regression. Of the 2158 patients, 1459, 375, and 324 underwent open, vaginal, and laparoscopic or robotic hysterectomy, respectively. The vaginal group (56) was older than the abdominal (52) or laparoscopic or robotic (49) groups, with a P value of <.05. Most patients were White with a mean body mass index of 30 kg/m2. The main indication was cancer for abdominal (33%) and laparoscopic or robotic hysterectomy (25%) and prolapse for vaginal hysterectomy (60%). Time to prolapse was shortest after vaginal surgery (27 months) and longest after laparoscopic or robotic surgery (71 months). After controlling for confounders, including surgery indication, the hazard ratio for subsequent prolapse was no different among vaginal (hazard ratio=1.36 [0.77-2.45]), laparoscopic or robotic (hazard ratio=1.47 [0.80-2.69]), or open (reference) hysterectomy. Prolapse grade was similar across the 3 groups. About 50% of women with recurrent prolapse received physical therapy, pessary, or surgical treatment. At the 17-year follow-up, the route of hysterectomy is not associated with a difference in recurrence, grade, or subsequent treatment of prolapse when the indication for hysterectomy is considered. Prolapse, as an indication for hysterectomy, increases risk for recurrence. Women planning a hysterectomy should be counseled appropriately about the risk of subsequent prolapse.


A simple method to immunopurify erthyropoiesis stimulating agents from urine, aiming to optimize erythropoietin screening by SAR-PAGE.
The efficiency of the immunopurification step of urinary erythropoietin (EPO) and recombinant forms is important for their optimal detection in antidoping screening. Previous investigations of immunopurification techniques have been done for immunomagnetic beads, EPO Purification Kit (EPK) columns (MAIIA Diagnostics), and enzyme-linked immunosorbent assay (ELISA) microplates (Stemcell Technologies) conjugated/coated with anti-EPO antibodies. In this study, a new immunopurification technique using anti-EPO sepharose gel beads, developed by MAIIA Diagnostics, to simplify and minimize sample handling was evaluated. This EPO Purification Gel Kit (EPGK) was compared with our current routine EPK for limit of detection (LOD). Linearity, recovery, repeatability, sample incubation time, and sample volume were also evaluated for EPGK. The LODs and linearity for EPK and EPGK were comparable to each other and the recovery for BRP, NESP, CERA, and EPO-Fc were within the range of other studies, and concentration of the sample eluate improved the recovery results. Little variation was seen within days, between days, and between operators. A 90 minute incubation of the sample with the sepharose gel beads is sufficient for most of the erythropoiesis stimulating agents (ESAs) tested, with 10 mL being an optimal sample volume for EPGK. The improved sample handling, higher sample throughput and the reduced working time demonstrate that the EPGK is a better alternative to the current MAIIA EPK immunopurification method for urine. The EPO Purification Gel Kit (from MAIIA Diagnostics) was evaluated and validated for immunopurification of endogenous erythropoietin and exogenous erythropoiesis stimulating agents from urine samples. The kit was a better alternative to that currently used (EPO Purification Kit) in many antidoping laboratories because it improves sample handling and increases sample throughput.


Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain.
The aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight. Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme-linked immunosorbent assay. A two compartment model with parallel linear and non-linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1 ), peripheral volume (V2 ), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 l day(-1) , 2.71 l, 1.98 l, 0.371 l day(-1) , 8.03 μg day(-1) and 27.7 ng ml(-1) , respectively. Inter-individual variability (IIV) was included on CL, V1 , V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV. The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.