Outcomes and toxicity following high-dose radiation therapy in 15 fractions for non-small cell lung cancer.
Accelerated hypofractionated radiation therapy (AHRT) is increasingly used for select lung cancer patients. We evaluated clinical outcomes and predictors of pulmonary/esophageal toxicity in patients treated with ≥52.5 Gy in 15 fractions. We evaluated 229 patients treated with radiation therapy doses ≥52.5 Gy in 15 fractions for non-small cell lung cancer from January 2009 through January 2016. Toxicity was scored using Common Terminology Criteria for Adverse Events, v4.0. Univariate and multivariate logistic regression was used to identify predictors of toxicity. Overall survival, progression-free survival, and local control were estimated using the Kaplan-Meier method. Predictors of clinical outcome were modeled using Cox proportional hazards regression. Median follow-up was 7 months. Forty-two patients (19%) developed grade ≥2 pneumonitis, and 9 (4%) developed grade ≥3 esophagitis. In multivariate analysis, age >75 years (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.24-5.25; P = .01) and percentage of lung volume receiving doses of >10 Gy higher than 32% were associated with grade ≥2 pneumonitis (OR, 2.79; 95% CI, 1.39-5.79; P = .005). On univariate analysis, esophagus mean dose ≥17 Gy (OR, 10.14; 95% CI, 1.82-189.8; P = .006), gross tumor volume size ≥71 cm3 (P = .002), and planning target volume size ≥409 cm3 (P = .02) were associated with development of grade ≥3 esophagitis. In patients with stage II/III disease (n = 73), median local control was not reached, median overall survival was 14 months, and median progression-free survival was 6 months. AHRT in 15 fractions can be safe and effective. Consideration for using AHRT with immunotherapy and sequential chemotherapy for improved out-of-radiation field and distant control is warranted.


Genetics of adult attachment and the endogenous opioid system.
Since the pioneering work by Panksepp et al, the neurobiological bases of attachment behavior have been closely linked with opioid neurotransmission. Candidate gene studies of adult individuals have shown that variation in the mu-opioid receptor gene (OPRM1) influences attachment behavior. Early maternal care and the A/A genotype of the A118G polymorphism interact in modulating levels of fearful attachment. Compared to their counterparts carrying the A/A genotype, individuals expressing the minor 118G allele show lower levels of avoidant attachment and experience more pleasure in social situations. Brain imaging research has strengthened the biological plausibility of candidate gene studies. The avoidance dimension of attachment correlates negatively with mu-opioid receptor availability in the thalamus and anterior cingulate cortex, as well as the frontal cortex, amygdala, and insula. Overall, findings from human studies combined with those from animal models suggest that research on the genetic bases of attachment should include the endogenous opioid system among the investigated variables.


Role of calcium and beta-adrenergic system in control of parathyroid hormone secretion.
In the rat, EDTA and isoproterenol stimulated PTH secretion, whereas high calcium and propranolol inhibited it. The stimulatory effects of EDTA and isoproterenol were still evident and unaltered in the presence of blocks induced by propranolol and high calcium, respectively. The findings suggest that: (i) both calcium and beta-adrenergic stimuli affect PTH secretion; and (ii) the two influences affect the PTH secretion by separate initial pathways.


New and Emerging Therapies for Dyslipidemia.
Atherosclerotic cardiovascular disease (ASCVD) continues to represent a growing global health challenge. Despite guideline-recommended treatment of ASCVD risk, including antihypertensive, high-intensity statin therapy, and antiaggregant agents, high-risk patients, especially those with established ASCVD and patients with type 2 diabetes, continue to experience cardiovascular events. Recent years have brought significant developments in lipid and atherosclerosis research. Several lipid drugs owe their existence, in part, to human genetic evidence. Here, the authors briefly review the mechanisms, the effect on lipid parameters, and safety profiles of some of the most promising new lipid-lowering approaches that will be soon available in our daily clinical practice.


An Epidemiological Study of Primary Bone Tumors of the Fibula.
Relatively low incidence has led to an under-rating of fibula tumors. This study aimed to evaluate fibula tumors as a whole and to give detailed information based on histological types according to the anatomic location of the tumors in the fibula. Evaluation was made of all the primary bone tumors of the fibula recorded in our bone tumor registry and institute of pathology from 2007 to 2018. Of these, 62 cases were identified. Analysis included assessment of age, gender, tumor localization, the presenting symptoms, the duration of symptoms, and treatment methods. There were 48 (77.4%%) benign and 14 (22.6%) malignant tumors. The most commonly found benign tumors were non-ossifying fibroma (12/48; 25%) and aneurysmal bone cyst (12/48; 25%), and the malignant tumors were chondrosarcoma (3/14; 21.4%) and chondroblastic osteosarcoma (3/14; 21.4%). The most common location for both benign and malignant tumors (58.3%, 71.4%) are the proximal fibula, followed by the distal fibula (27.1%, 28.6%) and the diaphysis (14.6%, 0%). Six (9.7%) patients presented with pathological fibula fractures. Fibular tumors are rarely encountered in clinical practice but are mostly benign, with malignancy determined in approximately a quarter of patients. However, as most benign tumors are asymptomatic, and therefore remain undetected, the actual proportion of malignant tumors will be much lower.


Helicobacter pylori: a poor man's gut pathogen?
Helicobacter pylori is one of the human pathogens with highest prevalence around the world; yet, its principal mode of transmission remains largely unknown. The role of H. pylori in gastric disease and cancer has not been established until the end of the 20th century. Since then, its epidemiology has been extensively studied, and an accruing body of literature suggests that not all humans are equally at risk of infection by this gut pathogen. Here, we briefly review the different epidemiological aspects of H. pylori infection with emphasis on those factors related to human poverty. The epidemiology of H. pylori infection is characterized by marked differences between developing and developed countries, notably among children. In addition, congruent lines of evidence point out to socioeconomic factors and living standards as main determinants of the age-dependent acquisition rate of H. pylori, and consequently its prevalence. These data are alarming in the light of the changing global climate and birth rate, which are expected to change the demography of our planet, putting more children at risk of H. pylori and its complications for years to come.


Ultrastructural evidence of enkephalinergic input to glucoreceptor neurons in ventromedial hypothalamic nucleus.
A combination of intracellular injection of horseradish peroxidase into the ventromedial hypothalamic nucleus glucoreceptor neurons and immunohistochemical staining for enkephalin allowed ultrastructural visualization of interrelations between these electrophysiologically identified neurons and enkephalin-like immunoreactive (ENK-IR) terminals. The results show that glucoreceptor neurons receive direct inputs from ENK-IR neurons. This is the first evidence that glucoreceptor neurons, identified electrophysiologically, can be affected monosynaptically by endogenous enkephalin, probably released from ENK-IR terminals.


The automaton as a surgeon: the future of artificial intelligence in emergency and general surgery.
Artificial intelligence (AI) is a field involving computational simulation of human intelligence processes; these applications of deep learning could have implications in the specialty of emergency surgery (ES). ES is a rapidly advancing area, and this review will outline the most recent advances. A literature search encompassing the uses of AI in surgery was conducted across large databases (Pubmed, OVID, SCOPUS). Two doctors (LR, CH) both collated relevant papers and appraised them. Papers included were published within the last 5 years, and a "snowball effect" used to collate further relevant literature. AI has been shown to provide value in predicting surgical outcomes and giving personalised patient risks based on inputted data. Further to this, image recognition technology within AI has showed success in fracture identification and breast cancer diagnosis. Regarding theatre presence, supervised robots have carried out suturing and anastomosis of bowel in controlled environments to a high standard. AI has potential for integration across surgical services, from diagnosis to treatment, and aiding the surgeon in key decision-making for risks per patient. Fully automated surgery may be the future, but at present, AI needs human supervision.


Alterations in transport path differentially affect temporal and spatial movement parameters.
Many studies have examined the coordination of reach-to-grasp movements. However, there is debate regarding the mechanism of coordination between the transport and grasp components. The current study investigated the stability of temporal and spatial measures for reaches in which transport path was altered early or late in the reaching action. Transport alteration was accomplished by placing an obstacle either 10 cm (near) or 20 cm (far) from the hand starting position. Obstacle location affected the formation of transport path such that maximum wrist elevation coincided with the location of the obstacle. Kinematic analyses revealed that reaches over the near obstacle significantly prolonged transport time and time to maximum velocity compared with reaches over the far obstacle. A similar pattern of results was observed for the grasp component; reaches over the near obstacle resulted in a prolongation of grip duration, time to maximum aperture, and time to maximum opening and closing velocity. Grip closing velocity was decreased in the obstacle conditions. These results confirm findings from earlier studies that have shown that changes in the transport component affect grasp formation. A spatial and temporal analysis of grasp opening and closing was also performed. Grasp closing time varied significantly between conditions, while closing distance or the distance traveled by the wrist after maximum aperture remained essentially constant across conditions. These results suggest that the central nervous system may be using a spatial controller to coordinate prehensile components.


Preparation of Aspergillus niger 426 naringinases for debittering citrus juice utilization of agro-industrial residues.
Naringin, considered as the main bitter component of grapefruit, requires the use of enzymes to reduce the level of this substance during juice processing. For this reason, it has been the focus of many studies. In this study, to increase the production of naringinase by Aspergillus niger cultivated in solid-state fermentation (SSF), a three-component simplex-centric mixing design along with a response surface methodology (RSM) was applied to generate statistical models and analyze the dataset. First, grapefruit peel, rice bran, and wheat bran were used for substrate selection for naringinase production and, finally, selected the best of the three inducers or their mixtures to remove the bitterness of grapefruit juice. Cultivation with 2.3 g of grapefruit peel, 2.5 g of rice bran, and 5.2 g of wheat bran and medium supplementation with a mixture of naringin, rutin, and hesperidin in the concentration of 2, 5, 4.5, and 3.0 g/L, respectively, resulted in a maximum activity of 28 U/mL. The results indicate that the sequencing procedure, which allowed the definition of an optimal mixture of components, is a new way for microorganisms to have a high naringinase yield, in particular by SSF, since our data showed a 96% increase in the production of naringinase. This dataset can help other researchers apply a mixing design to increase enzyme production.


Donation return time at fixed and mobile donation sites.
This study investigated the effect of blood donation environment, fixed or mobile with differing sponsor types, on donation return time. Data from 2006 through 2009 at six US blood centers participating in the Retrovirus Epidemiology Donor Study-II (REDS-II) were used for analysis. Descriptive statistics stratified by whole blood (WB), plateletpheresis (PP), and double red blood cell (R2) donations were obtained for fixed and mobile locations, including median number of donations and median interdonation interval. A survival analysis estimated median return time at fixed and mobile sites, while controlling for censored return times, demographics, blood center, and mandatory recovery times. Two-thirds (67.9%) of WB donations were made at mobile sites, 97.4% of PP donations were made at fixed sites, and R2 donations were equally distributed between fixed and mobile locations. For donations at fixed sites only or alternating between fixed and mobile sites, the highest median numbers of donations were nine and eight, respectively, and the shortest model-adjusted median return times (controlling for mandatory eligibility times of 56 and 112 days) were 36 and 30 days for WB and R2 donations, respectively. For PP donations, the shortest model-adjusted median return time was 23 days at a fixed location and the longest was 693 days at community locations. WB, PP, and R2 donors with the shortest time between donations were associated with fixed locations and those alternating between fixed and mobile locations, even after controlling for differing mandatory recovery times for the different blood donation procedures.


Deep Learning-Based Nuclear Morphometry Reveals an Independent Prognostic Factor in Mantle Cell Lymphoma.
Blastoid/pleomorphic morphology is associated with short survival in mantle cell lymphoma (MCL), but its prognostic value is overridden by Ki-67 in multivariate analysis. Herein, a nuclear segmentation model was developed using deep learning, and nuclei of tumor cells in 103 MCL cases were automatically delineated. Eight nuclear morphometric attributes were extracted from each nucleus. The mean, variance, skewness, and kurtosis of each attribute were calculated for each case, resulting in 32 morphometric parameters. Compared with those in classic MCL, 17 morphometric parameters were significantly different in blastoid/pleomorphic MCL. Using univariate analysis, 16 morphometric parameters (including 14 significantly different between classic and blastoid/pleomorphic MCL) emerged as significant prognostic factors. Using multivariate analysis, Biologic MCL International Prognostic Index (bMIPI) risk group (P = 0.025), low skewness of nuclear irregularity (P = 0.020), and high mean of nuclear irregularity (P = 0.047) emerged as independent adverse prognostic factors. Additionally, a morphometric score calculated from the skewness and mean of nuclear irregularity (P = 0.0038) was an independent prognostic factor in addition to bMIPI risk group (P = 0.025), and a summed morphometric bMIPI score was useful for risk stratification of patients with MCL (P = 0.000001). These results demonstrate, for the first time, that a nuclear morphometric score is an independent prognostic factor in MCL. It is more robust than blastoid/pleomorphic morphology and can be objectively measured.


Mass screening for cervical cancer in Norway: evaluation of the pilot project.
The Norwegian Department of Health and Social Affairs initiated a national screening program for cervical cancer in 1990, with all women aged 25 to 70 years to be offered cervical screening every three years. During the first three years of the program (November 1991-October 1994), all spontaneous cervical cytology in Norway was recorded at the Norwegian Cancer Registry. In addition, women in the counties of Vestfold and Sør-Trøndelag were invited individually to be screened. The aim of the present study was principally to evaluate the organization aspects of a nationwide, population-based screening program for cervical cancer in Norway. Special attention was paid to the coverage, the attendance rate, and the cytologic findings in the two-county study area. A total of 1,581,379 Pap smears were recorded from November 1991 to October 1994. Most smears were taken from women under age 30 years (31.7 percent). About 25 percent of the women aged 25 to 29 years had more than one normal smear. In the study area, a coverage of about 71 percent in the age group 25 to 69 years was achieved. The pilot project also has shown that it is possible to recruit elderly women into screening. However, no difference was noted between the study and the reference area with regard to findings per smear of precursor lesions (CIN 3, modified SNOMED coding system). The experiences from three years of recording and the implementation of the pilot project have provided useful guidelines for the national screening which began in January 1995.


[Ectopic hepatocellular carcinoma. A case report].
Ectopic liver (EL) is a rare developmental anomaly caused by the migration of hepatic cells to other locations during embryogenesis. Its incidence is thought to be between 0.24 and 0.47% and can occur in various sites, although the gall bladder is the most frequent. Approximately 100 cases of EL have been published, of which 28 developed hepatocellular carcinoma, whilst the orthotopic liver was unaffected. All cases are reported in Asian and Caucasian patients. We report the case of a 42-year-old patient with a solid lesion measuring 17×12×12cm apparently arising from the posterior wall of the stomach, displacing various organs and suggestive of a gastrointestinal stromal tumour (GIST). The liver, biliary tract and other structures were unremarkable. Histopathology revealed a diagnosis of hepatocellular carcinoma in ectopic liver tissue.


Punished behavior: increases in responding after d-amphetamine.
Responding maintained in squirrel monkeys under a 10-min fixed-interval schedule of food presentation was suppressed by presenting a shock after every 30th response (punishment). During alternate 10-min periods of the same experimental session, but in the presence of a different discriminative stimulus, responding either had no effect (extinction) or postponed delivery of an electric shock (avoidance). During sessions when the avoidance schedule was not in effect, d-amphetamine sulfate decreased punished responding. When the avoidance schedule was present during alternate 10-min periods, however, d-amphetamine (0.01 minus 0.56 mg/kg, i.m.) markedly increased responding during punishment components. Increases in responding during avoidance components were also evident. The effects of d-amphetamine on punished responding depend on the context in which that responding occurs.


Unraveling dynamic metabolomes underlying different maturation stages of berries harvested from Panax ginseng.
Ginseng berries (GBs) show temporal metabolic variations among different maturation stages, determining their organoleptic and functional properties. We analyzed metabolic variations concomitant to five different maturation stages of GBs including immature green (IG), mature green (MG), partially red (PR), fully red (FR), and overmature red (OR) using mass spectrometry (MS)-based metabolomic profiling and multivariate analyses. The partial least squares discriminant analysis score plot based on gas chromatography-MS datasets highlighted metabolic disparity between preharvest (IG and MG) and harvest/postharvest (PR, FR, and OR) GB extracts along PLS1 (34.9%) with MG distinctly segregated across PLS2 (18.2%). Forty-three significantly discriminant primary metabolites were identified encompassing five developmental stages (variable importance in projection > 1.0, p < 0.05). Among them, most amino acids, organic acids, 5-C sugars, ethanolamines, purines, and palmitic acid were detected in preharvest GB extracts, whereas 6-C sugars, phenolic acid, and oleamide levels were distinctly higher during later maturation stages. Similarly, the partial least squares discriminant analysis based on liquid chromatography-MS datasets displayed preharvest and harvest/postharvest stages clustered across PLS1 (11.1 %); however, MG and PR were separated from IG, FR, and OR along PLS2 (5.6 %). Overall, 24 secondary metabolites were observed significantly discriminant (variable importance in projection > 1.0, p < 0.05), with most displaying higher relative abundance during preharvest stages excluding ginsenosides Rg1 and Re. Furthermore, we observed strong positive correlations between total flavonoid and phenolic metabolite contents in GB extracts and antioxidant activity. Comprehending the dynamic metabolic variations associated with GB maturation stages rationalize their optimal harvest time per se the related agroeconomic traits.


Secondary myeloma in patients with chronic lymphoblastic leukemia: A case report and analysis of data from SEER database.
Both chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are common hematological malignancies originating from mature B cells of different differentiation stage. However, it is quite rare that MM could develop after CLL diagnosed. We reported a 66-year-old female progressed forward myeloma 3 years after she was diagnosed as CLL and conducted an analysis to investigate the epidemiology and clinical features among these patients based on the Surveillance, Epidemiology, and End Results (SEER) database. Our data demonstrated that CLL patients were 19% less likely to develop myeloma than general U.S. population (standardized incidence ratio 0.81; 95% confidence interval 0.62-1.03), although without statistical difference. The median overall survival from CLL diagnosed was 90 (58.1-121.9) months, which was the same as general CLL patients according to historical data. But the outcomes of secondary MM was much poorer than general MM patients. Age and gender were independent factors that impact the survival among these patients.


Salvianolic Acid A Inhibits OX-LDL Effects on Exacerbating Choroidal Neovascularization via Downregulating CYLD.
Age-related macular degeneration is closely related to lipid oxidation, while relationship between OX-LDL and choroidal neovascularization is unclear. Recently, cylindromatosis is proved to regulate angiogenesis. However, its role in CNV progression remained unclear. Salvianolic acid A is widely used in vascular diseases. We investigated the relationship between OX-LDL and CNV and explore antineovascularization mechanism of Sal A. C57BL6/J mice were randomized into four groups and injected with PBS or OX-LDL, together with Sal A for one week. CNV was induced by laser; CNV severity was analyzed by fundus fluorescein angiography, H&E staining, and choroid flat mount after 1 week. In in vitro experiments, ARPE-19 and HUVECs were cultured with OX-LDL (with or without Sal A) for 48 hours. Angiogenic proteins, cell junction integrity, and tube formation were measured. CYLD siRNA and specific inhibitors were used to explore mechanisms of CYLD in promoting OX-LDL-induced CNV progression. OX-LDL promoted laser-induced CNV volume by increasing VEGF, PDGF, and CYLD levels. Sal A antagonized OX-LDL effects and restrained CNV progression by decreasing VEGF/PDGF/CYLD, increasing antiangiostatin levels, and promoting P62-CYLD-TRAF6 interaction. We demonstrated oxidation damage exacerbates CNV progression, and Sal A could be a clinical therapeutic reagent to exudative AMD.


Effects of allisartan, a new AT(1) receptor blocker, on blood pressure and end-organ damage in hypertensive animals.
To investigate the effects of allisartan, a new angiotensin II type 1 (AT(1)) receptor antagonist, on blood pressure (BP) and end-organ damage (EOD) in hypertensive rats and dogs. First, a single dose of allisartan was given intragastrically to evaluate the BP reduction in spontaneously hypertensive rats (SHRs), two kidney-one clip (2K1C) renovascular hypertensive rats and dogs, and Beagle dogs with angiotensin II-induced hypertension. Second, allisartan was mixed in rat chow for long-term treatment. After 4 months of drug administration, rats were instrumented to determine BP and baroreflex sensitivity (BRS). Observation of morphologic changes was used to estimate EOD. Third, the acute toxicity of allisartan was compared with that of losartan in mice. BP was significantly decreased after intragastric administration of allisartan in SHRs, 2K1C rats, 2K1C dogs and Beagle dogs with angiotensin II-induced hypertension. Compared with the control, SHRs that received long-term treatment with allisartan exhibited an improved BRS and organ protective effects. Mice who were administered allisartan experienced less acute toxicity than those treated with losartan. Allisartan is highly effective for BP reduction and organ protection with low toxicity.


Behavioral Intervention Components Associated With Cost-effectiveness: A Comparison of Six Domains.
To help implement behavior change interventions (BCIs) it is important to be able to characterize their key components and determine their effectiveness. This study assessed and compared the components of BCIs in terms of intervention functions identified using the Behaviour Change Wheel Framework (BCW) and in terms of their specific behavior change techniques (BCTs) identified using the BCT TaxonomyV1, across six behavioral domains and the association of these with cost-effectiveness. BCIs in 251 studies targeting smoking, diet, exercise, sexual health, alcohol and multiple health behaviors, were specified in terms of their intervention functions and their BCTs, grouped into 16 categories. Associations with cost-effectiveness measured in terms of incremental cost-effectiveness ratio (ICER) upper and lower estimates were determined using regression analysis. The most prevalent functions were increasing knowledge through education (72.1%) and imparting skills through training (74.9%). The most prevalent BCT groupings were shaping knowledge (86.5%), changing behavioral antecedents (53.0%), supporting self-regulation (47.7%), and providing social support (44.6%). Intervention functions associated with better cost-effectiveness were those based on training (βlow = -15044.3; p = .002), persuasion (βlow = -19384.9; p = .001; βupp = -25947.6; p < .001) and restriction (βupp = -32286.1; p = .019), and with lower cost-effectiveness were those based on environmental restructuring (β = 15023.9low; p = .033). BCT groupings associated with better cost-effectiveness were goals and planning (βlow = -8537.3; p = .019 and βupp = -12416.9; p = .037) and comparison of behavior (βlow = -13561.9, p = .047 and βupp = -30650.2; p = .006). Those associated with lower cost-effectiveness were natural consequences (βlow = 7729.4; p = .033) and reward and threat (βlow = 20106.7; p = .004). BCIs that focused on training, persuasion and restriction may be more cost-effective, as may those that encourage goal setting and comparison of behaviors with others.


Differences in the effects of post-trial chlorpromazine, reserpine, and amphetamine on discrimination learning in rats.
Rats were trained to perform in discrimination learning reinforced by water for 6 days, and were intraperitoneally injected with chlorpromazine, reserpine, or d-amphetamine after each training session. Although chlorpromazine at the dose levels of 0.5 mg/kg or more injected immediately after training impaired learning, the drug did not affect learning when it was injected 60 min after training. Reserpine and amphetamine also impaired learning, but delaying the time intervals between training and injection to 60 min or more had no influence on this learning impairment. Post-trial chlorpromazine and amphetamine had no effect on, but reserpine decreased, motility in the subsequent training session. Chlorpromazine had no effect on water intake in the subsequent session, but reserpine and amphetamine decreased water intake at the dose levels that impaired learning. It was concluded that all three drugs impaired learning, but differed in their effects on learning; chlorpromazine impaired learning by a specific effect on learning itself; reserpine, by a non-specific effect on behavior due to a long acting sedation; and amphetamine, by an effect to decrease the motivation to drink water. The specific effect of chlorpromazine could be related to the hypothesis of "memory trace" synthesis.


Lymph node ratio predicts overall survival in patients with stage II non-small cell lung cancer: a population-based SEER analysis.
In non-small-cell lung cancer (NSCLC), there are many factors that affect prognosis, and the lymph node ratio (LNR) may play a significant role. Our study aimed to confirm the value of the LNR in the prognosis of patients with stage II NSCLC. Patient data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. The classification for the LNR was best determined using the X-tile method. The correlation between the LNR and overall survival (OS) was validated after the Kaplan-Meier analysis was performed. To determine the correlation between the LNR and survival, stratification and the Cox regression analysis were used. In our study, 14,183 stage II NSCLC patients were included. Among them, 8303 patients had N1 disease. According to the X-tile analysis, the optimal critical points for the LNR in N1 patients with NSCLC was 0.21 and 0.38. We categorized the cohorts as low (LNR-L ≤ 0.21; n = 5158, 62.1%), medium (0.21 < LNR-M ≤ 0.38; n = 1736, 20.9%), and high (LNR-H > 0.38; n = 1409, 17.0%). According to the Kaplan-Meier analysis, the patients with a high LNR were considerably worse than those with a medium or low LNR (P < 0.001), which was also proven by stratified and multivariate analyses. The value of the LNR was reflected in all the subgroup analyses, especially in patients ages < 60 years. The multivariate competing risks regression analysis revealed that younger age, female sex, T1 disease, adenocarcinoma and N0 disease was associated with a better prognosis after controlling for potential confounders (P < 0.001). For patients with stage II NSCLC, the LNR is valuable for assessing prognosis. A higher LNR indicates a worse prognosis.


Surgical technique for trigeminal microvascular decompression.
Microvascular decompression (MVD) is a non-ablative technique designed to resolve the neurovascular conflict responsible for typical idiopathic trigeminal neuralgia (TN). With the patient in a supine position, a small elliptical retrosigmoid craniectomy is used to approach the cerebellopontine angle and the trigeminal nerve. After careful exploration of the trigeminal root entry zone, the offending vessel is identified and moved away. Oxidized regenerated cellulose is used to keep the vessel in its new position far from the nerve. MVD represents the gold standard first line treatment for TN; its aim is to free the nerve from any contact.


The stability of multidimensional subclinical apathy during a pandemic and its relations to psycho-behavioral factors.
Apathy is a clinical symptom prevalent in many neuropsychiatric pathologies. Subclinical apathy is found in 35% of the general population. Despite high prevalence and negative consequences, underlying mechanisms are poorly understood, perhaps because the concept of apathy is one-dimensional. The current investigation aims to address the incidence of multidimensional apathetic trait in three distinct forms in a student population, to specify its determinants and to evaluate its stability during a global pandemic. Two online surveys, conducted 1 year apart on two separate cohorts of university students, with qualitative measures and validated scales. The final analysis included, respectively, 2789 and 1678 students. The three forms of apathetic trait were present, with the same debilitating consequences as apathetic symptom but independent determinants. Executive apathy was predicted by depressive symptoms, emotional apathy by motivational deficit and initiative apathy comprised a mixed executive-emotional form and a pure deficit of action initiation. The three forms of subclinical apathy remained similar in the context of increased depressive symptoms due to a global pandemic. This study confirmed the presence and independence of three forms of subclinical apathy in healthy students, which remained similar even in the light of increased depressive scores. These results shed light on cognitive and neuronal mechanisms underlying multidimensional apathy, allowing new, targeted treatments.


Traditional healers participate in tuberculosis control in The Gambia.
Twenty-three Gambian villages. To evaluate the feasibility of involving traditional healers in tuberculosis diagnosis and treatment in The Gambia. Twenty-eight traditional healers were educated in the recognition of signs and symptoms of tuberculosis and indications for referral. They administered medications to confirmed cases, and were revisited after 1 year to assess knowledge retention. Over 6 months, the traditional healers referred 66 suspects, from whom eight cases were diagnosed. All were successfully treated. Twenty-three of 24 traditional healers re-interviewed retained appropriate knowledge; 16 continued to refer suspects. Traditional healers can play a positive role in tuberculosis control.


Retrospective, monocentric analysis of late effects after Total Body Irradiation (TBI) in adults.
Total body irradiation (TBI) is a standard treatment modality within the multidisciplinary approach for allogeneous stem cell or bone marrow transplantation. However, surviving patients are at risk for developing a variety of late sequelae. This analysis aimed to retrospectively characterize late effects after TBI in adults treated in a single center. Patients ≥ 18 years treated with fractionated TBI (4-12 Gy) between 1996 and 2008 were included in this study. Treatment data were collected retrospectively from the treating departments. Late effects were evaluated using the clinic charts and/or were obtained from the general practitioners using a standardized questionnaire. Analyses were performed by calculation of the cumulative incidences using the Kaplan-Meier method and the log rank test. A total of 308 patients ≥ 18 years were treated including a TBI of whom 78 patients were excluded from further analysis due to death within less than 1 year after TBI. Patients suffered from leukemia in most cases. Late toxicity follow-up was available in 120 patients (mean age 46.1 years; range, 18-70 years) after a mean follow-up of 23 months (range, 12-96 months). The cumulative incidences (CI) at 3 years were 28% for pulmonary event, 8% for pulmonary toxicity, 25% for kidney toxicity, 8% for cataract, 17% for bone toxicity, and 10% for secondary malignancy. The CI of bone toxicity was higher in female than in male patients (p = 0.019). Late effects after TBI in the context of allogeneous stem cell or bone marrow transplantation can frequently be observed. Regular follow-up examinations are advised for the early registration and treatment of adverse effects.


The Role of Behavioral Economics in Improving Cardiovascular Health Behaviors and Outcomes.
Behavioral economics represents a promising set of principles to inform the design of health-promoting interventions. Techniques from the field have the potential to increase quality of cardiovascular care given suboptimal rates of guideline-directed care delivery and patient adherence to optimal health behaviors across the spectrum of cardiovascular care delivery. Cardiovascular health-promoting interventions have demonstrated success in using a wide array of principles from behavioral economics, including loss framing, social norms, and gamification. Such approaches are becoming increasingly sophisticated and focused on clinical cardiovascular outcomes in addition to health behaviors as a primary endpoint. Many approaches can be used to improve patient decisions remotely, which is particularly useful given the shift to virtual care in the context of the COVID-19 pandemic. Numerous applications for behavioral economics exist in the cardiovascular care delivery space, though more work is needed before we will have a full understanding of ways to best leverage such applications in each clinical context.


Development and validation of a short-form functional capacity evaluation for use in claimants with low back disorders.
Functional Capacity Evaluations (FCE) are used for making return-to-work decisions, yet FCE's modest predictive ability is currently outweighed by the administrative burden of testing. We attempted to develop a short-form FCE while maintaining comparable predictive ability. Three databases previously created for evaluating FCE predictive validity were used. Subjects were compensation claimants with low back disorders. FCE measures included items in the Isernhagen Work Systems' FCE. Days until benefit suspension served as an indicator of return-to-work. Analysis included Cox regression. Three items, floor-to-waist lift, crouching, and standing, were maintained in the short-form FCE. The short-form FCE was found to predict comparably to the entire FCE protocol in two validation cohorts (R (2) difference<3%). Subjects meeting job demands on all three items consistently experienced faster benefit suspension. A short-form FCE for determining future work status in claimants with low back disorders was developed. A substantially abbreviated FCE may offer an efficient alternative.


Experimental and Theoretical Studies of the Thermal Contact Conductance for Bundles of Round Steel Bars.
The paper presents investigations devoted to the analysis of the thermal contact conduction in a bundle of round steel bars. The phenomenon can be expressed quantitatively with the use of thermal contact conductance (hct). The starting points for the presented analysis were the results of the experimental measurements of the effective thermal conductivity. The measurements were performed for samples of a medium in the form of flat packed beds of bars with three different arrangements: staggered, in-line, and crossed and four bar diameters: 10, 20, 30, and 40 mm. Next, a mathematical model was developed, thanks to which the values of the hct coefficient were calculated for the analyzed cases. This approach consists in analyzing thermal resistances in the medium model, which is defined with an elementary cell. It was established that the value of the hct coefficient in the temperature range of 50-600 °C changes within the range of 50-175 W/(m2·K), and it decreases with an increase in the bar diameter. The final effect of the present study was to develop generalized approximation equations describing changes in thermal contact conductance in the heated bar bundle simultaneously in the temperature and bar diameter function.


Differential effects of osteogenic protein-1 (BMP-7) on gene expression of BMP and GDF family members during differentiation of the mouse MC615 chondrocyte cells.
The mRNA expression patterns of several bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs) in long-term cultures of the clonal mouse chondrocyte cell line MC615 were examined. Distinct spatial and temporal patterns of expression of BMPs and GDFs were observed. The temporal orders of expression were correlated with those of several biochemical markers characteristic of chondrocytic cell differentiation. BMP-1, -2, -5, and -6 mRNA expression increased throughout the chondrogenic process and BMP-4 mRNA expression was not changed. GDF-1 and -3 mRNA expression increased throughout the chondrogenic process, and GDF-5, -6, -8, and -9 mRNA expressions were not changed. Effects of osteogenic protein-1 (OP-1, BMP-7) on the expression patterns of several other members of the BMP family and of the GDF family were also examined. OP-1 downregulated the BMP-1, -4, -5, and -6 mRNA expression by a maximal 3-, 5-, 2.5-, and 3-fold, respectively. The BMP-2 mRNA expression was not changed significantly by a low concentration of OP-1, but was increased at 200 ng/ml at day 7 of treatment. In contrast to the BMPs, OP-1 upregulated significantly the six GDF members examined (GDF-1, -3, -5, -6, -8, and -9) by three- to four-fold. Our findings demonstrate that OP-1 differentially regulates the mRNA expression of several related members of the BMP family and upregulates the mRNA expression of several members of the GDF family. The observations suggest that OP-1 action on cartilage differentiation involves a complex regulation of gene expression of several members of the BMP and the GDF family.


Surgical treatment of jaw osteonecrosis in "Krokodil" drug addicted patients.
Retrospective study of jaw osteonecrosis treatment in patients using the "Krokodil" drug from 2009 to 2013. On the territory of the former USSR countries there is widespread use of a self-produced drug called "Krokodil". Codeine containing analgesics ("Sedalgin", "Pentalgin" etc), red phosphorus (from match boxes) and other easily acquired chemical components are used for synthesis of this drug, which used intravenously. Jaw osteonecrosis develops as a complication in patients who use "Krokodil". The main feature of this disease is jawbone exposure in the oral cavity. Surgery is the main method for the treatment of jaw osteonecrosis in patients using "Krokodil". 40 "Krokodil" drug addict patients with jaw osteonecrosis were treated. Involvement of maxilla was found in 11 patients (27.5%), mandible in 21 (52.5%), both jaws in 8 (20%) patients. 35 Lesions were found in 29 mandibles and 21 lesions in 19 maxillas. Main factors of treatment success are: cessation of "Krokodil" use in the pre- (minimum 1 month) and postoperative period and osteonecrosis area resection of a minimum of 0.5 cm beyond the visible borders of osteonecrosis towards the healthy tissues. Surgery was not delayed until sequestrum formation. In the mandible marginal or segmental resection (with or without TMJ exarticulation) was performed. After surgery recurrence of disease was seen in 8 (23%) cases in the mandible, with no cases of recurrence in the maxilla. According to our experience in this case series, surgery is the main method for the treatment of jaw osteonecrosis in patients using "Krokodil". Cessation of drug use and jaw resection minimize the rate of recurrences in such patients.


The ONS Longitudinal Study--a prestigious past and a bright future.
This issue of Population Trends includes a number of articles and reports resulting from research based on the ONS Longitudinal Study (ONS LS). They have been drawn together in one issue to highlight the value of this type of study for demographic research.2009 marked the 35th anniversary of the establishment of the ONS LS. The study now contains data from the last four censuses (1971 to 2001), linked to vital events data since 1971, for a sample of one per cent of the population of England and Wales.More recently, sister studies have been established in Scotland and Northern Ireland. The Scottish Longitudinal Study (SLS) started with 1991 Census data and the Northern Ireland Longitudinal Study (NILS)started with 2001 Census data.The lead article in this issue comes from an exemplar project that was established to explore how to utilise the three studies to carry out UK-wide longitudinal analysis. Two different methods were used to analyse socio-economic and country level differences in health and mortality across the studies. The article summarises the results of this analysis, reports on the relative strengths of the different methods used, and draws attention to a number of new resources that have been developed by the project researchers as aids to using all three studies.This is an excellent example of collaborative working across the UK, involving researchers from the Centre for Longitudinal Study Information and User Support (CeLSIUS) at the London School of Hygiene and Tropical Medicine, the Longitudinal Studies Centre - Scotland (LSCS) at the University of St.Andrews and the Northern Ireland Longitudinal Study - Research Support Unit (NILS-RSU) at Queen's University Belfast. The project also involved collaboration between ONS, the General Register Office for Scotland (GROS) and the Northern Ireland Statistics and Research Agency (NISRA) to ensure the secure transfer and handling of data from the three studies so that it could be brought together in one place for analysis.The other ONS LS-based articles and reports in this edition largely focus on research into issues related to families and households, as summarised below: A collaborative project involving Ben Wilson (ONS) and Rachel Stuchbury (CeLSIUS) comparing the stability of partnerships involving marriage and cohabitation.A project looking at transitions in children's experience of living in a workless household and how this varies by ethnic group, submitted by Lucinda Platt (Institute for Social & Economic Research, University of Essex).An article on the effect of a change in the census definition of a child between 1991 and 2001 submitted by Emily Grundy, Rachel Stuchbury and Harriet Young (CeLSIUS).The remainder of this introductory article will focus on the ONS LS, its history and some examples of its use, and gives a summary of planned developments over the coming years. Please refer to the contact details at the end of the article if you require further information on any of the three longitudinal studies.


Novel parvovirus in cats, China.
Parvovirus is a common element of the feline virus group and usually causes gastroenteritis and leukopenia in cats. In this study, we identified a novel protoparvovirus from the Chinese domestic cats, which is genetically similar to canine bufavirus (98.0%-99.8%), but sharing low amino acid identities in the viral structural proteins 2 (VP2) (36.1-37.2%) to the well-known canine parvovirus type 2 and feline panleukopenia virus. This virus was provisionally designated as feline bufavirus (FBuV). Screening of fecal samples revealed a prevalence of 7.4% (19/257) in domestic cats. Diarrhea was present in 52.6% (10/19) of cats positive for FBuV. However, statistical analysis showed no association between FBuV and clinical signs. VP2 gene of the 19 field FBuV was sequenced and phylogenetic analysis demonstrated that FBuV determined from China had a genetic diversity. This study will strengthen the understanding of the epidemiology and genetic diversity of bufavirus and provide a foundation for further studies.


Superoxide generation by human monocytes and macrophages.
Intracellular and extracellular superoxide (O2.-) generation by human monocytes and macrophages was quantitated by the nitroblue tetrazolium (NBT) reduction method. Human monocytes reduced 4.4 +/- 0.9 nmoles/10(6) cells/15 minutes with an increase to 12.4 +/- 1.3 during phagocytosis of zymosan. Based on inhibition by superoxide dismutase, superoxide generation of these cells was 1.8 +/- 0.9 nmoles in the resting state and 16.8 +/- 2.8 nmoles with zymosan phagocytosis. Human macrophages obtained by thoracentesis had comparable levels of NBT reduction and O2.-generation. Monocytes from a patient with chronic granulomatous disease demonstrated no increment in O2.-production during phagocytosis. Thus, human monocytes and macrophages appear capable of generating substantial amounts of O2.-during phagocytosis which may play an important role in bactericidal and other cell functions.


Committee Opinion No. 418: The Complete 11-14 Week Prenatal Sonographic Examination.
Sonography during the first trimester provides an opportunity to assess a pregnancy in its early stage. This document provides an opinion about the implementation and content of prenatal sonographic examinations at 11-14 weeks gestation in Canada. Pregnant women at 11-14 weeks gestation. The 11-14 week prenatal sonographic examination can provide important information that may contribute to pregnancy management. It can be used to confirm viability, establish gestational age, determine the number of fetuses, assess the adnexa/ovaries, and, in a multiple pregnancy, assess chorionicity and amnionicity. Scanning also offers an opportunity to detect fetal abnormalities and perform aneuploidy screening by measuring the nuchal translucency thickness. It may be valuable in screening for preeclampsia and other obstetrical disorders (by combining uterine artery Doppler scanning with other bio-clinical markers) and for invasive placentation. There are no physical harms to mother or fetus from offering a routine 11-14 week prenatal sonographic examination, and there are no extra costs for patients. Articles related to routine 11-14 week prenatal sonography were identified in a search of EMBASE and MEDLINE using the search terms first trimester ultrasound, nuchal translucency, and 11-14 week ultrasound. The search included all articles published on the topic until May 2019. Abstracts were reviewed by one author, and articles deemed relevant were then reviewed in full to determine whether to include them in the study. Articles that were not in English and articles that did not pertain to 11-14 week prenatal sonography were excluded. This document is intended for sonographers, midwives, family physicians, obstetricians, and maternal-fetal medicine specialists.


Excision repair of DNA in some photodermatoses.
Excision repair of DNA was measured in a number of photosensitive subjects by estimating unscheduled DNA synthesis in cultured fibroblasts after ultraviolet radiation. The amount of unscheduled DNA synthesis and the action spectrum for this process were estimated in each subject and compared with seven normal subjects. Two subjects with polymorphic light eruption and three with actinic reticuloid exhibited normal levels of DNA repair and normal action spectra. In one subject with classical xeroderma pigmentosum no excision repair could be demonstrated whilst in another the amount of repair was lower than normal. The finding of normal DNA excision repair in polymorphic light eruption does not support an earlier claim that this repair process is abnormal in this common photodermatosis.


Numerical chromosome changes in 165 malignant tumors. Evidence for a nonrandom distribution of normal chromosomes.
The numbers of normal copies of each of the chromosomes in representative karyotypes from 165 malignant tumors of the bladder, breast, cervix, colorectum, and testis studied in this laboratory or described in the literature were assessed to determine whether particular chromosomes were over- or underrepresented. For each chromosome, the mean number of copies was expressed as a percentage of the number expected on the basis of the total number of chromosomes in the karyotypes. The most highly represented autosomes in the tumors as a whole were, in descending order of frequency, numbers 7, 20, 12, 19, 21, and 3, while those most underrepresented were numbers 10, 1, 4, 5, 14, 17, 11, and 18. In tumors of males, the Y tended to be underrepresented. The X was highly represented in the testicular tumors (there were usually two or more copies) and in colorectal tumors of males, but not in the other tumor categories studied. For the tumors as a whole, statistically significant differences could be demonstrated between pairs of autosomes that were at opposite ends of the frequency range. Differences between tumors at the different sites studied were not demonstrable. It is suggested that the determination of the number of normal copies of chromosomes, i.e., whether there are more or fewer than expected, may usefully complement observations on structural changes by reflecting the presence of oncogenes and tumor-suppressor genes, respectively. It may also point to chromosomes that are involved in significant genic changes in which cytogenetic observations on structural changes are equivocal.


Metal ion removal using waste byssus from aquaculture.
Byssus is a thread-like seafood waste that has a natural high efficiency in anchoring many metal ions thanks to its richness of diverse functional groups. It also has structural stability in extreme chemical, physical and mechanical conditions. The combination of these properties, absent in other waste materials, has novelty suggested its use as matrix for water remediation. Thus, pristine byssus, upon de-metalation, was studied to remove metal ions from ideal solutions at pH 4 and 7, as model chemical systems of industrial and environmental polluted waters, respectively. The byssus matrix's uptake of metal ions was determined by ICP-OES and its surface microstructure investigated by SEM. The results showed that the byssus matrix excellently uptakes metal ions slightly reorganizing its surface micro-structure. As example of its efficiency: 50 mg of byssus absorbed 21.7 mg·g-1 of Cd2+ from a 10 mM solution at pH 7. The adsorption isotherm models of Freundlich and Langmuir were mainly used to describe the system at pH 7 and pH 4, respectively. In conclusion, we showed that the byssus, a waste material that is an environmental issue, has the potential to purify polluted industrial and environmental waters from metal ions.


Synthesis and Chemosensory Properties of New Cyanosubstituted 2,2'-Bipyridine Derivatives.
A series of novel 6-oxo-1,6-dihydro-[2,2'-bipyridine]-5-carbonitriles has been synthesized and characterized. Their photophysical properties in DMSO solution and aqueous medium as well as fluorescence response to the presence of metal ions have been investigated. The obtained 4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-[2,2'-bipyridine]-5-carbonitrile has been shown as a selective fluorescent "turn-ON" probe for Cd2+ ions with LoD 0.359 µM, 1:1 metal-ligand ratio and binding constant of 5.2 × 104 M-1.


Five and Ten-Year Outcomes of Neoadjuvant Chemotherapy and Surgery for High-Risk Upper Tract Urothelial Carcinoma.
Emerging data suggests improved outcomes in patients receiving neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. In one of the largest single-center experiences to date, we provide an updated analysis of outcomes of patients receiving NAC followed by RNU. A retrospective review of patients with high-risk UTUC who received NAC followed by surgery between 2004 to 2017 was conducted. 126 patients were evaluated as part of the analysis. Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox modeling was used to evaluate for association with outcomes, and the cumulative incidence factor was used for competing risk analysis. Median OS time was 106 months. 14.3% of patients had a pathologic complete response and 60% were down-staged to ypT0-1 ypN0. The estimated 5 and 10-year DSS rates were 89.8% and 80.6%, respectively. The estimated 5 and 10-year metastasis-free survival rates were 81% and 75.4%, respectively. The estimated 5 and 10-year OS rates were 73.7% and 35.9 %, respectively. Recurrences mainly occurred in lymph nodes and lung at a median time of 15.5 months (IQR 8.9-27). The estimated 5 and 10-year cumulative incidence factor for death from UTUC was 9.5% and 16.1%, respectively. Limitations include retrospective nature and challenge of accurate pre-surgical staging. NAC prior to RNU in high-risk UTUC shows durable 5 and 10-year OS and DSS rates in a large single-institution series, confirming prior findings in prospective trials and retrospective studies.


Clearance of buprenorphine during pregnancy and neonatal outcomes.
Buprenorphine is emerging as the preferred pharmacologic treatment for opioid use disorder during pregnancy. We examined the relative plasma clearance of buprenorphine (BUP) across pregnancy. Pregnant women with opioid use disorder participating in a prospective, observational study from 2013 to 2016 on stress in pregnancy who were receiving BUP for opioid use disorder were included. Women with an active eating disorder or suicidal ideation were excluded. Research visits occurred at 4-6-week intervals across pregnancy and the early postpartum period and included medication exposure history and blood samples. All assays for BUP serum concentrations at steady state were completed. Relative weight-adjusted clearance (Cl) was calculated using Cl = (daily dose [mg]/ body weight [kg])/serum concentration [ng/ml]. We collected 112 maternal blood samples from 29 women throughout pregnancy and the postpartum period. Serum concentrations for BUP ranged from < 0.2 to 15.8 ng/ml. Eleven women, with greater than three collected samples, increased their daily dose of BUP during pregnancy; however, there were no significant differences in relative clearance of BUP across this same period. This data suggests that women with opioid use disorder receiving BUP did not demonstrate a significant increase in BUP clearance across pregnancy despite increase in dosages during pregnancy. When selecting an appropriate BUP dosage for management of perinatal opioid use disorder, gestational stage appears not to be an important covariate and should be based on an individualized approach.


Assessment of Skin Toxicity in an in Vitro Reconstituted Human Epidermis Model Using Deep Learning.
Skin toxicity is a common safety concern associated with drugs that inhibit epidermal growth factor receptors as well as other targets involved in epidermal growth and differentiation. Recently, the use of a three-dimensional reconstructed human epidermis model enabled large-scale drug screening and showed potential for predicting skin toxicity. Although a decrease in epidermal thickness was often observed when the three-dimensional reconstructed tissues were exposed to drugs causing skin toxicity, the thickness evaluation of epidermal layers from a pathologist was subjective and not easily reproducible or scalable. In addition, the subtle differences in thickness among tissues, as well as the large number of samples tested, made cross-study comparison difficult when a manual evaluation strategy was used. The current study used deep learning and image-processing algorithms to measure the viable epidermal thickness from multiple studies and found that the measured thickness was not only significantly correlated with a pathologist's semi-quantitative evaluation but was also in close agreement with the quantitative measurement performed by pathologists. Moreover, a sensitivity of 0.8 and a specificity of 0.75 were achieved when predicting the toxicity of 18 compounds with clinical observations with these epidermal thickness algorithms. This approach is fully automated, reproducible, and highly scalable. It not only shows reasonable accuracy in predicting skin toxicity but also enables cross-study comparison and high-throughput compound screening.


Pharmacist assessment of drug-gene interactions and drug-induced phenoconversion in major depressive disorder: a case report.
Response to antidepressant therapy is highly variable among individuals. Pharmacogenomic (PGx) testing presents an opportunity to guide drug selection while optimizing therapy outcomes and/or decreasing the risk for toxicity. A patient with multiple comorbidities, including severe major depressive disorder (MDD), experienced adverse drug events and undesirable response to multiple antidepressant medications (i.e., bupropion, escitalopram, and venlafaxine). A clinical pharmacist assessed significant drug-gene, drug-drug, and drug-drug-gene interactions as well as other clinical factors to provide recommendations for antidepressant therapy optimization. This case highlights the importance of PGx testing and the key role of pharmacists in identifying and mitigating drug-related problems and optimizing drug therapy in patients with MDD.


Comparison of mechanical properties of beta-titanium wires between leveled and unleveled brackets: an in vitro study.
The objective of this study is to evaluate the force-deflection behavior of beta-titanium alloy wires between two leveled and unleveled bracket alignment scenarios using a three-point bending test. Six groups of ten beta-titanium alloy wire segments (0.017 × 0.025-in. diameter) of different manufacturers (Orthometric, Ortho Organizers, GAC, Morelli, and Ormco) were used. Both brackets were bonded to an acrylic jig with a 10-mm interbracket distance. A 1-mm deflection test in two hypothetical conditions (with aligned brackets and by simulating a 2-mm horizontal displacement of the brackets) was explored. Forces of activation and deactivation of the wires during both tests were compared by an analysis of variance (ANOVA) tests followed by a Tukey test. A statistically significant difference was found in the force-deflection behavior between some of the wires in both simulated in vitro conditions. For the leveled-type alignment scenario, the differences between wires were up to 70 g (range 110 to 179 g). For the unleveled-type alignment scenario, these differences were up to 65 g (range 111 to 175 g). The study showed some significant differences in forces generated during activation and deactivation among the five types of beta-titanium wires tested. In comparing leveled and unleveled brackets during activation, only Orthometric Beta Flexy and Ormco Beta-titanium were different between them.


A benzodiazepine-anticholinergic drug synergism in the prevention of stress-induced gastric mucosal erosion in mice.
Chlordiazepoxide and clidinium each, as a function of dose, prevent stress-induced gastric mucosal erosion in mice. Clidinium was 2.5 times more potent than chlordiazepoxide. When used in a combination of 2 parts chlordiazepoxide and 1 part clidinium, the protective effect was nearly five times greater than that produced by clidinium alone. Furthermore, the combination dosing proved nearly three times more potent than the potency that was predicted from simple additivity of the individual drug effects. This potentiation appears related to the number of ways in which the combination treatment can decrease autonomic input to the gastric mucosa. Thus, the peripheral cholinergic blockade by clidinium may be potentiated by a central chlordiazepoxide suppression of both sympathetic and parasympathetic activities. Therefore, the combined use of these drugs in the therapy of stress-induced gastric disorder appears to have a rational pharmacologic basis.


A comparison of newer classifications of bronchopulmonary dysplasia: findings from the Children's Hospitals Neonatal Consortium Severe BPD Group.
To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. Data from the Children's Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7-21-fold higher for death and 23-56-fold higher for tracheostomy. Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.


Mineral composition of organic and conventional white wines from Italy.
Despite of the increased interest of consumers for organic agro-food products and of the growing demand for organic wines, scientific literature reports a limited number of studies aimed to evaluate the chemical composition of organic wine with respect to conventional wine in terms of major and trace metals. In the present study the concentrations of 19 elements (Al, As, B, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Ni, Pb, Sr, V, and Zn) were determined in samples of white wines from Italy, conventionally and organically produced. No significant difference in the mineral composition was found between the two groups, except for Ni, which showed a higher concentration in organic wines. By comparing our data with data from literature it can be pointed out that there is no agreement among the results presented in the different studies referring to comparisons between organically and conventionally produced wines, concluding that the mineral composition of wines depends on factors different from organic/conventional production method.


Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition.
Mouse embryonic fibroblasts (MEFs) that lack p53 are hypersensitive to the cytotoxic and genotoxic effect of ultraviolet (UV-C) light. They also display a defect in the recovery from UV-C-induced DNA replication inhibition. An enzyme involved in processing stalled DNA replication forks is flap endonuclease 1 (Fen1). Gene expression profiling of UV-C-irradiated MEFs revealed fen1 to be upregulated, which was confirmed by RT-PCR and Western blot experiments. Increased Fen1 levels upon UV-C exposure are due to transcriptional activation, as revealed by inhibitor studies. Fen1 induction was dose- and time-dependent; it occurred on protein level already 3 h after irradiation. Induction of Fen1 by UV-C requires p53 since it was observed in p53 wild-type (wt) but not in p53 null (p53-/-) fibroblasts. Fen1 upregulation paralleled the increase in p53 protein level in replicating wt cells, whereas in nonreplicating cells both Fen1 and p53 were not induced by UV-C. The mouse fen1 promoter was cloned and shown to harbor a p53 consensus sequence to which p53 binds. In cotransfection experiments, p53 stimulated the expression of a fen1 promoter-reporter construct. Transgenic expression of Fen1 in p53 null cells attenuated UV-C light-induced DNA replication inhibition, supporting the hypothesis that Fen1 induction is involved in the recovery of cells from DNA damage.


Cu-Catalyzed Oxyalkynylation and Aminoalkynylation of Unactivated Alkenes: Synthesis of Alkynyl-Featured Isoxazolines and Cyclic Nitrones.
A convenient and efficient vicinal oxyalkynylation/aminoalkynylation of internal unactivated alkenes is achieved by means of a Cu-catalyzed radical cascade reaction of unsaturated ketoximes with ethynylbenziodoxolone (EBX) reagents. This protocol enables the synthesis of structurally valuable isoxazolines or cyclic nitrones and the introduction of an important alkyne group in a single operation. The reaction is characterized by a broad substrate scope for both unsaturated ketoximes and alkynylation reagents and a low catalyst loading.


Protective effect of different doses of terfenadine on the conjunctival provocation test.
The protective effect of terfenadine on inflammatory processes following the early phase of conjunctival provocation tests by specific allergen was assessed in 24 patients suffering from seasonal allergic rhinoconjunctivitis, in a single-blind, randomized, placebo-controlled, parallel-group study. Patients were randomly assigned to four treatment groups, each being given terfenadine 60, 120, 180 mg daily, or placebo, respectively, for 7 days, out of the pollen season. Clinical severity (burning, itching, lacrimation and hyperemia), and number of inflammatory cells obtained by conjunctival scraping (neutrophils, eosinophils, lymphocytes, and monocytes) were evaluated before and after treatment. Pre-treatment with terfenadine resulted in a significantly higher allergen threshold dose than placebo (p less than 0.01), regardless of drug dose. Patients given terfenadine experienced a significant reduction (p less than 0.03) in conjunctival symptom severity, as compared with placebo, following conjunctival challenge. Accordingly, the number of inflammatory cells in terfenadine-treated patients was significantly lower (p less than 0.01) than in the placebo-treated after the conjunctival provocation test. The results of this study suggest that terfenadine has a significant protective effect on the early-phase cellular and clinical events of conjunctival reaction induced by allergen challenge in atopic patients.


The impact of medication side effects on adherence and persistence to hormone therapy in breast cancer survivors: A qualitative systematic review and thematic synthesis.
Hormone Therapy (HT) reduces the risk of breast cancer recurrence and mortality in women with breast cancer. Despite these clinical benefits, rates of HT non-adherence and non-persistence are high. Research suggests this may be due to the impact of HT side effects. However, little research has explored the individual contribution of side effects to non-adherence and non-persistence behaviours, thereby hindering the implementation of targeted intervention strategies. Our aim is to review the published literature on breast cancer survivors' lived experiences of HT side effects and explore how these may be related to non-adherence and non-persistence behaviour. Electronic searches were conducted from inception to May 2020, utilising Cochrane CENTRAL, Medline, Embase, Web of Science and PsycINFO databases. Searches included a combination of terms related to breast cancer, adherence, hormone therapy and side effects. Sixteen eligible papers were identified, and study quality was high. Data were thematically synthesised into four analytical themes, which encompassed 13 descriptive sub-themes: 'Daily impact of side-effects', 'Role of Health Care Professionals', 'Managing HT side-effects', and 'Weighing up the pros and cons'. HT side effects significantly impact breast cancer survivor's quality of life. A lack of support from healthcare providers leads to self-management strategies, which negatively affects adherence and persistence behaviour.


The influence of gender on functional outcomes of lower extremity bypass.
Our aim was to evaluate the effect of gender on early and late procedural and functional outcomes of lower extremity bypass (LEB). We reviewed the records of 2576 patients (828 women; 32%) who underwent LEB for claudication or critical limb ischemia (CLI) in the Vascular Study Group of New England from 2003 to 2010. Logistic regression and proportional hazards models were used to adjust for potential confounding differences between genders. Morbidity, mortality, graft patency, freedom from major amputation, ambulation, and living status were analyzed postoperatively and over 1 year. Women were older (70 vs 68 years; P < .001), had more hypertension (89% vs 85%; P = .006), less coronary artery disease (35% vs 39%; P = .03), smoking (73% vs 88%; P < .001), and preoperative statin use (60% vs 64%; P = .04). Women were more likely to have CLI (76% vs 71%; P = .003), and ambulate with assistance at presentation (19% vs 16%; P = .02). Morbidity was similar except women had higher rates of reoperation for thrombosis (4% vs 2%; P < .001) without differences in major amputation (2% vs 1%; P = .13) or in-hospital mortality (1.7% vs 1.7%; P = .96). Women and men with claudication had similar 1-year graft patency rates. Women with CLI had lower rates of primary (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.48; P = .02), assisted primary (HR, 1.42; 95% CI, 1.15-1.76; P = .001) and secondary patency (HR, 1.40; 95% CI, 1.10-1.77; P = .006) during the first year compared with men. Freedom from amputation was similar for men and women with CLI (HR, 1.17; 95% CI, 0.84-1.63; P = .36). There were no differences in late survival between women and men with claudication (HR, 0.89; 95% CI, 0.60-1.31; P = .36) or CLI (HR, 0.94; 95% CI, 0.81-1.09; P = .39). More female claudicants were not independently ambulatory at discharge (30% vs 19%; P = .002) and were discharged to a nursing home (15% vs 5%; P < .001) but these differences did not persist at 1 year. Women with CLI were more likely to be nonambulatory at discharge (13% vs 9%; P = .006) and at 1 year (13% vs 8%; P < .001). More women with CLI were discharged to a nursing home (44% vs 35%; P = .01) and resided there at 1 year (11% vs 7%; P = .02). Women have complication rates similar to men with inferior early and late functional outcomes after LEB. The reduced patency rates in women with CLI did not translate into differences in limb salvage. These findings might help define physician and patient expectations for women before revascularization.


Localization of melanoma with radiolabelled monoclonal antibody fragments and iodoamphetamine.
In two melanoma patients, metastases accumulated both 99mTc-labelled monoclonal anti-tumor F(ab')2 fragments and N-isopropyl-p-(123I)-iodoamphetamine. Small metastatic deposits were localized only by labelled antibody, for which a higher target-to-nontarget ratio was observed than for radioiodoamphetamine, indicating that immunoscintigraphy may be the more sensitive method. In these two patients positive immunohistochemical staining for the antibody used was observed, whereas in a third patient, with no concentration of labelled antibody, the staining result was negative showing the specificity of the immunoscintigraphy findings. It is possible that the accumulation of radio-iodoamphetamine is due to binding to melanin but this is not certain as tissue samples from one of the two patients with positive scintigrams did not contain stainable melanin.


Evaluation of a tumor electric field treatment system in a rat model of glioma.
Glioma is a devastating disease lacking effective treatment. Tumor electric field therapy is emerging as a novel non-invasive therapy. The current study evaluates the efficacy and safety of a self-designed tumor electric field therapy system (TEFTS ASCLU-300) in a rat orthotopic transplantation model of glioma. A model of intracranial orthotopic transplantation was established in rats using glioma C6 cells. For electric field therapy, glioma-bearing rats were exposed to alternating electric fields generated by a self-developed TEFTS starting on either 1st (Group 2) or 3rd (Group 3) day after transplantation, while other conditions were maintained the same as non-treated rats (Group 1). Glioma size, body weight, and overall survival (OS) were compared between groups. Immunohistochemical staining was applied to access tumor cell death and microvessel density within the tumor. In addition, the systemic effects of TEFTS on blood cells, vital organs, and hepatorenal functions were evaluated. TEFTS treatment significantly elongated the OS of tumor-bearing rats compared with non-treated rats (non-treated vs treated: 24.77 ± 7.08 days vs 40.31 ± 19.11 days, P = .0031). Continuous TEFTS treatment starting on 1st or 3rd day significantly reduced glioma size at 2 and 3 weeks after tumor cell inoculation (Week 2: Group 1:289.95 ± 101.69 mm3 ; Group 2:70.45 ± 17.79 mm3 ; Group 3:73.88 ± 33.21 mm3 , P < .0001. Week 3: Group 1:544.096 ± 78.53 mm3 ; Group 2:187.58 ± 78.44 mm3 ; Group 3:167.14 ± 109.96 mm3 , P = .0005). Continuous treatment for more than 4 weeks inhibited tumor growth. The TEFTS treatment promoted tumor cell death, as demonstrated by increased number of Caspase 3+ cells within the tumor (non-treated vs treated: 38.06 ± 10.04 vs 68.57 ± 8.09 cells/field, P = .0007), but had minimal effect on microvessel density, as shown by CD31 expression (non-treated vs treated: 1.63 ± 0.09 vs 1.57 ± 0.13% of positively stained areas, P > .05). No remarkable differences were observed in hepatorenal function, blood cell counts, or other vital organs between non-treated and treated groups. The TEFTS developed by our research team was proved to be effective and safe to inhibit tumor growth and improve general outcomes in a rat model of brain glioma.


Septicemia as a complication of percutaneous liver biopsy.
Three cases of septicemic shock after liver biopsy are reported. Escherichia coli was cultured in 2 patients and in 1 E. coli was cultured with Streptococcus viridans. All 3 patients were afebrile and had normal WBC counts before the procedure. Two had cholangitis and the 3rd had primary hepatoma and cirrhosis of the liver. Septicemic shock should be recognized as a rare complication of liver biopsy in patients with biliary obstruction.


High sugar worse than high sodium in oral rehydration solutions.
The literature on oral sugar-electrolyte mixtures for treatment of acute diarrhoea is reviewed. Several trials have shown that the solution proposed by the WHO for developing countries containing inter alia 90 mmol/l of sodium and 111 mmol/l of glucose is safe for short term oral rehydration. When used in this manner there is no risk for development of hypernatraemia. The surplus base of the solution is not essential and, furthermore, other anions e.g. acetate may be substitute for bicarbonate. Other modifications of the WHO formula have also been successfully tried, e.g. sucrose 4% (117 mmol/l) instead of glucose 2% (111 mmol/l). A somewhat lower concentration of sucrose may, however, prove to be better. Most acute childhood diarrhoeas are not mediated by enterotoxin and thus not of the secretory type, but temporary malabsorption is common. Therefore, the amount of carbohydrate in oral sugar-electrolyte mixtures should be limited. Osmotic diarrhoea due to carbohydrate malabsorption is a more likely cause of hypernatraemia in dehydrated children than too much dietary sodium. In developed countries prepacked oral sugar-electrolyte mixtures are mainly designed for moderately sick children treated at home. There is no reason to raise the carbohydrate content of these mixtures above that of the WHO formula, but the sodium content must be lower. For most situations in home treatment 50 mmol/l of sodium will be adequate.


The Relation between Serum Endostatin Level and Carotid Atherosclerosis in Healthy Residents of Japan: Results from the Kyushu and Okinawa Population Study (KOPS).
To examine the association between the serum endostatin levels and subclinical atherosclerosis independent of traditional risk factors in a healthy Japanese population. Among 1,057 residents who attended free public physical examinations between 2010 and 2011, we evaluated the data of 648 healthy residents for whom the serum endostatin level and common carotid intima-media thickness (IMT) were successfully measured. The median endostatin level was 63.7 ng/mL (interquartile ranges: 49.7-93.2 ng/mL), and the mean carotid IMT was 0.68±0.12 mm. Residents with above median endostatin had significantly higher carotid IMT than did those with below median endostatin (0.71±0.14 vs. 0.65±0.09 mm, P<0.001). Multiple linear regression analysis demonstrated that increased serum endostatin is significantly associated with carotid IMT (above vs. below median endostatin level; beta=0.11, P=0.03), independent of the known covariates of age, sex, body mass index, drinking and smoking status, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, low density lipoprotein cholesterol, estimated glomerular filtration rate, and log-transformed high sensitive C-reactive protein. A higher serum endostatin level reflected subclinical atherosclerosis in this Japanese population.


Utilising International Statistical Classification of Diseases and Related Health Conditions (ICD)-10 Australian Modification Classifications of "Health Conditions" to Achieve Population Health Surveillance in an Australian Spinal Cord Injury Cohort.
Retrospective, non-randomised, registry controlled. To develop a conceptual ICD-10 taxonomic framework for population health surveillance across all-phases of spinal cord injury and disorders (SCI/D). Public Hospital Admitted Patient Care (APC) collection, South Australian Dept. Health, South Australia, Australia. A core ICD-10-Australian Modification (AM) coded dataset was retrieved from the APC hospital patient admission collection (2012-2017). Search filters and key words referenced to the National Library of Medicine thesaurus identified and quantified incident SCI/D cases. Incident SCI/D case data held in the Australian Spinal Cord Injury Registry (ASCIR) of South Australia (2012-2017) tested fidelity. Data linkage to the South Australian Death Registry controlled for cohort attrition. Both unadjusted and case-mix adjusted core data set yields were evaluated. Outcomes were assessed in terms of APC frequency difference (Δ%) versus ASCIR. 3,504 APC cases were extracted, of which 504 (mean, SD age 55 ± 20 yrs; 348 [69%] male, 202 [39%] traumatic; 135 [32%]) cervical; 51 [10.1%] thoracic and (16 [3.2%]) lumbar met criteria. Comparator data were 385 ASCIR new index cases mean, SD age 56 ± 19 yrs, 229 [75%] male, 162 [42%] traumatic. Case-mix adjusted analysis yielded 336 (APC Δ33%) all-cause incident cases (vs. ASCIR -13 Δ%) and 131 incident cases of traumatic aetiologies (vs. ASCIR -19 Δ%). The ICD-10 core "Health Condition" data-set assembled extends our understanding of SCI/D epidemiology and with further development may create a cost-efficient and sustainable framework that will improve health system performance and equity within and between countries. The Lifetime Support Authority of South Australia sponsored the study.


Purification and characterization of a novel cytosolic NADP(H)-dependent retinol oxidoreductase from rabbit liver.
Rabbit liver cytosol exhibits very high retinol dehydrogenase activity. At least two retinol dehydrogenases were demonstrated to exist in rabbit liver cytosol, and the major one, a cytosolic NADP(H)-dependent retinol dehydrogenase (systematic name: retinol oxidoreductase) was purified about 1795-fold to electrophoretic and column chromatographic homogeneity by a procedure involving column chromatography on AF-Red Toyopearl twice and then hydroxyapatite. Its molecular mass was estimated to be 34 kDa by SDS-PAGE, and 144 kDa by HPLC gel filtration, suggesting that it is a homo-tetramer. The enzyme uses free retinol and retinal, and their complexes with CRBP as substrates in vitro. The optimum pH values for retinol oxidation of free retinol and CRBP-retinol were 8.8-9.2 and 8.0-9.0, respectively, and those for retinal reduction of free retinal and retinal-CRBP were the same, 7.0-7.6. Km for free retinol and Vmax for retinal formation were 2.8 microM and 2893 nmol/min per mg protein at 37 degrees C (pH 9.0) and the corresponding values with retinol-CRBP as a substrate were 2.5 microM and 2428 nmol/min per mg protein at 37 degrees C (pH 8.6); Km for free retinal and Vmax for retinol formation were 6.5 microM and 4108 nmol/min per mg protein, and the corresponding values with retinal-CRBP as a substrate were 5.1 microM and 3067 nmol/min per mg protein at 37 degrees C, pH 7.4. NAD(H) was not effective as a cofactor. 4-Methylpyrazole was a weak inhibitor (IC50 = 28 mM) of the enzyme, and ethanol was neither a substrate nor an inhibitor of the enzyme. This enzyme exhibits relatively broad aldehyde reductase activity and some ketone reductase activity, the activity for aromatic substitutive aldehydes being especially high and effective. Whereas, except in the case of retinol, oxidative activity toward the corresponding alcohols was not detected. This novel cytosolic enzyme may play an important role in vivo in maintaining the homeostasis of retinal, the substrate of retinoic acid synthesis, at least in rabbit liver, since a high concentration of retinol in liver and the lower Km of the enzyme for retinol force the oxidative reaction, while higher activity of retinal reductase at physiological pH forces the reductive reaction.


Niacin prevents DNA strand breakage by adenosine deaminase inhibitors.
The adenosine deaminase inhibitors deoxycoformycin and erythro-9-(2-hydroxy-3 nonyl) adenine (EHNA) induce single-strand DNA breaks in cultured human lymphocytes. Deoxycoformycin produced a significant number of strand breaks (4-fold increase compared to controls) and EHNA induced strand breaks in a dose-dependent manner. Strand breaks stimulate repair by poly(ADP-ribosylation) which requires NAD+ as a cofactor. Niacin is a precursor of NAD+ and when preincubated with human lymphocytes prior to exposure to adenosine deaminase inhibitors, strand breakage was reduced significantly. The administration of niacin may represent an approach to decreasing the toxicity associated with these agents.


Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer.
Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC). Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes. In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis. Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.


Development and validation of ischemic heart disease and stroke prognostic models using large-scale real-world data from Japan.
Previous cardiovascular risk prediction models in Japan have utilized prospective cohort studies with concise data. As the health information including health check-up records and administrative claims becomes digitalized and publicly available, application of large datasets based on such real-world data can achieve prediction accuracy and support social implementation of cardiovascular disease risk prediction models in preventive and clinical practice. In this study, classical regression and machine learning methods were explored to develop ischemic heart disease (IHD) and stroke prognostic models using real-world data. IQVIA Japan Claims Database was searched to include 691,160 individuals (predominantly corporate employees and their families working in secondary and tertiary industries) with at least one annual health check-up record during the identification period (April 2013-December 2018). The primary outcome of the study was the first recorded IHD or stroke event. Predictors were annual health check-up records at the index year-month, comprising demographic characteristics, laboratory tests, and questionnaire features. Four prediction models (Cox, Elnet-Cox, XGBoost, and Ensemble) were assessed in the present study to develop a cardiovascular disease risk prediction model for Japan. The analysis cohort consisted of 572,971 invididuals. All prediction models showed similarly good performance. The Harrell's C-index was close to 0.9 for all IHD models, and above 0.7 for stroke models. In IHD models, age, sex, high-density lipoprotein, low-density lipoprotein, cholesterol, and systolic blood pressure had higher importance, while in stroke models systolic blood pressure and age had higher importance. Our study analyzed classical regression and machine learning algorithms to develop cardiovascular disease risk prediction models for IHD and stroke in Japan that can be applied to practical use in a large population with predictive accuracy.


Thin bronchoscopic cryobiopsy using a nasobronchial tube.
Transbronchial lung cryobiopsy is useful when diagnosing lung lesions. However, prevention of associated bleeding complications is essential. This study aimed to evaluate the safety and efficacy of our novel bronchoscopic cryobiopsy technique, which uses a long nasobronchial tube to prevent blood flooding the central airway. Patients with localized or diffuse lung lesions were prospectively enrolled and underwent cryobiopsy using a 1.9 mm diameter cryoprobe and a 4.0 mm diameter thin bronchoscope under conscious sedation. For cryobiopsy, a long silicone tube (inner diameter, 5.0 mm) was advanced through the nose to the target bronchus, then wedged to drain blood under thin-tube bronchoscopic control. The primary endpoint was the frequency of bleeding complications. Of the 80 patients initially enrolled, 73 that underwent at least one cryobiopsy were ultimately included. Mild bleeding during cryobiopsy occurred in 58 patients (79.5%), but there was no moderate or severe bleeding. Other complications occurred in four patients (two pneumothorax, one pneumomediastinum, and one pneumonia). Tube dislocation was noted in eight patients (11%). Cryobiopsy specimens were significantly larger than forceps biopsy specimens (9.0 mm2 vs. 2.7 mm2, P < .001) and allowed specific diagnoses in 50 patients (68.5%). Thin bronchoscopic cryobiopsy using a nasobronchial tube in consciously sedated patients is safe and effective. Trial registration Date of registration: 24/06/2019. UMIN-Clinical Trials Registry; Identifier: UMIN000037156 https://www.umin.ac.jp/ctr/index.htm.


A complex interplay of Gβ and Gγ proteins regulates plant growth and defence traits in the allotetraploid Brassica juncea.
Gene expression analysis coupled with in-planta studies showed that specific Gβγ combination regulates plant growth and defence traits in the allotetraploid Brassica juncea. Plant heterotrimeric G-proteins regulate a wide range of responses despite their limited repertoire of core components. The roles and functional interactions between different G-protein subunits are quite perplexing, which get further complicated with polyploidy. Here, we show that the allotetraploid Brassica juncea comprises multiple homologs of G-protein genes, encoding six BjuGβ and ten highly divergent BjuGγ subunit proteins, later being classified into type-A1, type-A2 and type-C Gγ proteins. The encoded BjuGβ and BjuGγ proteins shared close evolutionary relationship and have retained distinct spatio-temporal expression patterns during plant developmental stages and in response to the necrotrophic pathogen, Sclerotinia sclerotiorum. RNAi based suppression of BjuGβ and BjuGγ genes suggested functional overlap and selectivity of BjuGβs with three distinct BjuGγ type subunits, to regulate plant height (BjuGβγA2 and BjuGβγC), seed weight (BjuGβGγA1 and BjuGβGγC), silique size (BjuGβGγC) and pathogen response (BjuGβGγA1 and BjuGβGγC). Further, the triplicated BjuGβ genes, formed due to Brassica specific whole-genome-triplication event, showed differential involvement during pathogen response, wherein overexpression of BjuGβ2 displayed higher resistance to Sclerotinia infection. Taken together, our study demonstrates that multiple BjuGβ and BjuGγ proteins have retained distinct spatio-temporal expression and functional selectivity to regulate specific plant growth and defence traits in the oilseed B. juncea.


Erythropoiesis-stimulating agents and cardiovascular events in patients with myelodysplastic syndrome and multiple myeloma.
Erythropoiesis-stimulating agent (ESA) treatment has been associated with an increased risk of venous thromboembolism (VTE) in patients with solid tumors and with an increased risk of cardiovascular events in patients with chronic kidney disease. The ESA-related risk in patients with hematological neoplasms remains unclear. We, therefore, aimed to assess the ESA-related risk of VTE, myocardial infarction (MI), and stroke in patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). We conducted a population-based cohort study in Denmark, using medical databases to identify 2,114 MDS patients and 3,105 MM patients diagnosed in 2004-2013. Incidence rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE, MI, and stroke associated with ESA treatment were computed. HRs were calculated in time-dependent Cox regression and adjusted for age, sex, MDS prognosis group, comorbidities, and treatments. Incidence rates per 1,000 person-years for VTE, MI, and stroke were 10.8, 8.2, and 16.0 in MDS patients, and 21.9, 10.2 and 9.9 in MM patients without ESA treatment, respectively. MDS patients with ESA treatment had a 1.6-fold increased risk of MI (HR 1.60 [95% CI 0.90-2.86]) and an almost twofold increased risk of stroke (HR 1.94 [95% CI 1.28-2.94]). Adjusted HR for VTE was 1.04 (95% CI 0.57-1.89) compared with MDS patients without ESAs. In MM patients with ESAs compared with patients without ESAs, HRs were 1.41 (95% CI 0.96-2.08) for VTE, 1.23 (95% CI 0.68-2.20) for MI, and 1.63 (95% CI 0.96-2.77) for stroke. ESA use was associated with stroke in MDS patients. Among MM patients, ESA treatment was associated with a higher risk of all cardiovascular events, although all CIs included equivalence.


Clinical review 2: Genetic determinants of bone density and fracture risk--state of the art and future directions.
Osteoporosis is a common, highly heritable condition that causes substantial morbidity and mortality, the etiopathogenesis of which is poorly understood. Genetic studies are making increasingly rapid progress in identifying the genes involved. In this review, we will summarize the current understanding of the genetics of osteoporosis based on publications from PubMed from the year 1987 onward. Most genes involved in osteoporosis identified to date encode components of known pathways involved in bone synthesis or resorption, but as the field progresses, new pathways are being identified. Only a small proportion of the total genetic variation involved in osteoporosis has been identified, and new approaches will be required to identify most of the remaining genes.


Teprotumumab for the treatment of mild compressive optic neuropathy in thyroid eye disease: A report of two cases.
To report two cases of thyroid eye disease (TED) associated compressive optic neuropathy (CON) that resolved after treatment with teprotumumab. Two patients presented with active TED resulting in mild CON with the typical corresponding visual field (VF) defects. Both patients were initiated on intravenous (IV) corticosteroid therapy but despite treatment had persistent VF defects. Both patients were then treated with teprotumumab and demonstrated marked clinical improvement and complete resolution of TED-CON VF defects early in their infusion course. These cases suggest that teprotumumab can be a rapid and effective treatment for TED-CON, and raises the question of whether it may be superior to IV corticosteroid therapy.


A 54-Year-Old Man With Chronic Cough and Recurrent Upper Respiratory Infection.
A 54-year-old man sought treatment at the ED for a productive cough with green phlegm of approximately 6 months' duration that was accompanied by a 10-pound weight loss, night sweats, and occasional subjective fevers. He had made several prior visits to the ED for the cough and was hospitalized 4 months earlier for similar symptoms, at which time he underwent a bronchoscopy with BAL and was discharged with antibiotics for presumed pneumonia. He did not report any itching, rashes, sinus infections, joint swelling, joint pain, or GI symptoms. His long-term medications included omeprazole and amlodipine. The patient had a past medical history of grade III follicular lymphoma for which he completed six cycles of bendamustine 4 years before presentation and had been in remission since. He was a never smoker, had a recent travel history to the Dominican Republic 8 months before admission, and had no recent sick contacts.


Differential biomarker expression in head and neck cancer correlates with anatomical localization.
We tested the expression of known (p16(ink4), Ki67, p53, EGFR) and a new immunohistochemical (collagen XVII/BP180) biomarker in head and neck squamous cell carcinomas (SCC) of diverse anatomical localization. Tissue microarrays (TMA) of 124 SCC were created, immunostained, and analyzed following whole slide digitalization using the Pannoramic Scan and the TMA Module software (3DHISTECH Kft, Budapest, Hungary). Statistical analysis of scoring results was carried out using Pearson's chi-square test. We observed the significant elevation of p16(ink4) and Ki67 expression in supraglottic, tonsillar and tonsillo-lingual SCCs compared to those affecting the oral cavity, oropharynx without tonsils, larynx without supraglottis and the hypopharynx. This differential antigen expression may reflect the diverse route of embryologic differentiation followed by the affected regions except those of the tonsils and the supraglottis which show similar antigenic pattern but diverse developmental path. All the other biomarkers tested including p53, collagen XVII and EGFR were detected in the majority of cancers including high grade cases, but did not reveal any significant regional difference. Based on our results oropharyngeal squamous cell carcinomas may not be regarded as one entity. Concerning the oral cavity and the oropharynx, cancers affecting the tonsils (palatine and lingual) show significantly elevated p16(ink4) and Ki67 expression; so as the cancers of the supraglottis compared to the rest of larynx. Consequently, tonsillar and supraglottic cancers show similar biomarker profiles. Correlation of differential biomarker expression with diverse biological behavior in head and neck cancers need further investigations.


Bending stiffness of lipid bilayers: IV. Interpretation of red cell shape change.
Two mechanisms are operative when the resting shape of human red cells is changed into an echinocyte or a stomatocyte. The first (bilayer couple) is a differential change in the surface area of the two monolayers. It rests on the two-dimensional isotropic elasticity of the two monolayers and their fixed distance. The second (single layer) is a change in the average cone angle of the molecules comprising a monolayer. It rests on the intrinsic bending elasticity of each single layer. With a few exceptions the first mechanism has been quoted to interpret experimentally observed shape changes. To reconsider this preference two types of spontaneous curvatures (in bilayer couple bending and in single-layer bending) are defined. It is shown that (a) disregarding the single-layer mechanism is not justified and (b) there is too little basic information for quantitative interpretations of shape change.