Arm-Cranking Exercise Training Reduces Plasminogen Activator Inhibitor 1 in People With Spinal Cord Injury.
To investigate the effects of arm-cranking exercise training on plasminogen activator inhibitor 1 (PAI-1) as a risk factor of deep vein thrombosis, along with general physical parameters such as muscle strength, aerobic capacity, and hemodynamics, in individuals with spinal cord injury (SCI) and control subjects. Longitudinal study. Community-based supervised intervention. Participants (N=17) comprised individuals with SCI (n=9) who volunteered for this study, and able-bodied individuals (n=8) matched for age, height, and body mass index who were assessed at baseline only. The arm-cranking exercise program was performed for 10 weeks with 4 sessions per week. Sessions consisted of 2 sets of warmup (5min) and arm crank exercises (25min) with a 10-minute recovery at an intensity of 50% to 70% of heart rate reserve. Body mass (BM), waist circumference (WC), aerobic capacity (peak oxygen consumption [Vo2peak]), PAI-1, blood pressure, glucose metabolism, and lipids. PAI-1, BM, WC, systolic blood pressure, and triglycerides (TG) decreased, and Vo2peak increased after training (P<.05, respectively). Spearman rank-order analysis revealed that changes in PAI-1 were related to changes in Vo2peak, BM, WC, TG, and high-density lipoprotein cholesterol. Multiple linear regression analysis revealed that WC was the most sensitive factor for predicting changes in PAI-1 (P=.038). These results suggest that 10 weeks of arm-cranking exercise training for people with SCI may help to reduce the risk factors of cardiovascular disease. In addition, changes in abdominal fat may be related to changes in PAI-1 in the SCI population.


Kzp regulates the transcription of gata2 and pu.1 during primitive hematopoiesis in zebrafish embryos.
Kaiso zinc finger-containing protein (Kzp), a maternally-derived transcription factor, controls dorsoventral patterning during zebrafish gastrulation. Here, we uncovered a new function for Kzp in zebrafish embryonic primitive hematopoiesis. The depletion of kzp led to defects in primitive hematopoiesis including the development of the erythroid and myeloid lineages. On the other hand, overexpression of kzp caused the ectopic expression of gata1, gata2, and pu.1. Chromosome immunoprecipitation assays revealed that Kzp protein directly binds to gata1, gata2, and pu.1 promoters. Interestingly, the ectopic expression of gata2 was able to rescue the erythroid, but not the myeloid lineage in kzp-depleted zebrafish embryos. gata1 expression controlled by Kzp was dependent on gata2 during primitive erythropoiesis. Our results indicate that Kzp is a critical transcriptional factor for the expression of gata2 and pu.1 to modulate primitive hematopoiesis.


Autofluorescence characteristics of suspicious choroidal nevi.
The aim of this study was to describe autofluorescence characteristics of 30 suspicious choroidal nevi. Fundus autofluorescence (FAF) images were reviewed retrospectively on 30 consecutive cases of suspicious choroidal nevi. Autofluorescence imaging was achieved using a fundus camera-based system with a barrier filter of 695 nm and excitation of 580 nm. All nevi exhibited one or more of the following characteristics: tumor thickness, basal dimension greater than 5 mm, subretinal fluid, posterior location, ophthalmic symptoms, or lipofuscin (orange pigment). Suspicious choroidal nevi were found to have specific FAF features. Orange pigment was noted in 67% of the nevi and appeared as very bright hyperfluorescent areas. Overlying retinal pigment epithelium hypertrophy and atrophy were noted in 50% and appeared darkly hypofluorescent. Subretinal fluid (17%) and drusen (17%) both appeared mildly hyperfluorescent. Orange pigment was the most hyperfluorescent FAF finding. Because the presence of orange pigment is a known risk factor for malignant transformation, the use of camera-based FAF imaging may improve our ability to identify those choroidal nevi that will transform into malignant melanoma. More long-term follow-up studies will be required to determine the exact prognostic value of our findings.


Integration in descending motor pathways controlling the forelimb in the cat. 2. Convergence on neurones mediating disynaptic cortico-motoneuronal excitation.
With intracellular recording from forelimb motoneurones the spatial facilitation technique has been used to investigate interaction between descending pathways and forelimb afferents. As previously shown for the hindlimb, pyramidal volleys effectively facilitate interneuronal transmission in reflex pathways from different primary afferents. Evidence is presented suggesting disynaptic excitation from corticospinal fibres of interneurones in the reciprocal Ia inhibitory pathway. Interneurones of other reflex pathways from group I muscle afferents recieve monosynaptic pyramidal excitation. During pyramidal facilitation volleys in cutaneous afferents may evoke PSPs in motoneurones after a central delay of 1.3 ms suggesting that the minimal linkage is disynaptic. Information regarding convergence on the neurones intercalated in the disynaptic cortico-motoneuronal pathway was obtained by investigating the effect from primary afferents and from other descending pathways on the disynaptic pyramidal EPSPs. Volleys in cutaneous and group I muscle affferents facilitate transmission in the disynaptic cortico-motoneuronal transmission with a time course showing oligosynaptic (probably monosynaptic) action the intercalated neurone. Rubrospinal volleys likewise effectively facilitate disynaptic cortico-motoneuronal pathway with a time course showing oligosynaptic (probably monosynaptic) action on the intercalated neurone. Rubrospinal volleys likewise effectively facilitate disynaptic cortico-motoneuronal transmission with a time course showing monosynaptic action on the intercalated neurone. Spatial facilitation experiments involving three tests revealed that those intercalated neurones which receive convergent monosynaptic excitation from corticospinal and rubrospinal fibres are excited also from cutaneous forelimb afferents. Disynaptic cortico-motoneuronal transmission was also monosynaptically facilitated by stimuli in the dorsal mesencephalic tegmentum probably activating tectospinal fibres. Disynaptic, presumed tectospinal EPSPs were facilitated from cutaneous forelimb afferents. The convergence onto the neurones intercalated in the disynaptic excitatory cortico-motoneuronal pathway suggests that these neurones integrate the activity in different descending pathways and primary forelimb afferents.


Role of MMP-7 in the pathogenesis of systemic lupus erythematosus (SLE).
Systemic lupus erythematosus (SLE) is a clinically heterogeneous chronic, inflammatory autoimmune disorder. The association of MMP-7 and disease severity is still unclear. A total of 150 SLE patients and matched healthy controls were recruited for this study. Disease activity was scored according to SLEDAI (98 active and 52 inactive disease). Mean serum MMP-7 levels were significantly higher in SLE patients than controls ( p < 0.001). Patients with active disease showed higher levels (16.24 ± 6.2 ng/ml) as against inactive disease (10.50 ± 3.97 ng/ml) ( p ≤ 0.0001). Mean MMP-7 mRNA expression was significantly higher in patients (RQ = 3.16 ± 0.93) as compared to controls (RQ = 2.21 ± 0.89, p = 0.006). A positive correlation between MMP-7 levels, mRNA expression and SLEDAI score was observed ( r = 0.563, r = 0.427). The MMP-7 -181 G allele was found to be significantly higher among SLE patients ( p < 0.0001). A significant association was noted between MMP-7 -181 A/G +G/G genotypes with renal ( p = 0.0027) and CNS ( p = 0.0031) manifestations and anti-dsDNA autoantibodies ( p = 0.0312). Serum MMP-7 levels and mRNA expression were elevated in advanced stages of SLE, indicating that MMP-7 is associated with disease activity in SLE.


Silibinin Effect on Methotrexate-Induced Hepatotoxicity in Rats.
Hepatotoxicity is one of the major side effects of methotrexate and limits its use. In this study, we investigated the hepatoprotective effect of silibinin and the role of oxidative stress markers and cytokines on high-dose methotrexate-induced hepatotoxicity in rats. In this study, rats were randomly divided into 5 groups (n=7). Methotrexate (20 mg/kg, intraperitoneally) was administered on the first day in all groups except control. Silibinin was injected for 5 days to methotrexate-silibinin25, methotrexate-silibinin50, and methotrexate-silibinin100 groups at a dose of 25, 50, and 100 mg/kg/day, respectively. On the sixth day, blood and liver samples were obtained and rats were sacrificed. Serum total antioxidant capacity, total oxidant status, total thiol, native thiol, alanine aminotransferase, aspartate transaminase, bilirubin, albumin, tumor necrosis factor-alpha, and interleukin-10 levels were measured. In addition, a histopathological evaluation of liver tissues was performed. Methotrexate reduced total antioxidant capacity and increased disulfide/total thiol ratio. Histopathologic examination revealed that methotrexate increased hepatic damage and 50 mg/kg/dose of silibinin prevented inflammatory cell infiltration in particular. Our results suggest that silibinin (50 mg/kg/day) may reduce the hepatic damage in methotrexate-induced hepatotoxicity in rats by increasing antioxidant capacity.


Pregnancy increases cardiovascular toxicity to cocaine.
The effects of intravenous cocaine on heart rate and blood pressure were studied in pregnant and oophorectomized nonpregnant ewes. In response to intravenous cocaine doses of 1.0 and 2.0 mg/kg, both pregnant and nonpregnant ewes demonstrated dose-dependent increases in systolic, diastolic, mean arterial, and pulse pressures with return to baseline by 30 to 60 minutes after cocaine administration. However, at both doses (1.0 and 2.0 mg/kg) pregnant ewes demonstrated greater increases in mean arterial pressure (+29.6%, +48.7%) than nonpregnant ewes (+15.6%, +27.7%) during the first 5 minutes after cocaine administration. Thereafter the responses were similar. Thus pregnancy increases the cardiovascular toxicity to cocaine.


Assessing Staff's and Stroke Patients' Experiences in 8 Hospitals in Greece: Results from a Prospective Multi-Center Study ("SUN4Patients").
To assess stroke patient-reported experiences and hospital staff experiences, during hospital stay. Stroke patient-reported experiences (n=387) were recorded using the translated and culturally adapted NHS-Stroke Questionnaire into Greek and staff experiences (n=236) were investigated using the Compassion Satisfaction and Burnout subscales of the ProQOL questionnaire. Staff's mean compassion satisfaction score was 39.2 (SD=6.3) and mean burnout score was 24.3 (SD=5.6). Only 38.5% of the staff stated that there is smooth cooperation with healthcare professionals of other specialties/disciplines. Personnel working in an NHS Hospital was more satisfied and less burned-out when compared to personnel working at a University Hospital (p=0.02 and p<0.001, respectively). Mean total patient-reported experiences score was 81.9 (SD=9.5). Bivariate analysis revealed statistically significant differences for total patient-reported experiences among the eight study hospitals (p>0.001). Health policy planners and decision-makers must take into consideration the results of such self-reported measures to establish innovative techniques to accomplish goals such as staff-specialization, continuous training and applying formal frameworks for efficient cooperation amongst different disciplines.


Sequence of two related P-450 mRNAs transcriptionally increased during rat development. An R.dre.1 sequence occupies the complete 3' untranslated region of a liver mRNA.
Polyclonal antibody against a cytochrome P-450 expressed in adult male rats was utilized to screen a lambda gt-11 library. Two cDNAs were isolated and sequenced. The cDNA and deduced protein sequence revealed that these P-450s correspond to previously isolated P-450 PB1 (Waxman D. T., Ko, A., and Walsh, C., (1983) J. Biol. Chem. 258, 11937-11947) and P-450f (Ryan, D. E., Iida, S., Wood, A. W., Thomas, P. E., Lieber, C. S., and Levin, W., (1984) J. Biol. Chem. 259, 1239-1250). Both P-450s contain 490 amino acids and share 75% similarity with each other and 50% similarity with P-450b and P-450e. Southern blot analysis indicates that these enzymes are part of a small P-450 gene subfamily composed of two or three members. An unusual feature of P-450 PB1 is the presence of a rat brain identifier-type repetitive sequence (R.dre.1) that encompasses the complete 3' untranslated region of the mRNA. This sequence is absent from P-450f mRNA. A cDNA from an apparent allelic form of P-450 PB1 mRNA was isolated and sequenced. This cDNA was identical to the other P-450 PB1 cDNA except for a single base substitution in the R.dre.1 repeat and the presence of a repeat (AAATAAA)13 at the 3' end of the mRNA. By use of a 3' specific probe for P-450f mRNA and a probe common to P-450 PB1 and P-450f mRNAs, the mechanism by which these P-450s are elevated during rat development was studied. Both RNAs are virtually absent in newborn rats and become elevated between 1 and 4 weeks after birth. Maximal levels of P-450f mRNA levels continue to increase up to 12 weeks after birth, and 2-fold higher levels of P-450f mRNA are reached in 12-week-old female rats compared with male rats. P-450 PB1 mRNA reached maximal levels at 4 weeks and no sex difference in mRNA level was detected for P-450 PB1. Nuclear run-on transcription assays confirmed that the increase in these mRNAs is due to transcriptional activation.


Factors affecting the degree of QT prolongation with drug challenge in a large cohort of normal volunteers.
The degree of QT prolongation by drug is highly variable and related to risk for polymorphic ventricular tachycardia due to drugs. The purpose of this study was to determine factors that affect the degree of QT prolongation by drugs. QT and QTc were measured before and after administration of the QT-prolonging drug ibutilide in 253 normal volunteers aged 18 to 40 years. Drug effect on QTc prolongation was defined as ΔQTc = QTc after drug minus QTc before drug. Ibutilide prolonged QT from 396 ± 31 ms to 418 ± 39 ms (P <.001) and QTc from 406 ± 15 ms to 446 ± 33 ms (P <.001). ΔQTc did not correlate with baseline QTc (Pearson correlation 0.016, P = .8). Postdrug QTc was correlated weakly with predrug QTc (Pearson correlation 0.484, P <.001), and strongly with ΔQTc (Pearson correlation 0.882, P <.001). ΔQTc was identical for men and women (39 ± 29 ms vs 39 ± 27 ms, P = .9) but displayed significant differences among body mass index categories (P <.001). Overweight (48 ± 27 ms) and obese (61 ± 31 ms) subjects had significantly more QT prolongation by drug than normal (31 ± 25 ms) or underweight (24 ± 12 ms) subjects. QT prolongation by ibutilide does not correlate to baseline QTc and does not differ between men and women. Overweight and obese subjects have greater drug effect on QTc than subjects with normal or low body mass index. These findings have implications for drug-induced long QT syndrome.


Precision and accuracy of the new XPrecia Stride mobile coagulometer.
Oral anticoagulation therapy (OAT) with coumarins (vitamin K antagonist) is the most used against thromboembolism. Prothrombin time (PT) International Normalized Ratio (INR) monitoring is fundamental to establish coumarins dosage and prevent bleeding complications or thrombotic events. In this contest, the method and apparatus used for providing the INR measurements are crucial. Several studies have been published regarding the precision and accuracy of mobile coagulometers with different conclusions. No studies have been published regarding the new XPrecia Stride Mobile Coagulometer (Siemens). The aim of this work is to analyze precision and accuracy of the new XPrecia Stride mobile coagulometer to provide recommendations for clinical use and quality control. A total of 163 patients (mean age=77.4years old) under Warfarin OAT for whom the INR was assessed by both the traditional cs 2100i Sysmex and the new Xprecia Stride Mobile Coagulometer were included in this pilot study. The precision of the new mobile coagulometer resulted very good (CV<3%). The analytical accuracy was also within the acceptable ranges of reliability (Lin's concordance=0.962). Finally, the clinical accuracy was also acceptable (deviation>15% from the true value in 20% of cases). Considering the overall results obtained by the new Xprecia Stride in comparison to that ones obtained from the other commercial devices, we can conclude that the new coagulometer is enough reliable for clinical settings. However, a larger trial to confirm these data is needed.


Should ICSI be recommended routinely in patients with four or fewer oocytes retrieved?
To determine if patients with a low response to controlled ovarian hyperstimulation during IVF benefit from intracytoplasmic sperm injection (ICSI) METHODS: Retrospective analysis of 350 IVF cycles in which four or fewer oocytes were retrieved. Severe male factor cases were excluded from analysis. Conventional insemination (CI) and ICSI were compared, with primary outcome measures of fertilization rate, implantation rate, clinical pregnancy rate per embryo transfer, and pregnancy loss rate. Fertilization rates per oocyte retrieved for CI and ICSI were comparable (51.5% vs. 51.8%). Parallel implantation rates (22% vs. 25%), clinical pregnancy rates (32.8% vs. 33.3%), and loss rates (26.7% vs. 39.5%) were also noted. No difference in cancelled cycles was reported. Our results demonstrate that in the presence of normal semen parameters, low egg number is not an indication to perform ICSI.


Dissipation study of difenoconazole in/on chili fruit and soil in India.
One field experiment was conducted with Difenoconazole (25% EC) on chili crop during December 2009 to January 2010 at two different locations of West Bengal and Maharashtra. The main objective was to understand the residue and persistence behaviour of fungicide difenoconazole in chili fruit and soil samples. Difenoconazole was applied in chili field at 50 mL and 100 mL/100 liter of water. Its residue was analyzed by using LC-MS/MS and it dissipated in chili fruit and soil following first order kinetics. The half life values of difenoconazole were found in the range 2.15-2.32 days and 4.68-8.09 days for chili fruit and soil, respectively.


Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis.
BACKGROUND: Insomnia is a common disorder associated with a substantial burden of illness, particularly in older adults. OBJECTIVE: To compare the efficacy and safety of lemborexant with specified other insomnia treatments through a systematic literature review and network meta-analysis (NMA). METHODS: Medline and Embase were systematically searched from inception to February 2019 and updated with a targeted search of PubMed for pivotal trials in March 2021. Randomized controlled trials in adults with primary insomnia were included if they reported results following at least 1 week of treatment. Interventions of interest were specified as lemborexant, suvorexant, benzodiazepines, benzodiazepine receptor agonists (also called Z-drugs [zolpidem, eszopiclone, zaleplon, zopiclone]), trazodone, and ramelteon. Efficacy outcomes included wake after sleep onset (WASO), sleep efficiency (SE), latency to persistent sleep (LPS)/sleep onset latency (SOL), total sleep time (TST) and Insomnia Severity Index (ISI). Bayesian NMA were performed at predetermined time intervals approximating 4 weeks, 3 months, and 6 months. Safety outcomes included serious adverse events (SAEs), withdrawals due to adverse events (AEs), and specified AEs (dizziness, somnolence, and falls). Subgroup analysis was conducted in the older population. RESULTS: 45 studies were included in the NMA. At 4 weeks, lemborexant had the highest probability of being the best treatment for 3 of the 4 outcomes measured objectively by polysomnography-TST, LPS, and SE-and was ranked second to suvorexant on WASO. Eszopiclone was highly ranked for subjectively measured SOL and ISI at 4 weeks, 3 months, and 6 months. Lemborexant was rated more highly than suvorexant in subjective measures of WASO, TST, and SOL at 4 weeks (the differences were not statistically significant). No statistically significant interactions between treatment effect and older subpopulations were found, indicating that the treatment effect was similar in older and adult populations. The safety profile of lemborexant was broadly similar to the other treatments for SAEs and withdrawals due to AEs. A limitation is the age of some of the included studies (3 were published in 1990 or earlier). A further limitation is the lack of stratification of recommended doses. If the doses used in the study publications do not reflect doses used in clinical practice, this could potentially bias the results. CONCLUSIONS: Lemborexant was ranked highest of the treatments studied on 3 out of the 4 objectively measured insomnia efficacy outcomes, with a safety profile broadly similar to other insomnia treatments. DISCLOSURES: This work was funded by Eisai Inc., which was involved with all stages of the study and analysis. McElroy, O'Leary, and Adena are consultants with Datalytics Pty Ltd., which was paid by Eisai Inc. for conducting the literature review and analysis. They were not financially compensated for collaborative efforts on publication-related activities. Campbell, Tahami Monfared, and Meier are employed by Eisai Inc. This study was presented as a poster at AMCP Nexus Virtual, October 20-23, 2020 and at the AGS Virtual Annual Scientific Meeting 2021, May 13-15, 2021.


Meniere's disease in children.
Meniere's disease is an uncommon cause of dizziness or hearing loss in children. Clinicians must maintain a high level of suspicion to make this diagnosis in the pediatric age group. Careful attention to history and diagnostic testing can help in differentiating Meniere's disease from other more common childhood conditions. Treatment is similar to adult patients and may be tried empirically in difficult or suspicious cases.


International survey responses from an interdisciplinary cohort of spinal cord injury clinicians assessing professional burnout and meaning in work.
While clinicians who care for patients with spinal cord injury may experience heightened levels of workplace stress related to secondary trauma, little is known about the characteristics of burnout and potential protective factors among interdisciplinary professionals who care for this distinct clinical population. An online survey of self-reported burnout symptoms and meaning in work was conducted to assess the prevalence of burnout and characteristics of meaning in work among spinal cord injury professionals. To assess symptoms of professional burnout and meaning in work among a broad-ranging cohort of spinal cord injury clinicians and researchers. A group of international spinal cord injury professionals. An online survey was developed using commonly assessed metrics of burnout and meaning in work based upon prior literature. A majority of survey respondents reported feeling exhaustion (60.1%), while fewer reported feelings of burnout (41.1%) or work-life imbalance (31.9%). Many respondents found support in personal relationship from friends and family and reported using various strategies to deal with work stress, including exercise, meditation, and engaging in personally meaningful activities outside of work. Exhaustion is a prevalent issue for many spinal cord injury professionals and burnout appears to be a significant issue for a subset of responders, yet despite potential workplace stressors, spinal cord injury professionals reported high meaningfulness of work, positive impact from colleagues, and satisfaction with intellectual stimulation at work.


The associations of leptin and adiponectin with the metabolic syndrome in an Indonesian and a Dutch population.
At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population. We performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia-Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6-1.2) in Indonesian men, 1.1 (0.9-1.4) in Indonesian women, 2.2 (1.6-2.8) in Dutch men, and 1.2 (1.0-1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7-1.2), 0.8 (0.7-1.0), 0.6 (0.6-0.8), and 0.4 (0.4-0.5), respectively. Despite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI.


Determinants of red blood cell transfusions in a pediatric critical care unit: a prospective, descriptive epidemiological study.
To determine the incidence and to characterize the determinants of red blood cell transfusions in critically ill children. Prospective, descriptive epidemiologic study. A single-center, multidisciplinary, tertiary care level, university-affiliated, pediatric intensive care unit (PICU). Critically ill children. None. Of 1,047 consecutive admissions over a 1-yr period, 985 were retained for study. At least one transfusion was given in 139 cases (14%). Incidence rate of transfusion was 304 transfusions/1,000 cases. Possible determinants of red blood cell transfusions were identified and prospectively monitored during PICU stay until a first transfusion event (transfused cases) or up until the time of death or discharge from PICU (nontransfused cases). Four significant determinants of a first red blood cell transfusion event were retained in the multivariate analysis (odds ratio, 95% confidence interval, p): a hemoglobin level <9.5 g/dL during PICU stay (13.26, 8.04-21.88, p < .001), an admission diagnosis of cardiac disease (8.07, 5.14-14.65, p < .001), an admission Pediatric Risk of Mortality score >10 (4.83, 2.33-10.04, p < .001), and the presence of multiple organ dysfunction syndrome during the stay (2.06, 1.18-3.57, p = .01). A significant proportion of critically ill children receive at least one red blood cell transfusion during their PICU stay. Presence of anemia, cardiac disease, severe critical illness, and multiple organ dysfunction syndrome are the most significant determinants of red blood cell transfusions in PICU.


Metal-DNA Interactions Improve signal in High-Resolution Melting of DNA for Species Differentiation of Plasmodium Parasite.
The success of high-resolution melting (HRM) analysis for distinguishing similar DNAs with minor base mismatch differences is limited. Here, metal-mediated structural change in DNA has been exploited to amplify HRM signals leading to differentiation of target DNAs in an orthologous gene corresponding to four Plasmodium species. Conserved 26-mer ssDNAs from ldh gene of the four Plasmodium species were employed as targets. A capture probe (CP) that is fully complementary to the Plasmodium falciparum target (FT) and has two base mismatches each, with the targets of Plasmodium vivax (VT), Plasmodium malariae, (MT), and Plasmodium ovale (OT), was considered. The DNA duplexes were treated with metal ions for structural perturbation and analyzed by HRM. Distinct resolution of melting fluorescence signal in otherwise identical HRM profiles for each of the DNA duplexes was achieved by using Ca+2 or Mg+2 ions, where, Ca+2 conferred higher resolution. The increase in resolution for CP-FT versus CP-OT, CP-FT versus CP-VT, CP-FT versus CP-MT, CP-VT versus CP-OT, and CP-MT versus CP-OT with Ca-DNA as compared to control was 67.3-, 20.4-, 22.0-, 10.9-, and 8.3-fold, respectively. The signal resolution was the highest at pH 8. The method could detect 0.25 pmol/µl of the target DNA. Structural analysis showed that Ca+2 and Mg+2 ions perturbed the structure of DNA. This perturbation helped to improve HRM signal resolution among DNA targets corresponding to the orthologous gene of four Plasmodium species. This novel approach has potential application not only for Plasmodium species-specific diagnosis but also for differentiation of DNAs with minor sequence variation.


Lateral Flow Microarray-Based ELISA for Cytokines.
Cytokines are well known to be involved in numerous biological responses with diverse mechanisms of action, including the inflammatory process. The so-called "cytokine storm" has recently been associated with cases of severe COVID-19 infection.Lateral flow microarray (LFM) devices have been constructed for multiplex detection of cytokines. The LFM-cytokine rapid test involves the immobilization of an array of capture anti-cytokine antibodies. Here, we describe the methods to create and use multiplex lateral flow-based immunoassays based upon the enzyme-linked immunosorbent assay (ELISA).


Exercise training improves basal blood glucose metabolism with no changes of cytosolic inhibitor B kinase or c-Jun N-terminal kinase activation in skeletal muscle of Otsuka Long-Evans Tokushima fatty rats.
Redox-sensitive stress kinases and heat shock protein 72 (Hsp72) have been considered to be associated with the development of type 2 diabetes in skeletal muscle. However, the effect of exercise training on skeletal muscle of type 2 diabetic models is largely unknown. The purpose of this study was to investigate the effect of 12 weeks of exercise training on gastrocnemius of type 2 diabetic rats, by examining the activation of c-Jun N-terminal kinase (JNK), the nuclear factor B (NF-B) pathway and Hsp72. Total hydroperoxide and 4-hydroxynoneal, as oxidative stress markers, were also examined. Otsuka Long-Evans Tokushima fatty (OLEFT) rats were randomly divided into an exercise training group (Ex-OLETF, n = 8) and a sedentary group (Sed-OLETF, n = 8), while Long-Evans Tokushima Otsuka (LETO) rats were used as a control group (Con-LETO, n = 5). The Ex-OLETF rats were trained on a treadmill five times a week for 12 weeks. The levels of hydroperoxide and 4-hydroxynoneal in both Ex-OLETF and Sed-OLETF were significantly higher compared with Con-LETO, but there was no difference between Ex-OLETF and Sed-OLETF. Levels of inhibitor B kinase, JNK activation and p65 nuclear translocation followed a similar pattern to that observed in oxidative stress markers. The level of Hsp72 in Ex-OLETF was increased by exercise training, but it did not reach the level observed in Con-LETO. The NF-B DNA binding activity in Sed-OLETF was significantly higher compared with Con-LETO. Although it was not statistically significant, exercise training in Ex-OLETF showed a trend to reduce the activation of NF-B DNA binding activity compared with Sed-OLETF (P = 0.104). Our findings indicate that exercise training improves basal glucose metabolism without a change in stress kinases, and that nuclear regulation of NF-B activity in diabetic muscle could be regulated independently of the cytosolic pathway. Our study also suggests a possibility that exercise-induced Hsp72 serves as a protective mechanism in skeletal muscle of OLETF rats.


Utilizing Large Functional and Population Genomics Resources for CRISPR/Cas Perturbation Experiment Design.
Genome sequencing technologies have rapidly evolved in the past decades, enabling us to interpret the human genome through multiple perspectives, ranging from cross-species comparisons, naturally occurring variation in health and disease state to regulatory mechanisms.Although such perspectives are all informative to narrow down the list of genes or variants for perturbation experiments based on specific biological aims, utilizing multiple sources of information is often challenging in practice.In this chapter, we provide an overview of major large-scale functional and population genomics resources, followed by a practical example of selecting target variants for genetic perturbation experiments involving genome engineering techniques such as CRISPR/Cas.


Identification and characterization of the gene for Drosophila S20 ribosomal protein.
A cDNA clone that encodes a Drosophila homologue of ribosomal protein S20 was isolated from a Drosophila ovary cDNA library. The Drosophila S20 gene (RpS20) is highly conserved with S20 genes in other organisms. It is a single copy gene and maps to position 92F-93A on polytene chromosomes. No Minute mutation in this location has been reported; at least five essential genes are possible candidates to encode RpS20. RpS20 message is expressed ubiquitously in embryos, but is expressed at high levels in the midgut.


A neural network model for selective attention in visual pattern recognition.
A neural network model of the mechanism of selective attention in visual pattern recognition is proposed and simulated on a digital computer. When a complex figure consisting of two patterns or more is presented to the model, it is segmented into individual patterns, and each pattern is recognized separately. Even if one of the patterns to which the model is paying selective attention is affected by noise or defects, the model can recall the complete pattern from which the noise has been eliminated and the defects corrected. It is not necessary for perfect recall that the stimulus pattern should be identical in shape to the training pattern. Even though the pattern is distorted in shape or changed in size, it can be correctly recognized and the missing portions restored. The model consists of a hierarchical neural network which has efferent as well as afferent connections between cells. The afferent and the efferent signals interact with each other in the network: the efferent signals, that is, the signals for selective attention, have a facilitating effect on the afferent ones, and, at the same time, the afferent signals gate efferent signal flow. When some feature in the stimulus is not extracted in the afferent paths, the threshold for detection of that feature is automatically lowered by decreasing the efficiency of inhibition, and the model tries to extract even vague traces of the undetected feature.


Simulation-based education with deliberate practice may improve intraoperative handoff skills: a pilot study.
To examine the results of simulation-based education with deliberate practice on the acquisition of handoff skills by studying resident intraoperative handoff communication performances. Preinvention and postintervention pilot study. Simulated operating room of a university-affiliated hospital. Resident handoff performances during 27 encounters simulating elective surgery were studied. Ten residents (CA-1, CA-2, and CA-3) participated in a one-day simulation-based handoff course. Each resident repeated simulated handoffs to deliberately practice with an intraoperative handoff checklist. One year later, 7 of the 10 residents participated in simulated intraoperative handoffs. All handoffs were videotaped and later scored for accuracy by trained raters. A handoff assessment tool was used to characterize the type and frequency of communication failures. The percentage of handoff errors and omissions were compared before simulation and postsimulation-based education with deliberate practice and at one year following the course. Initially, the overall communication failure rate, defined as the percentage of handoff omissions plus errors, was 29.7%. After deliberate practice with the intraoperative handoff checklist, the communication failure rate decreased to 16.8%, and decreased further to 13.2% one year after the course. Simulation-based education using deliberate practice may result in improved intraoperative handoff communication and retention of skills at one year.


Anglo-Saxon pharmacopoeia revisited: a potential treasure in drug discovery.
Three of the four major Anglo-Saxon collections reporting medicinal formulations in England from the 10th century, the Old English Herbarium, Bald's Leechbook and the Lacnunga, could contain leads and insights into new medicinal uses. Previous pharmacological studies of medicinal plants mentioned in Anglo-Saxon medical texts suggested that some were effective and led to the identification and isolation of natural compounds. For example, matricin from yarrow Achillea millefolium L., is a proprionic acid analogue that yields chamazulene carboxylic acid with cyclooxygenase-2 activity similar to that of ibuprofen. As we discuss here, multidisciplinary projects could further explore historical texts to discover additional plant metabolites with potential pharmacological applications.


Gasdermin D in pyroptosis.
Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water, eventually resulting in strong inflammation and cell death. Since GsdmD is the effector of pyroptosis, promising inhibitors of GsdmD have been developed for inflammatory diseases. This review will focus on the roles of GsdmD during pyroptosis and in diseases.


Adjustable slings versus other surgical methods in female stress urinary incontinence: a systematic review and meta-analysis.
The objective of this study was to evaluate the efficacy and safety of different adjustable slings compared to other surgical methods for the treatment of stress urinary incontinence (SUI) among women. The inclusion criteria were as follows: randomized controlled trials (RCTs) and non-RCTs assessing adult women with SUI. The exclusion criteria were as follows: other types of urinary incontinence, studies that combined conservative interventions and pharmacological treatment, pregnant and lactating patients. Databases were searched up to November 2022 to identify articles evaluating the effectiveness and safety of different adjustable slings compared to other surgical methods for the treatment of SUI among women. The systematic review was conducted in accordance with the PRISMA 2020 checklist and registered in PROSPERO. Risk-of-bias assessment tools recommended by the Cochrane Society were used to evaluate the risk of bias in the included studies. Eighteen clinical trials were included in this systematic review, and 11 studies were included in the meta-analysis. Fourteen studies were RCTs, and four were retrospective studies. Only RCTs were included in the meta-analyses. There was no statistically significant difference in the objective cure rate, subjective cure rate, or long-term postoperative complication rate between Ajust single-incision mini-slings (SIMS) and standard mid-urethral slings (SMUS) or MiniArc SIMS. However, the operation time in the adjustable SIMS group was significantly shorter (RR = -4.20, 95% CI: [-7.51, -0.89], p = 0.01). This systematic review and meta-analysis revealed that adjustable SIMS is equally effective when compared with SMUS for the treatment of SUI among women. Moreover, the operation time for the adjustable SIMS was shorter. However, additional well-designed studies with standard outcome measures and complete follow-up periods will help to increase confidence in the choice of different options for treating SUI among women.


Rat bite fever due to Streptobacillus notomytis complicated by meningitis and spondylodiscitis: a case report.
Only three other cases of rat bite fever caused by Streptobacillus notomytis in humans have been reported since this species was identified in 2015. Data specific to the differences in clinical features and geographic distribution between S. notomytis infection and S. moniliformis infection are scarce. All previous cases of human S. notomytis infection were reported from Japan. This is the first case of S. notomytis infection reported from outside of Japan. A 72-year-old Thai woman was admitted to Siriraj Hospital (Bangkok, Thailand)-Thailand's largest university-based national tertiary referral center-in August 2020 with fever, myalgia, and polyarthralgia for 3 days, and gradually decreased consciousness for the past 1 day. Physical examination and laboratory investigations revealed septic arthritis of both knee joints, meningitis, and hepatitis. She was initially misdiagnosed as rheumatoid arthritis in the elderly since the initial investigations were unable to detect a causative pathogen. However, S. notomytis infection was later confirmed by polymerase chain reaction amplification of a part of the 16S rRNA gene and sequencing from synovial fluid. Her clinical course was also complicated by spondylodiscitis and epidural abscess caused by S. notomytis, which was detected from tissue biopsy. Therefore, rat bite fever in this patient manifested as meningitis, septic polyarthritis, hepatitis, and spondylodiscitis. The patient was treated with intravenous ceftriaxone then switched to oral amoxicillin with complete recovery. The clinical manifestations of S. notomytis infection are similar to those demonstrated in S. moniliformis infection. This case also showed that arthritis caused by S. notomytis mimics rheumatoid arthritis, and that meningitis and spondylodiscitis are potential coexisting complications that can be found in S. notomytis infection.


Transcriptome analysis reveals the regulatory effects of Bacillus amyloliquefaciens and Bacillus pumilus on immune and digestive related genes in the spleen of weanling black goats.
The aim of the present study was to evaluate the effects of Bacillus amyloliquefaciens fsznc-06 and Bacillus pumilus fsznc-09 on the expressions of spleen genes in weanling Jintang black goats. Bacillus amyloliquefaciens fsznc-06 (BA-treated group) and Bacillus pumilus fsznc-09 (BP-treated group) were directly fed to goats, and the spleens were harvested for transcriptome analysis. The KEGG pathway analysis showed that the differentially expressed genes (DEGs) in BA-treated vs CON group were mainly involved in digestive system and immune system, while those in BP-treated vs CON group were mainly involved in immune system, and those in BA-treated vs BP-treated group were mainly involved in digestive system. In conclusion, Bacillus amyloliquefaciens fsznc-06 might promote the expressions of genes related to immune system and digestive system, reduce the expressions of disease genes related to digestive system and might promote mutual accommodation of some immune genes in weanling black goat. Bacillus pumilus fsznc-09 might promote the expressions of genes related to immune system and mutual accommodation of some immune genes in weanling black goat. Bacillus amyloliquefaciens fsznc-06 has advantages over Bacillus pumilus fsznc-09 in promoting the expressions of genes related to digestive system and mutual accommodation of some immune genes.


Effects of Valsalva Maneuver by Different Breath-holding Techniques to Detect Pulmonary Thromboembolism in a Contrast-enhanced Computed Tomography Examination.
The purpose of this study is to measure the hemodynamics on the effect of Valsalva maneuver aiming at pulmonary thromboembolism (PTE) using 2-dimensional (2D) phase contrast imaging of magnetic resonance image (MRI), Philips Ingenia 3.0-tesla (T). The maximal inspiration reduced the blood flow rate in various degrees at all measurement positions, superior vena cava (SVC), inferior vena cava (IVC), pulmonary artery (PA), ascending aorta (AA), and descending aorta (DA). This result suggests that the contrast effect in the PA might become weak during general PA phase to give a substantial influence of Valsalva maneuver in the condition after maximum inspiration. A contrast-enhanced computed tomography (CT) examination aiming at detection for PTE should be scanned without an advance maximum inspiration.


Looking Back: Cancer Stem Cells.
Over the past decade, our growing understanding of cancer stem cell characteristics and function continues to guide innovative new treatments to eradicate cancer. For our tenth anniversary, we asked authors who cited a selection of our most popular papers in this area about the broad influences these studies have had.


Rapid and Sensitive Detection of Cancer Cells with Activatable Fluorescent Probes for Enzyme Activity.
Fluorescence (FL)-guided detection of cancer is one of the most promising approaches to achieve intraoperative assessment of surgical margins. Enzymes, such as aminopeptidase, carboxypeptidase, and glycosidase, whose activities are increased in cancer, have attracted great interest as imaging targets for rapid and sensitive visualization of cancerous tissues with fluorescent probes. Activatable probes, which are initially nonfluorescent but become strongly fluorescent upon rapid one-step cleavage of their substrate moiety by the target enzyme, are especially promising for practical clinical application during surgical or endoscopic procedures due to the highly amplified FL change generated by enzyme-catalyzed turnover at lesion sites. Here, we describe robust protocols for using activatable fluorescent probes targeting cancer-associated enzyme activities to visualize cultured cancer cells, metastatic cancer in a mouse model, and cancerous lesions in surgical specimens from patients.


Overexpressed beta cell CART increases insulin secretion in mouse models of insulin resistance and diabetes.
Impaired beta cell function and beta cell death are key features of type 2 diabetes (T2D). Cocaine- and amphetamine-regulated transcript (CART) is necessary for normal islet function in mice. CART increases glucose-stimulated insulin secretion in vivo in mice and in vitro in human islets and CART protects beta cells against glucotoxicity-induced cell death in vitro in rats. Furthermore, beta cell CART is upregulated in T2D patients and in diabetic rodent models as a consequence of hyperglycaemia. The aim of this study was to assess the impact of upregulated beta cell CART on islet hormone secretion and glucose homeostasis in a transgenic mouse model. To this end, mice with beta cell-specific overexpression of CART (CARTtg mice) were generated. CARTtg mice challenged by aging, high fat diet feeding or streptozotocin treatment were phenotyped with respect to in vivo and in vitro insulin and glucagon secretion, glucose homeostasis, and beta cell mass. In addition, the impact of adenoviral overexpression of CART on insulin secretion was studied in INS-1 832/13 cells. CARTtg mice had a normal metabolic phenotype under basal conditions. On the other hand, with age CARTtg mice displayed increased insulin secretion and improved glucose elimination, compared with age-matched WT mice. Furthermore, compared with WT controls, CARTtg mice had increased insulin secretion after feeding a high fat diet, as well as lower glucose levels and higher insulin secretion after streptozotocin treatment. Viral overexpression of CART in INS-1 832/13 cells resulted in increased glucose-stimulated insulin secretion. Together, these results imply that beta cell CART acts to increase insulin secretion when beta cell function is challenged. We propose that the increase in beta cell CART is part of a compensatory mechanisms trying to counteract the hyperglycaemia in T2D.


Pharmacological potential of Astragali Radix for the treatment of kidney diseases.
With the increasing prevalence of hypertension, diabetes, and obesity, the incidence of kidney diseases is also increasing, resulting in a serious public burden. Conventional treatments for kidney diseases have unsatisfactory effects and are associated with adverse reactions. Traditional Chinese medicines have good curative effects and advantages over conventional treatments for preventing and treating kidney diseases. Astragali Radix is a Chinese herbal medicine widely used to treat kidney diseases. To review the potential applications and molecular mechanisms underlying the renal protective effects of Astragali Radix and its components and to provide direction and reference for new therapeutic strategies and future research and development of Astragali Radix. PubMed, Google Scholar, and Web of Science were searched using keywords, including "Astragali Radix," "Astragalus," "Astragaloside IV" (AS-IV), "Astragali Radix polysaccharide" (APS), and "kidney diseases." Reports on the effects of Astragali Radix and its components on kidney diseases were identified and reviewed. The main components of Astragali Radix with kidney-protective properties include AS-IV, APS, calycosin, formononetin, and hederagenin. Astragali Radix and its active components have potential pharmacological effects for the treatment of kidney diseases, including acute kidney injury, diabetic nephropathy, hypertensive renal damage, chronic glomerulonephritis, and kidney stones. The pharmacological effects of Astragali Radix are manifested through the inhibition of inflammation, oxidative stress, fibrosis, endoplasmic reticulum stress, apoptosis, and ferroptosis, as well as the regulation of autophagy. Astragali Radix is a promising drug candidate for treating kidney diseases. However, current research is limited to animal and cell studies, underscoring the need for further verifications using high-quality clinical data.


Streptococcus pneumoniae type 3 encodes a protein highly similar to the human glutamate decarboxylase (GAD65).
A 2.5-kb ScaI fragment of the type 3 pneumococcal strain 406 DNA containing a 1425-nucleotide open reading frame (gadA) and encoding a 475-amino acid protein (M(r) 54,427) was characterised. The gene gadA was expressed in Salmonella typhimurium. Pulsed-field gel electrophoresis and Southern blotting analysis of DNAs prepared from several pneumococcal serotypes showed that only those clinical isolates belonging to serotype 3 harbour the gadA gene. Sequence comparison of GadA with proteins included in the data banks revealed the highest similarity with human glutamate decarboxylase (GAD65) (59% similarity, 28% identity). Auto-antibodies to GAD65 have been associated with the onset of insulin-dependent diabetes mellitus. Interestingly, several epitopes of GAD65 that have been identified as immunodominant are particularly well conserved in the pneumococcal GadA.


Pulmonary arteriovenous malformations: evidence of physician under-education.
PAVMs pose unique management challenges; publication patterns indicate their importance remains poorly recognised http://ow.ly/7iIT304WYl2.


[Vitamin C - New Option in Sepsis Therapy?]
Vitamin C deficiency often occurs in critical illness and especially in patients with sepsis. Low plasma levels correlate with organ dysfunction and outcome parameters. Vitamin C offers pleiotropic effects possibly attenuating pathophysiology in sepsis. This includes antioxidative effects like scavenging reactive oxygen species or restoring other antioxidants. Vitamin C is a cofactor for norepinephrine biosynthesis and it protects endothelial function. In addition, it modulates immune response. A combined therapy with vitamin C, hydrocortisone and thiamine could be beneficial because of synergistic effects. Some clinical studies have shown reduced mortality due to vitamin C alone or in combination with hydrocortisone and thiamine, others do not. Adverse events are rare. So data supporting a therapy with vitamin C is still unclear. Further randomised controlled trials are necessary.


Supracutaneous plating using a locking plate for the treatment of a tibial fracture in a cat.
Radiographs revealed a slightly displaced long oblique diaphyseal tibial fracture with bone fissures running distally in a 2-year-old, 4.5 kg cat that had been hit by a car. An angle stable implant was applied in a supracutaneous fashion. The patient tolerated the external implant and had a satisfactory functional recovery. Radiographic follow-up after 60 days revealed sign of osseous union; therefore, the plate was removed.


Characterization of the long-lasting activator protein-1 complex induced by kainic acid treatment.
Kainic acid is known to induce seizures, neuronal damage and cell loss in the rat hippocampus. Our laboratory has shown that a single kainic acid injection elicits acute increases of activator protein-1 DNA-binding activity and this activity stays at an elevated level for 2 weeks after kainic acid injection. However, some pathological changes such as mossy fiber sprouting do not occur until 2-3 weeks after the kainic acid injection and the specific transcription factors regulating the long-term events after kainic acid treatment are not clear. To determine the involvement of activator protein-1 transcription factors in the long-term events after kainic acid treatment, gel mobility-shift and Western blot analyses were used. The results showed that two activator protein-1 complexes with different mobilities occur during the acute stage. However, only the faster-migrating complex as well as the 35-37-kDa fos-related antigen and Jun-D proteins were seen during the late stage. These results suggest that different activator protein-1 complexes exist at different stages after convulsions and that they regulate ensembles of different genes.


Cookies Fortified with Lonicera japonica Thunb. Extracts: Impact on Phenolic Acid Content, Antioxidant Activity and Physical Properties.
Lonicera japonica Thunb [...].


Nonlinear indices of circadian changes in individuals with dementia and aggression.
Nonlinear analyses of actigraphy data were utilized to investigate circadian rest-activity system motor control in nursing-home residents with dementia and with/without aggressive behavior (AB). Significant differences observed between groups in measures of approximate entropy (ApEn) and fractal dimension (FD). ApEn and FD are sensitive to detecting and characterizing discrete changes in central motoric control and temporality of behaviors in dementia. Findings may inform understanding of clinical heterogeneity and possible physiologic sub-classifications of Alzheimer's dementia.


Evaluation of chest X-ray with automated interpretation algorithms for mass tuberculosis screening in prisons: a cross-sectional study.
The World Health Organization (WHO) recommends systematic tuberculosis (TB) screening in prisons. Evidence is lacking for accurate and scalable screening approaches in this setting. We aimed to assess the accuracy of artificial intelligence-based chest x-ray interpretation algorithms for TB screening in prisons. We performed prospective TB screening in three male prisons in Brazil from October 2017 to December 2019. We administered a standardized questionnaire, performed a chest x-ray in a mobile unit, and collected sputum for confirmatory testing using Xpert MTB/RIF and culture. We evaluated x-ray images using three algorithms (CAD4TB version 6, Lunit version 18.104.22.168 and qXR version 3) and compared their accuracy. We utilized multivariable logistic regression to assess the effect of demographic and clinical characteristics on algorithm accuracy. Finally, we investigated the relationship between abnormality scores and Xpert semi-quantitative results. Among 2075 incarcerated individuals, 259 (12.5%) had confirmed TB. All three algorithms performed similarly overall with area under the receiver operating characteristic curve (AUC) of 0.88-0.91. At 90% sensitivity, only LunitTB and qXR met the WHO Target Product Profile requirements for a triage test, with specificity of 84% and 74%, respectively. All algorithms had variable performance by age, prior TB, smoking, and presence of TB symptoms. LunitTB was the most robust to this heterogeneity but nonetheless failed to meet the TPP for individuals with previous TB. Abnormality scores of all three algorithms were significantly correlated with sputum bacillary load. Automated x-ray interpretation algorithms can be an effective triage tool for TB screening in prisons. However, their specificity is insufficient in individuals with previous TB. This study was supported by the US National Institutes of Health (grant numbers R01 AI130058 and R01 AI149620) and the State Secretary of Health of Mato Grosso do Sul.


Awareness, Perceptions, and Literacy Surrounding Hearing Loss and Hearing Rehabilitation Among the Adult Population in the United States.
To characterize current awareness, perceptions, and literacy surrounding hearing loss among the adult population in the United States. National cross-sectional survey study. United States. Adults between 50 and 80 years of age in the United States. Survey respondents included 1,250 adults between the ages of 50 and 80 years, including 500 who indicated at least moderate hearing loss and were using hearing aids and 750 who denied having hearing loss and were not using hearing aids.Only 9% of patients were able to correctly identify what constitutes a "normal" or "average" range for hearing. By comparison, a "normal" range of values for vision, blood pressure, and total cholesterol were identified correctly by 93%, 85%, and 52% of the 1,250 surveyed adults, respectively. When asked to rank the importance of addressing hearing loss within the context of 10 other common health conditions, hearing loss was ranked third to least important. When considering annual health maintenance, respondents indicated they were "very likely" to have an annual physical exam (72%), a cholesterol test (70%), an eye exam (66%), and bring their pet to a veterinarian (59%) over twice as frequently as having their hearing evaluated (27%).When evaluating awareness surrounding associations between hearing loss and other health and social issues, less than one-fourth indicated strong awareness about links between hearing loss and depression, employability and income, fall risk, dementia, and type 2 diabetes. While most patients acknowledge the potential impacts of hearing loss on safety, quality of life, and health, less than half believe that hearing loss is treatable and less than 20% believe that hearing loss is preventable. Despite widespread literacy of what constitutes normal vision, blood pressure, and total cholesterol levels, respondents exhibit substantially poorer understanding of "normal" hearing levels. Most adults believe that few treatment options exist for the management of hearing loss. Underlying the uniformly limited literacy surrounding hearing loss and its treatment options is the adult population's lack of appreciation for the long-term health sequelae of untreated hearing loss.


Deep brain stimulation of the inferior colliculus: a possible animal model to study paradoxical kinesia observed in some parkinsonian patients?
The inferior colliculus (IC) plays an important role in the normal processing of the acoustic message and is also involved in the filtering of acoustic stimuli of aversive nature. The neural substrate of the IC can also influence haloperidol-induced catalepsy. Considering that (i) paradoxical kinesia, observed in some parkinsonian patients, seems to be dependent of their emotional state and (ii) deep brain stimulation (DBS) represents an alternative therapeutic route for the relief of parkinsonian symptoms, the present study investigated the consequence of DBS at the IC on the catalepsy induced by haloperidol in rats. Additionally, we investigated if DBS of the IC can elicit motor responses in anesthetized rats and whether DBS elicits distinct neural firing patterns of activity at the dorsal cortex (DCIC) or central nucleus (CNIC) of the IC. A significant reduction of the catalepsy response was seen in rats previously given haloperidol and receiving DBS at the IC. In addition, electrical stimulation to the ventral part of the CNIC induced immediate motor responses in anesthetized rats. The neuronal spontaneous activity was higher at the ventral part of the CNIC than the dorsal part. DBS to the ventral part but not to the dorsal part of the CNIC increased the spike rate at neurons a few hundred microns away from the stimulation site. It is possible that the IC plays a role in the sensorimotor gating activated by emotional stimuli, and that DBS at the IC can be a promising new animal model to study paradoxical kinesia in rats.


Cardiac resynchronization therapy: the issue of non-response.
Cardiac resynchronization therapy reduces mortality and morbidity in heart failure patients with wide QRS and severe impairment of left ventricular systolic function, who are symptomatic despite optimal medical therapy. However, a high percentage of patients fail to show clinical or echocardiographic response to this treatment. Beyond current selection criteria, other elements, such as QRS duration and morphology, concomitant medical therapy, degree of right ventricle dysfunction, myocardial viability, presence of left ventricular dyssynchrony, and associated renal dysfunction, play a crucial role in modulating the response to cardiac resynchronization. Consequently, they should be part of the standard pre-implant evaluation, as they could be used to identify patients who are very unlikely to be responders.


The Metabolic Landscape of Breast Cancer and Its Therapeutic Implications.
Breast cancer is the most common malignant tumor globally as of 2020 and remains the second leading cause of cancer-related death among female individuals worldwide. Metabolic reprogramming is well recognized as a hallmark of malignancy owing to the rewiring of multiple biological processes, notably, glycolysis, oxidative phosphorylation, pentose phosphate pathway, as well as lipid metabolism, which support the demands for the relentless growth of tumor cells and allows distant metastasis of cancer cells. Breast cancer cells are well documented to reprogram their metabolism via mutations or inactivation of intrinsic factors such as c-Myc, TP53, hypoxia-inducible factor, and the PI3K/AKT/mTOR pathway or crosstalk with the surrounding tumor microenvironments, including hypoxia, extracellular acidification and interaction with immune cells, cancer-associated fibroblasts, and adipocytes. Furthermore, altered metabolism contributes to acquired or inherent therapeutic resistance. Therefore, there is an urgent need to understand the metabolic plasticity underlying breast cancer progression as well as to dictate metabolic reprogramming that accounts for the resistance to standard of care. This review aims to illustrate the altered metabolism in breast cancer and its underlying mechanisms, as well as metabolic interventions in breast cancer treatment, with the intention to provide strategies for developing novel therapeutic treatments for breast cancer.


Spatiotemporal ecological quality assessment of metropolitan cities: a case study of central Iran.
The present study used the recently developed Remote Sensing-Based Ecological Index (RSEI) to assess the temporal-spatial variation of ecological quality in the metropolitan city of Isfahan (Iran) as a member of the UNESCO Creative Cities Network. This study was conducted from the Landsat TM/OLI satellite images of 2004, 2009, 2014 and 2019. The RSEI was synthesized by principal component analysis for four indices of Normalized Difference Vegetation Index (NDVI), Land Surface Temperature (LST), Land Surface Moisture (LSM) and Normalized Differential Build-up, and Bare Soil Index (NDBSI) based on the framework of the Pressure-State-Response (PSR) in the aforementioned years. The ecological quality of the city was assessed by RSEI over a 15-year period. The index has a value range of 0 (completely poor ecological quality) to 1 (completely desirable). In addition, the spatial heterogeneity of RSEIs at different intervals was assessed by the Moran index. The results showed that the RSEI value was always less than 0.4, which indicated the unfavourable ecological quality of the city. This index was 0.34, 0.37, 0.26 and 0.30 in 2004, 2009, 2014 and 2019, respectively. Therefore, the ecological quality of the city did not have a constant trend during the studied period and had several fluctuations, which could be attributed to the natural and anthropogenic changes in the studied period. Additionally, the results of the Moran index showed a steady decline, which indicated a declining homogeneity during this period. Matching the calculated RSEIs with the realities of the region at each time interval suggested that the index could be a useful tool for assessing urban ecological quality.


Effect of magnetite nanoparticle agglomerates on ultrasound induced inertial cavitation.
High intensity focused ultrasound (HIFU) induced inertial cavitation has been shown to improve release and cellular uptake of drugs. The effects of magnetite nanoparticle agglomerates (290+/-10nm diameter), silica coated magnetite nanoparticle agglomerates (320+/-10nm diameter) and silica particles (320+/-10nm diameter) suspended in MilliQ water on the degree of inertial cavitation due to HIFU were investigated. The HIFU transducer was operated at a frequency of 1.1 MHz, 1.67 kHz pulse repetition frequency, with applied duty cycles (DC) between 0% and 5% and different peak negative focal pressures (PNFPs) applied up to 7.2 MPa. The inertial cavitation dose (ICD: time averaged root-mean-squared broadband noise amplitude in the frequency domain) was measured in the presence and absence of nanoparticles when subjected to HIFU. Magnetite nanoparticle agglomerates caused a significant increase in the ICD above 2.7 MPa PNFP compared with MilliQ water, silica coated magnetite agglomerates and silica particles. With the dramatic increase in ICD on introduction of these magnetite agglomerates, this technique could provide a method of HIFU triggered drug delivery by enhancing inertial cavitation. The superparamagnetic properties of these particles offer the possibility of magnetic targeting to the site of disease.


Antigen receptor therapy in bone metastasis via optimal control for different human life stages.
In this work we propose a bone metastasis model using power law growth functions in order to describe the biochemical interactions between bone cells and cancer cells. Experimental studies indicate that bone remodeling cycles are different for human life stages: childhood, young adulthood, and adulthood. In order to include such differences in our study, we estimate the model parameter values for each human life stage via bifurcation analysis. Results reveal an intrinsic relationship between the active period of remodeling cycles and the proliferation of cancer cells. Subsequently, using optimal control theory we analyze a possible antigen receptor therapy as a new treatment for bone metastasis. Theoretical results such as existence of optimal solutions are proved. Numerical simulations for late stages of bone metastasis are presented and a discussion of our results is carried out.


Clinical significance of large unstained cell count in estimating the current activity of antineutrophil cytoplasmic antibody-associated vasculitis.
We investigated whether large unstained cell (LUC) count could estimate the current high activity according to Birmingham vasculitis activity score (BVAS) in patients with antineutrophil cytoplasmic antibody (ANCA) positive ANCA-associated vasculitis (AAV). We retrospectively reviewed the medical records of 176 immunosuppressive drug-naïve patients with ANCA positive AAV. Clinical and laboratory data at diagnosis, including LUC count, were collected. High BVAS was defined as the highest tertile of BVAS (BVAS ≥ 15) in this study. The median age was 61.0 years, and 64.8% were female. The median LUC count was 60.0 mm3 , and LUC was detected in 106 patients. LUC count was significantly correlated with BVAS, age, white blood cell count, haemoglobin, platelet count, serum albumin, erythrocyte sedimentation rate and C-reactive protein. Overall, the median BVAS in AAV patients with LUC positivity was significantly higher than that in those without (14.0 vs 10.0). When the cut-off of LUC count for the current high BVAS was set as BVAS ≥ 15 mm3 , AAV patients with LUC count ≥ 15 mm3 had a significantly higher risk for the current high BVAS than those with LUC count < 15 mm3 (relative risk 2.596). However, in the multivariable linear and logistic regression analyses, LUC did not seem to estimate the current BVAS independently among clinical and laboratory variables. LUC count was significantly correlated with the current BVAS and LUC count ≥ 15 mm3 could estimate the current high BVAS in patients with ANCA positive AAV.


Development of a navigation system for minimally invasive esophagectomy.
A major challenge of minimally invasive esophagectomy is the uncertainty about the exact location of the tumor and associated lymph nodes. This study aimed to develop a navigation system for visualizing surgical instruments in relation to the tumor and anatomic structures in the chest. An immobilization device consisting of a vacuum mattress fixed to a stretcher was built to decrease patient movement and organ deformation. Computer tomography (CT) markers were embedded in the stretcher at a defined distance to a detachable plate with optical markers on the side of the stretcher. A second plate of optical markers was fixed to the operating instrument. These two optical marker plates were tracked with an optical tracking system. Their positions were then registered in a preoperative CT data set using the authors' navigation software. This allowed a real-time visualization of the instrument and target structures. To assess the accuracy of the system, the authors designed a phantom consisting of a box containing small spheres in a specific three-dimensional layout. The positions of the spheres were first measured with the navigation system and then compared with the known real positions to determine the accuracy of the system. In the accuracy assessment, the navigation system showed a precision of 0.95 +/- 0.78 mm. In a test data set, the instrument could be successfully navigated to the tumor and target structures. The described navigation system provided real-time information about the position and orientation of the working instrument in relation to the tumor in an experimental setup. Consequently, it might improve minimally invasive esophagectomy and allow for surgical dissection in an adequate distance to the tumor margin and ease the location of affected lymph nodes.


Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors.
The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.


Understanding workforce participation as a continuous rather than dichotomous variable: implications for improving workforce health.
To explore the changing nature of Australia's potential workforce, and comment on the limitations of existing fragmented infrastructure to address the health needs of all potential workers. This paper analyses the changing nature of work in Australia and the challenges this presents to existing health infrastructure. This paper argues that there are more than 1.5 million Australians who are currently unemployed, under-employed or potentially employable who should be seen as part of the workforce. Australia cannot afford to have so many people exposed to the significant health risks of unemployment and underemployment. Given the changing nature of employment, it may be more appropriate to see employment as a continuous variable from secure full-time employment to systematic social exclusion from the workforce, rather than a dichotomous variable of employed and unemployed. Structural responsibility for the health of the workforce is currently based on services for those in the workforce and those out of the workforce. Transforming these systems will be a complex but necessary task if we are to engage the entire potential workforce in productive activity.


Changes in the relative frequency of gastric adenocarcinoma in southern California.
The incidence of gastric cancer is decreasing in most counties of the developed world, but at the Los Angeles County-University of Southern California Medical Center, we diagnosed 99.8 cases of gastric adenocarcinoma per 10(5) discharges in the period 1982 to 1986 as opposed to 62.2 per 10(5) discharges in 1972 to 1976 (P less than .0001). This change involved primarily Hispanics younger than 30 years of age with 30 cases per 10(5) vs 4.2 cases per 10(5) (P less than .0001) and whites older than 30 years: 87 cases per 10(5) vs 54 cases per 10(5) (P less than .05) during 1982 to 1986 and 1972 to 1976, respectively. There was no change in the relative frequency rates of gastric adenocarcinoma among African Americans and Asians. Although these changes do not seem important enough to make the detection of gastric cancer a high-priority public health problem, they should alert physicians working in areas with high Hispanic populations of the relative possibility of the occurrence of gastric malignancy even in young patients. Also, we have found that gastric cancer is still prevalent in whites of low socioeconomic class.


DNA-induced conformational changes in RecA protein. Evidence for structural heterogeneity among nucleoprotein filaments and implications for homologous pairing.
We have used circular dichroism as a probe to characterize the solution conformational changes in RecA protein upon binding to DNA. This approach revealed that RecA protein acquires significant amounts of alpha-helix upon interaction with DNA. These observations, consistent with the data from crystal structure (Story, R. M., Weber, I., and Steitz, T. (1992) Nature 355, 318-325), support the notion that some basic domains including the DNA binding motifs of RecA protein are unstructured and might contribute to the formation of alpha-helix. A comparison of nucleoprotein filaments comprised of RecA protein and a variety of DNA substrates revealed important structural heterogeneity. The most significant difference was observed with poly(dG). poly(dC) and related polymers, rich in GC sequences, which induced minimal amounts of alpha-helix in RecA protein. The magnitude of induction of alpha-helix in RecA protein, which occurred concomitant with the production of ternary complexes, was 2-fold higher with homologous than heterologous duplex DNA. Most importantly, the stimulation of ATP hydrolysis by high salt coincided with that of the induction of alpha-helix in RecA protein. These conformational differences provide a basis for thinking about the biochemical and structural transitions that RecA protein experiences during the formal steps of presynapsis, recognition, and alignment of homologous sequences.


Melanin production in black medullary thyroid carcinoma (MTC).
Melanin production by two medullary carcinomas of the thyroid is reported and discussed. In both tumours, melanin and calcitonin could be detected in the same cells.


Identification of up- and down-regulated proteins in doxorubicin-resistant uterine cancer cells: reticulocalbin-1 plays a key role in the development of doxorubicin-associated resistance.
Drug resistance is a frequent cause of failure in cancer chemotherapy treatments. In this study, a pair of uterine sarcoma cancer lines, MES-SA, and doxorubicin-resistant partners, MES-SA/DxR-2μM cells and MES-SA/DxR-8μM cells, as a model system to investigate resistance-dependent proteome alterations and to identify potential therapeutic targets. We used two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to perform this research and the results revealed that doxorubicin-resistance altered the expression of 208 proteins in which 129 identified proteins showed dose-dependent manners in response to the levels of resistance. Further studies have used RNA interference, H2A.X phosphorylation assay, cell viability analysis, and analysis of apoptosis against reticulocalbin-1 (RCN1) proteins, to prove its potency on the formation of doxorubicin resistance as well as the attenuation of doxorubicin-associated DNA double strand breakage. To sum up, our results provide useful diagnostic markers and therapeutic candidates such as RCN1 for the treatment of doxorubicin-resistant uterine cancer.


Atractylodis macrocephalae Koidz. polysaccharides enhance both serum IgG response and gut mucosal immunity.
Fifty-six mice were randomly divided into four groups with 14 mice in each. Two groups were subcutaneously injected twice with a foot-and-mouth disease vaccine with 2-week intervals; each of them had been orally administered 0.89% saline or Atractylodis macrocephalae Koidz. polysaccharides (RAMPS) 0.05 g for 4 days before immunization. The rest were not immunized but treated in the same way. One-week after the primary and two weeks after the booster immunization, half in each group were sacrificed to measure serum IgG and the parameters for the intestinal mucosal immunity. Results indicated that oral administration of RAMPS increased both serum specific IgG response and intestinal mucosal immunity as shown by elevated total sIgA, mRNA expression of TGF-β, IL-6, TNF-α, IgA(+) cells and intestinal intraepithelial lymphocytes in duodenum. It is suggested that increased serum IgG response may be associated with enhanced local mucosal immunity by oral administration of RAMPS.


A diversity-oriented synthesis of 3-(2-amino-1,6-dihydro-6-oxo-pyrimidin-5-yl)propanoic esters.
The synthesis of dimethyl 2-(methoxymethylene) pentanedioates by an unusual Michael addition of 3,3-dimethoxypropionate to α, β-unsaturated esters is described. These new intermediates can subsequently be converted to methyl 3-(2-amino-1,6-dihydro-6-oxo-pyrimidin-5-yl)propanoates upon treatment with guanidine carbonate. The resulting pyrimidine derivatives are open-chain analogues of pyrido[2,3-d]pyrimidines with interesting biological activities.


[Effect of prolonged intracardiac catecholamine infusion on the active nature of neuronal uptake in the atrium of the rat].
A preliminary saturation of the blood with catecholamines enhanced the ability of atria for neuronal uptake of labeled 3H-noradrenaline. Reserpine potentiated the effect. Issuing from the pattern of formation and disintegration of the agonist receptor complexes, the data obtained are interpreted as the mechanism of increasing the heart adrenoreactivity. The activating effect of catecholamines on the neuronal uptake has a certain threshold and does not depend on the duration of pre-infusion or concentration of administered catecholamines.


Carotid angiography in cerebral metastases.
Carotid angiography was performed in 138 cases of brain metastases. No pathologic vascularity was found in 55 per cent, pathologic arterial phase in 10 per cent, capillary phase in 14 per cent and pathologic venous phase in 12 per cent. In six cases, pathologic vascularity was found in all three phases; five of these were hypernephromas.


Ablation of peri-"mitral" flutter in a patient with congenitally corrected transposition of great vessels and situs inversus.
This case reports the successful ablation of a peri-"mitral" flutter in a patient with congenitally corrected transposition of the great vessels and situs inversus using an anterior mitral line.


Bio-stimuli-responsive multi-scale hyaluronic acid nanoparticles for deepened tumor penetration and enhanced therapy.
In this study, we developed bio-stimuli-responsive multi-scale hyaluronic acid (HA) nanoparticles encapsulated with polyamidoamine (PAMAM) dendrimers as the subunits. These HA/PAMAM nanoparticles of large scale (197.10±3.00nm) were stable during systematic circulation then enriched at the tumor sites; however, they were prone to be degraded by the high expressed hyaluronidase (HAase) to release inner PAMAM dendrimers and regained a small scale (5.77±0.25nm) with positive charge. After employing tumor spheroids penetration assay on A549 3D tumor spheroids for 8h, the fluorescein isothiocyanate (FITC) labeled multi-scale HA/PAMAM-FITC nanoparticles could penetrate deeply into these tumor spheroids with the degradation of HAase. Moreover, small animal imaging technology in male nude mice bearing H22 tumor showed HA/PAMAM-FITC nanoparticles possess higher prolonged systematic circulation compared with both PAMAM-FITC nanoparticles and free FITC. In addition, after intravenous administration in mice bearing H22 tumors, methotrexate (MTX) loaded multi-scale HA/PAMAM-MTX nanoparticles exhibited a 2.68-fold greater antitumor activity.


Diabetes is not a risk factor for myocardial infarction in patients without coronary artery disease: A study from the Western Denmark Heart Registry.
Diabetes is considered a risk factor for myocardial infarction. However, we have previously found that diabetes was not a short-term risk factor for myocardial infarction in the absence of obstructive coronary artery disease. We conducted a cohort study of patients undergoing coronary angiography from 2003 to 2012 and followed them by cross-linking Danish health registries. Patients were stratified according to coronary artery disease and diabetes. Endpoints included myocardial infarction, cardiac death, all-cause death and coronary revascularization. 86,202 patients were included in total (diabetes: n = 12,652). Median follow-up was 8.8 years. Using patients with neither coronary artery disease nor diabetes as reference (cumulative myocardial infarction incidence 2.6%), the risk of myocardial infarction was low and not substantially increased for patients with diabetes alone (3.2%; hazard ratio 1.202, 95% confidence interval 0.996-1.451), was increased for patients with coronary artery disease alone (9.3%; hazard ratio 2.75, 95% confidence interval 2.52-3.01) and was highest for patients with both coronary artery disease and diabetes (12.3%; hazard ratio 3.79, 95% confidence interval 3.43-4.20). Similar associations were observed for cardiac death and coronary revascularization. Diabetes patients without coronary artery disease by coronary angiography have a low risk of myocardial infarction, not substantially increased compared to patients with neither coronary artery disease nor diabetes. In the presence of coronary artery disease, however, diabetes increases the risk of myocardial infarction.


A Phase 0 Microdosing PET/CT Study Using O-[18F]Fluoromethyl-d-Tyrosine in Normal Human Brain and Brain Tumor.
The aim of the present study was to obtain information about distribution, radiation dosimetry, toxicity, and pharmacokinetics of O-[18F]fluoromethyl-d-tyrosine (d-18F-FMT), an amino acid PET tracer, in patients with brain tumors. A total of 6 healthy controls (age = 19-25 years, 3 males and 3 females) with brain PET images and radiation dosimetry and 12 patients (median age = 60 years, 6 males and 6 females) with primary (n = 5) or metastatic brain tumor (n = 7) were enrolled. We acquired 60-minute dynamic brain PET images after injecting 370 MBq of d-18F-FMT. Time-activity curves of d-18F-FMT uptake in normal brain versus brain tumors and tumor-to-background ratio were analyzed for each PET data set. Normal cerebral uptake of d-18F-FMT decreased from 0 to 5 minutes after injection, but gradually increased from 10 to 60 minutes. Tumoral uptake of d-18F-FMT reached a peak before 30 minutes. Tumor-to-background ratio peaked at less than 15 minutes for 8 patients and more than 15 minutes for 4 patients. The mean effective dose was calculated to be 13.2 μSv/MBq. Using d-18F-FMT as a PET radiotracer is safe. It can distinguish brain tumor from surrounding normal brain tissues with a high contrast. Early-time PET images of brain tumors should be acquired because the tumor-to-background ratio tended to reach a peak within 15 minutes after injection.


Metastatic cutaneous squamous cell carcinoma to the parotid: Adjuvant radiotherapy and treatment outcomes.
Adjuvant radiotherapy is an established component in the management of metastatic cutaneous squamous cell carcinoma (SCC) involving the parotid gland. Radiotherapy technique, dose and volumes are seldom described sufficiently to allow close examination. We report our treatment outcomes and focus on treatment-related factors that affect outcomes in this cohort. We performed a retrospective review of patients with metastatic cutaneous SCCs who underwent parotidectomy with or without ipsilateral neck dissection. All patients received adjuvant radiotherapy. Demographics, clinical data and treatment details were collected from an intuitional electronic database. Individual patient-level radiotherapy technique, volumes and doses were reviewed. Between July 2008 and July 2018, 60 patients met our inclusion criteria. Median follow-up duration was 32.7 months. The mean age was 66.4 years. The majority of patients (49 patients) received full neck irradiation. The 2-year and 5-year loco-regional failure-free survival was 87% (95% confidence interval (CI): 0.74-0.93) and 71% (95% CI: 0.52, 0.83), respectively. The 2-year and 5-year overall survival was 76% (95% CI: 0.62, 0.85) and 60% (95% CI: 0.45, 0.72), respectively. There were 15 cases of loco-regional failures, with 6 cases with dermal involvement. Lymphovascular invasion (LVI) was associated with higher loco-regional failure (hazard ratio: 8.43, 95% CI: 1.85-38.39, P = 0.005) and cancer-specific mortality (hazard ratio: 5.40, 95% CI: 1.40-20.87, P = 0.015). Treatment technique, intensity-modulated radiation therapy (IMRT) vs 3D conformal radiotherapy (3D CRT), bolus use, perineural invasion (PNI) and surgical margins were not significantly associated with loco-regional failure. We demonstrated high loco-regional control rates with routine use of comprehensive adjuvant radiotherapy. The presence of LVI was identified as a strong predictor for recurrence. Further analysis will help to define optimal radiation dose and techniques.


Using HIPE data as a research and planning tool: limitations and opportunities.
The Hospital Inpatient Enquiry (HIPE) system is an important information source for research and health service planning activities. However, as it was not designed explicitly for these purposes, some limitations exist. To make recommendations that would increase the value of HIPE as a research and planning tool. Experiences of using HIPE for research and planning exercises were analysed so as to identify its limitations and their impact on research and planning. Limitations were identified regarding data quality, policy issues and the general system. To increase the utility of HIPE as a research and planning tool, a number of changes are recommended, including: expanding the system to cover private hospitals and outpatient and emergency services; adopting routine small area and socio-economic coding; adopting unique personal identifiers; publishing regular detailed reports with in-depth analyses; and considering making hospital identifiers available in certain circumstances.


Lipopolysaccharide-induced depression is associated with estrogen receptor-α/SIRT1/NF-κB signaling pathway in old female mice.
The present study aims to investigate the influence of sex/age on depressive-like behaviors in lipopolysaccharide (LPS)-challenged mice model, and explore the underlying mechanisms. Tail suspension test and forced swimming test were used to evaluate the depressive-like behaviors. SIRT1 mRNA expression was assessed by PCR. Levels of 17β-estradiol (E2), SIRT1, NF-κB, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). In the behavior tests, under the same LPS stimulation, significant depressive-like behavior was observed in young male mice but not in young female mice, however, female mice were more likely to be depressed than male mice in the old age. Moreover, we found age-related depression difference existed only in female mice. In the experiments of mechanism exploration in old female mice, E2 improved LPS-induced depressive-like behavior, and simultaneously elevated SIRT1 levels and downregulated expressions of NF-κB and inflammatory cytokines in the hippocampus and frontal cortex. Interestingly, ERα inhibition, not ERβ inhibition, abolished E2's function. Additionally, SIRT1 antagonist also reversed E2's effects on depressive-like behavior and the expressions of NF-κB and inflammatory cytokines. These results suggested that E2 could protect the old female mice from depression via E2/ERα/SIRT1/NF-κB signaling pathway. In other words, LPS-induced depression was associated with ER-α/SIRT1/NF-κB signaling pathway in old female mice. By comparing the results of mechanism exploration in old male mice and old female mice and the different expression levels of E2, SIRT1, NF-κB and inflammatory cytokines in young female mice and old female mice, we speculate that the age or gender-related depression difference may be associated with the different activation levels of the ERα/SIRT1/NF-κB signaling pathway.


A Novel ypTLM Staging System Based on LODDS for Gastric Cancer After Neoadjuvant Therapy: Multicenter and Large-Sample Retrospective Study.
The accuracy of the eighth AJCC ypTNM staging system on the prognosis of gastric cancer (GC) patients after neoadjuvant therapy (NAT) is controversial. This study aimed to develop and validate a novel staging system using the log odds of positive lymph nodes scheme (LODDS). A retrospective analysis of 606 GC patients who underwent radical gastrectomy after neoadjuvant therapy was conducted as the development cohort. (Fujian Medical University Affiliated Union Hospital (n = 183), Qinghai University Affiliated Hospital (n = 169), Mayo Clinic (n = 236), Lanzhou University First Hospital (n = 18)). The validation cohort came from the SEER database (n = 1701). A novel ypTLoddsS (ypTLM) staging system was established using the 3-year overall survival. The predictive performance of two systems was compared. Two-step multivariate Cox regression analysis in both cohorts showed that ypTLM was an independent predictor of overall survival of GC patients after neoadjuvant therapy (HR: 1.57, 95% CI: 1.30-1.88, p < 0.001). In the development cohort, ypTLM had better discrimination ability than ypTNM (C-index: 0.663 vs 0.633, p < 0.001), better prediction homogeneity (LR: 97.7 vs. 70.9), and better prediction accuracy (BIC: 3067.01 vs 3093.82; NRI: 0.36). In the validation cohort, ypTLM had a better prognostic predictive ability (C-index: 0.614 vs 0.588, p < 0.001; LR: 11,909.05 vs. 11,975.75; BIC: 13,263.71 vs 13,328.24; NRI: 0.22). The time-dependent ROC curve shows that the predictive performance of ypTLM is better than ypTNM, and the analysis of the decision curve shows that ypTLM achieved better net benefits. A LODDS-based ypTLM staging system based on multicenter data was established and validated. The predictive performance was superior to the eighth AJCC ypTNM staging system.


Fate and health risk assessment of heavy metals in Brassica chinensis L. (pak-choi) and soil amended by sludge-based biochar.
Biochar is widely used in agriculture to efficiently solve the problem of sludge. In this study, sludge-based biochar (referred to as BC1, BC2, and BC3) was prepared by mixing sludge with FeCl3, Na2SiO3, and Ca (H2PO4)2, respectively. Then, it was mixed with fresh soil to plant Brassica chinensis L. The analysis of the effects of the three biochar types showed that all of them were beneficial to the growth of Brassica chinensis L. We added the biochar to the soil and found that the concentration of heavy metals did not exceed the recommended threshold. Additionally, the aboveground part of Brassica chinensis L. met the standard requirement for food safety (GB 2761-2017). Notably, BC3 stood out with the best effect on the growth of Brassica chinensis L. and resulted in the improvement of the physical and chemical properties of soil such as ammonium nitrogen, available phosphorus, and available potassium (BC3 was followed by BC2 and BC1). BC3 could efficiently inhibit the migration of heavy metals, thereby reducing the overall heavy metal pollution level and ameliorating the soil nutrients. BC3 could increase the organic carbon by 258.92%, available phosphorus by 234.45%, and available potassium by 37.12% compared with the CK group. The THQ and TTHQ estimates of Brassica chinensis L. were lower than one, indicating that the health risk of heavy metal intake was not prominent. Additionally, the application of the proposed biochar could reduce the form of F1 (acid extracted state) and increase the form of F4 (residue state) in soil. Overall, we conclude that the application of the proposed biochar can promote the root absorption of heavy metals and inhibit the migration of heavy metals.


Less Illusion of a Just World in People with Formally Diagnosed Autism and Higher Autistic Traits.
People differ in how strongly they believe that, in general, one gets what (s)he deserves (i.e., individual differences in the general belief in a just world). In this study (N = 588; n = 60 with a formal autism diagnosis), whether or not autistic people and those with high autistic traits have a relatively low general belief in a just world is examined. The results revealed the expected relationship between autism/higher autistic traits and a lower general belief in a just world. In a subsample (n = 388), personal belief in a just world, external locus of control, and self-deception mediated this relationship. These findings are discussed in terms of autistic strengths (less biased information processing) and problems (lowered well-being).


Fetal ingestion and metabolism of amniotic fluid protein.
Fetal swallowing, digestion, and utilization of amniotic fluid protein were studied in near-term rhesus monkeys in which 35S-protein, synthesized biologically from 35S-methionine, was injected into the amniotic sac. The half-time of the injected protein in amniotic fluid was 1.1 days, a figure consistent with findings of others that fetal swallowing represents the principal mechanism of clearance of amniotic fluid protein. On delivery at timed intervals up to 7 days after injection, evidence of progressive proteolysis along the fetal alimentary tract was found. The amnio acids liberated from protein hydrolysis were apparently utilized in protein synthesis in the gut wall as well as absorbed in fetal plasma, where they equilibrated rapidly with maternal plasma and amniotic fluid. Maximal amino acid radioactivity in these three compartments occurred 3 days after injection and was followed 1 day later by maximal fetal plasma protein radioactivity. Incorporation into protein of amino acids absorbed after hydrolysis was found in fetal lung, liver, skeletal muscle, and brain. The results indicate that ingested amniotic fluid protein undergoes proteolysis in the fetal alimentary tract and the amino acids thus made available are utilized in protein synthesis by the developing fetus. While this mechanism can provide only a relatively minor proportion (estimated at 10 to 15 per cent) of fetal nitrogen requirements, it may represent an important aspect physiologically by preparing the fetus for extrauterine nutrition. Moreover, the use of intra-amniotic nutrition as a mode of fetal therapy, while speculative at present, offers possibilities for the furture.


Divergent cognitive trajectories in early stage Huntington's disease: A 3-year longitudinal study.
Cognitive impairment is a central feature of Huntington's disease (HD), but it is unclear to what extent more aggressive cognitive phenotypes exist in HD among individuals with the same genetic load and equivalence in other clinical and sociodemographic variables. We included Enroll-HD study participants in early and early-mid stages of HD at baseline and with three consecutive yearly follow-ups for whom several clinical and sociodemographic as well as cognitive measures were recorded. We excluded participants with low and large CAG repeat length (CAG < 39 & > 55), with juvenile or late onset HD, and with dementia at baseline. We explored the existence of different groups according to the profile of cognitive progression using a two-step k-means cluster analysis model based on the combination of different cognitive outcomes. We identified a slow cognitive progression group of 293 participants and an aggressive progression group (F-CogHD) of 235 for which there were no differences at the baseline visit in any of the measures explored, with the exception of a slightly higher motor score in the F-CogHD group. This group showed a more pronounced annual loss of functionality and a more marked motor and psychiatric deterioration. The rate of progression of cognitive deterioration in HD is strongly variable even between patients sharing, among other variables, equivalent CAG repeat length, age, and disease duration. We can recognize at least two phenotypes that differ in terms of rate of progression. Our findings open new avenues to study additional mechanisms contributing to HD heterogeneity.