Heterocellular spheroids of the neurovascular blood-brain barrier as a platform for personalized nanoneuromedicine.
Nanoneuromedicine investigates nanotechnology to target the brain and treat neurological diseases. In this work, we biofabricated heterocellular spheroids comprising human brain microvascular endothelial cells, brain vascular pericytes and astrocytes combined with primary cortical neurons and microglia isolated from neonate rats. The structure and function are characterized by confocal laser scanning and light sheet fluorescence microscopy, electron microscopy, western blotting, and RNA sequencing. The spheroid bulk is formed by neural cells and microglia and the surface by endothelial cells and they upregulate key structural and functional proteins of the blood-brain barrier. These cellular constructs are utilized to preliminary screen the permeability of polymeric, metallic, and ceramic nanoparticles (NPs). Findings reveal that penetration and distribution patterns depend on the NP type and that microglia would play a key role in this pathway, highlighting the promise of this platform to investigate the interaction of different nanomaterials with the central nervous system in nanomedicine, nanosafety and nanotoxicology.


Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway.
Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.


5-Hydroxytryptamine1A receptor responsivity in obsessive-compulsive disorder. Comparison of patients and controls.
To evaluate 5-hydroxytryptamine1A receptor responsivity in obsessive-compulsive disorder, we examined hypothermic, neuroendocrine, and behavioral responses to the selective 5-hydroxytryptamine1A receptor ligand ipsapirone in patients with primary obsessive-compulsive disorder and healthy controls. Twelve patients and 22 controls received a single dose of ipsapirone, 0.3 mg/kg, or placebo under double-blind, random assignment conditions. Ipsapirone induced hypothermia and release of corticotropin and cortisol but had no effect on behavior, including obsessive or compulsive symptoms. Thermoregulatory and neuroendocrine responses to ipsapirone were not consistently different between healthy controls and patients with obsessive-compulsive disorder. These results provide no direct support for the hypothesis that a serotonergic dysfunction related to 5-hydroxytryptamine1A receptors may be linked to the pathophysiologic characteristics of obsessive-compulsive disorder and point to the need for the evaluation of other 5-hydroxytryptamine receptor subtypes. Future studies of the responsivity of 5-hydroxytryptamine1A receptors to direct-acting ligands, such as ipsapirone, should facilitate assessment of the integrity of the 5-hydroxytryptamine system and its involvement in antiobsessional drug effects.


Regulation of the plastochron by three many-noded dwarf genes in barley.
The plastochron, the time interval between the formation of two successive leaves, is an important determinant of plant architecture. We genetically and phenotypically investigated many-noded dwarf (mnd) mutants in barley. The mnd mutants exhibited a shortened plastochron and a decreased leaf blade length, and resembled previously reported plastochron1 (pla1), pla2, and pla3 mutants in rice. In addition, the maturation of mnd leaves was accelerated, similar to pla mutants in rice. Several barley mnd alleles were derived from three genes-MND1, MND4, and MND8. Although MND4 coincided with a cytochrome P450 family gene that is a homolog of rice PLA1, we clarified that MND1 and MND8 encode an N-acetyltransferase-like protein and a MATE transporter-family protein, which are respectively orthologs of rice GW6a and maize BIGE1 and unrelated to PLA2 or PLA3. Expression analyses of the three MND genes revealed that MND1 and MND4 were expressed in limited regions of the shoot apical meristem and leaf primordia, but MND8 did not exhibit a specific expression pattern around the shoot apex. In addition, the expression levels of the three genes were interdependent among the various mutant backgrounds. Genetic analyses using the double mutants mnd4mnd8 and mnd1mnd8 indicated that MND1 and MND4 regulate the plastochron independently of MND8, suggesting that the plastochron in barley is controlled by multiple genetic pathways involving MND1, MND4, and MND8. Correlation analysis between leaf number and leaf blade length indicated that both traits exhibited a strong negative association among different genetic backgrounds but not in the same genetic background. We propose that MND genes function in the regulation of the plastochron and leaf growth and revealed conserved and diverse aspects of plastochron regulation via comparative analysis of barley and rice.


Keeping the Finger on the Pulse: Cardiac Arrhythmias in Hand Surgery Using Local Anesthesia with Adrenaline.
The wide-awake local anesthesia no tourniquet (WALANT) technique in hand surgery is gaining popularity. The authors aimed to prospectively analyze the frequency and type of arrhythmias in patients undergoing hand surgery under local anesthesia and to examine whether the addition of adrenaline affects their incidence. Adult patients undergoing hand surgery under local anesthesia were randomized into two groups: group 1, local anesthesia with lidocaine and tourniquet; and group 2, local anesthesia with lidocaine and adrenaline (WALANT). Patients with a history of arrhythmias were excluded. Patients were connected to Holter electrocardiographic monitoring before surgery and up until discharge. The records were blindly compared between the groups regarding types of arrhythmias, and frequency and timing relative to injection and tourniquet inflation. One hundred two patients were included between August of 2018 and August of 2019 (age, 59.7 ± 13.6 years; 71 percent women; 51 in each group). No major arrhythmia (ventricular tachycardia, ventricular fibrillation, atrial fibrillation) or arrhythmia-related symptoms were recorded for either group. Minor arrhythmias (including atrial premature beats, ventricular premature beats, and atrial tachycardia) were recorded in 68 patients (66.6 percent), with no statistical difference between the groups. There were three patients with minor arrhythmias during inflation of the tourniquet. Patients in the adrenaline group had 2 percent sinus tachycardia during injection and 4 percent asymptomatic bradyarrhythmias. These findings do not require any further treatment. The authors' results show that hand operations using WALANT technique in patients with no history of arrhythmia are safe and are not arrhythmogenic; therefore, there is no need for routine perioperative continuous electrocardiographic monitoring. Therapeutic, II.


Cost-effectiveness of surgery in low- and middle-income countries: a systematic review.
There is increasing interest in provision of essential surgical care as part of public health policy in low- and middle-income countries (LMIC). Relatively simple interventions have been shown to prevent death and disability. We reviewed the published literature to examine the cost-effectiveness of simple surgical interventions which could be made available at any district hospital, and compared these to standard public health interventions. PubMed and EMBASE were searched using single and combinations of the search terms "disability adjusted life year" (DALY), "quality adjusted life year," "cost-effectiveness," and "surgery." Articles were included if they detailed the cost-effectiveness of a surgical intervention of relevance to a LMIC, which could be made available at any district hospital. Suitable articles with both cost and effectiveness data were identified and, where possible, data were extrapolated to enable comparison across studies. Twenty-seven articles met our inclusion criteria, representing 64 LMIC over 16 years of study. Interventions that were found to be cost-effective included cataract surgery (cost/DALY averted range US$5.06-$106.00), elective inguinal hernia repair (cost/DALY averted range US$12.88-$78.18), male circumcision (cost/DALY averted range US$7.38-$319.29), emergency cesarean section (cost/DALY averted range US$18-$3,462.00), and cleft lip and palate repair (cost/DALY averted range US$15.44-$96.04). A small district hospital with basic surgical services was also found to be highly cost-effective (cost/DALY averted 1 US$0.93), as were larger hospitals offering emergency and trauma surgery (cost/DALY averted US$32.78-$223.00). This compares favorably with other standard public health interventions, such as oral rehydration therapy (US$1,062.00), vitamin A supplementation (US$6.00-$12.00), breast feeding promotion (US$930.00), and highly active anti-retroviral therapy for HIV (US$922.00). Simple surgical interventions that are life-saving and disability-preventing should be considered as part of public health policy in LMIC. We recommend an investment in surgical care and its integration with other public health measures at the district hospital level, rather than investment in single disease strategies.


Estimated Burden of Fungal Infections in Namibia.
Namibia is a sub-Saharan country with one of the highest HIV infection rates in the world. Although care and support services are available that cater for opportunistic infections related to HIV, the main focus is narrow and predominantly aimed at tuberculosis. We aimed to estimate the burden of serious fungal infections in Namibia, currently unknown, based on the size of the population at risk and available epidemiological data. Data were obtained from the World Health Organization (WHO), Joint United Nations Programme on HIV/AIDS (UNAIDS), and published reports. When no data existed, risk populations were used to estimate the frequencies of fungal infections, using the previously described methodology. The population of Namibia in 2011 was estimated at 2,459,000 and 37% were children. Among approximately 516,390 adult women, recurrent vulvovaginal candidiasis (≥4 episodes /year) is estimated to occur in 37,390 (3003/100,000 females). Using a low international average rate of 5/100,000, we estimated 125 cases of candidemia, and 19 patients with intra-abdominal candidiasis. Among survivors of pulmonary tuberculosis (TB) in Namibia 2017, 112 new cases of chronic pulmonary aspergillosis (CPA) are likely, a prevalence of 354 post-TB and a total prevalence estimate of 453 CPA patients in all. Asthma affects 11.2% of adults, 178,483 people, and so allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) were estimated in approximately 179/100,000 and 237/100,000 people, respectively. Invasive aspergillosis (IA) is estimated to affect 15 patients following leukaemia therapy, and an estimated 0.13% patients admitted to hospital with chronic obstructive pulmonary disease (COPD) (259) and 4% of HIV-related deaths (108) - a total of 383 people. The total HIV-infected population is estimated at 200,000, with 32,371 not on antiretroviral therapy (ART). Among HIV-infected patients, 543 cases of cryptococcal meningitis and 836 cases of Pneumocystis pneumonia are estimated each year. Tinea capitis infections were estimated at 53,784 cases, and mucormycosis at five cases. Data were missing for fungal keratitis and skin neglected fungal tropical diseases such as mycetoma. The present study indicates that approximately 5% of the Namibian population is affected by fungal infections. This study is not an epidemiological study-it illustrates estimates based on assumptions derived from similar studies. The estimates are incomplete and need further epidemiological and diagnostic studies to corroborate, amend them, and improve the diagnosis and management of these diseases.


A comparison of the effect of three sedatives on esophageal sphincters in cats.
Children 5 years old and younger often require sedation for esophageal motility studies (EMS). At our institution, an intramuscular cocktail of meperidine, promethazine and chlorpromazine (MPC) has been used as the standard sedative for young children undergoing EMS. Administering the intramuscular sedative may, however, be more traumatic to the child than the procedure. Moreover, its effect on esophageal motility is not known and prolonged sedation is common. The aim of this study was to determine the effects of MPC and two orally-administered sedatives on esophageal sphincter function, using the cat model, with a goal to identify a potentially suitable orally-administered sedative for use in young children requiring sedation for EMS. We measured upper (UESP) and lower (LESP) esophageal sphincter pressures in 25 cats initially without sedation, and then following sedation with midazolam, chloral hydrate and MPC. The results were compared. All three sedatives significantly decreased LESP compared to the control (p<0.05). Midazolam decreased LESP the most; however, the difference from the other sedatives did not reach statistical significance. All three sedatives decreased UESP, compared to control, but the differences were not statistically significant. Of the two oral sedatives, chloral hydrate had the least effect on the esophageal sphincters although its effect was not statistically different from that of midazolam. Ethically appropriate studies are needed to determine which oral sedative would be most beneficial for use in sedating children undergoing esophageal motility studies. Until studies can be done, the choice between chloral hydrate and midazolam should be based on the experience and comfort of the attending physician with regard to the potential side effects of the medications.


Structural Heart Disease Emergencies.
Structural heart disease (SHD) emergencies include acute deterioration of a stable lesion or development of a new critical lesion. Structural heart disease emergencies can produce heart failure and cardiogenic shock despite preserved systolic function that may not respond to standard medical therapy and typically necessitate surgical or percutaneous intervention. Comprehensive Doppler echocardiography is the initial diagnostic modality of choice to determine the cause and severity of the underlying SHD lesion. Patients with chronic SHD lesions which deteriorate due to intercurrent illness (eg, infection or arrhythmia) may not require urgent intervention, whereas patients with an acute SHD lesion often require definitive therapy. Medical stabilization prior to definitive intervention differs substantially between stenotic lesions (aortic stenosis, mitral stenosis, left ventricular outflow tract obstruction) and regurgitant lesions (aortic regurgitation, mitral regurgitation, ventricular septal defect). Patients with regurgitant lesions typically require aggressive afterload reduction and inotropic support, whereas patients with stenotic lesions may paradoxically require β-blockade and vasoconstrictors. Emergent cardiac surgery for patients with decompensated heart failure or cardiogenic shock carries a substantial mortality risk but may be necessary for patients who are not eligible for catheter-based percutaneous SHD intervention. This review explores initial medical stabilization and subsequent definitive therapy for patients with SHD emergencies.


Optical coherence tomography changes in macular CMV retinitis.
Cytomegalovirus (CMV) retinitis characteristically causes peripheral retinitis with associated vasculitis. It rarely begins in the macula or causes macular necrosis exclusively. We report a case of unilateral macular CMV retinitis in a 65-year-old immunosuppressed patient and document changes in the macula during treatment through optical coherence tomography (OCT).


Therapeutic effect of folate-targeted and PEGylated phytosomes loaded with a mitomycin C-soybean phosphatidyhlcholine complex.
A mitomycin C (MMC)-soybean phosphatidyhlcholine complex loaded in phytosomes was previously reported for the purpose of developing a MMC drug delivery system (Mol. Pharmaceutics 2013, 10, 90-101), but this approach was limited by rapid elimination from the body and lack of target specificity. In this article, to overcome these limitations, MMC-soybean phosphatidyhlcholine complex-loaded phytosomes (MMC-loaded phytosomes) as drug carriers were surface-functionalized with folate-PEG (FA-PEG) to achieve reduced toxicity and a superior MMC-mediated therapeutic effect. For this purpose, FA was conjugated to DSPE-PEG-NH2, and the resultant DSPE-PEG-FA was introduced into the lipid moiety of the phytosomes via a postinsertion technique. The prepared FA-PEG-functionalized MMC-loaded phytosomes (FA-PEG-MMC-loaded phytosomes) have a particle size of 201.9 ± 2.4 nm, a PDI of 0.143 ± 0.010, a zeta potential of -27.50 ± 1.67 mV, a spherical shape, and sustained drug release. The remarkable features of FA-PEG-MMC-loaded phytosomes included increased cellular uptake in HeLa cells and higher accumulation in H22 tumor-bearing mice over that of the PEG-MMC-loaded phytosomes. Furthermore, FA-PEG-MMC-loaded phytosomes were associated with enhanced cytotoxic activity in vitro and an improved antitumor effect in vivo compared to that resulting from free MMC injection. These results suggest that FA-PEG-MMC-loaded phytosomes may be useful drug delivery systems for widening the therapeutic window of MMC in clinical trials.


Purification and characterization of a recombinant human thyroid peroxidase expressed in insect cells.
Thyroid peroxidase (TPO) is an essential enzyme for thyroid hormone biosynthesis and is an autoantigen against which antibodies are found in a number of autoimmune thyroid disorders. Large quantities of pure TPO are essential for understanding its structure and role in normal thyroid function and thyroid diseases. In this study, we describe the production of human TPO (hTPO) using a baculovirus expression vector in insect cells. TPO was sequentially extracted from insect cells using various buffers and the protein was purified to homogeneity on a C4 reversed-phase semipreparative column using high-performance liquid chromatography. The purified protein was identified as hTPO by enzyme-linked immunosorbent assay, Western blot, and amino acid sequence analyses. Carbohydrate analysis of the recombinant hTPO showed that the protein is glycosylated and mannose is the major oligosaccharide. We have extended the carbohydrate analysis by establishing the occurrence of N-acetyl galactosamine which suggested that the recombinant hTPO might contain O-glycosyl moieties. Purified hTPO reacted specifically with sera from patients with Hashimoto's thyroiditis. Crude as well as purified hTPO did not show any enzymatic activity when produced in Sf9 insect cells grown in serum free medium. In contrast, hTPO produced in the presence of 10% fetal bovine serum containing 1 microgram/ml of haematin was enzymatically active. However, the enzymatic activity of the recombinant hTPO was lower than that often found with hTPO purified from thyroid tissue. Availability of purified hTPO in relatively large quantities should allow further structural and immunological studies.


First trimester screening cannot predict adverse outcomes yet.
The use of first trimester screening to detect aneuploidy has become an integral part of prenatal care. The application of similar screening algorithms to identify women at the highest risk for other adverse pregnancy outcomes in the first trimester could potentially have a major clinical impact. There has been much investigation into the ability to identify patients early in pregnancy at high risk for adverse pregnancy outcomes who may benefit from further surveillance and/or intervention. For this to be the case, however, as is true of any useful screening test, effective interventions need to be available. Unfortunately, for fetal growth restriction and stillbirth, no such interventions exist short of delivery. For preeclampsia, low dose aspirin has been demonstrated to be of benefit in specific subgroups. For preterm birth, although there are efficacious treatments, first trimester serum markers or cervical length measurements do not add significantly beyond historical or demographic factors, in prediction of preterm birth. Given the current evidence, first trimester screening, via serum or ultrasound markers, does not have sufficiently high enough positive predictive values for the development of preeclampsia, fetal growth restriction, preterm birth or stillbirth. In order to develop effective screening algorithms for adverse pregnancy outcomes in the first trimester, understanding the heterogeneous phenotype of these complications and the underlying pathophysiology is needed.


Cannabis and Alcohol Use and Their Associations with Sleep: A Daily Diary Investigation of Single-Use and Co-Use in College Students.
Introduction: Sleep continuity problems are widespread among college students and may be influenced by single-use and co-use of alcohol and cannabis. We examined the within-person associations of alcohol and cannabis use with subsequent sleep experiences in the everyday life of college students. Materials and Methods: A sample of 80 college students reported prior-night alcohol and cannabis use and sleep experiences for 14 consecutive days. Mixed-effects models examined the within-person relationships between alcohol and cannabis use (single- and co-use) and subsequent (1) sleep-onset latency, (2) total sleep time, (3) number of awakenings, and (4) early awakenings that night. Results: Compared to no-use evenings, alcohol and cannabis, used separately or together (co-use), were associated with shorter sleep-onset latency and longer total sleep time. Students reported more nightly awakenings after alcohol-only use compared to no-use and after co-use, and they reported fewer early awakenings after no-use and co-use. Conclusions: In line with previous experimental findings, we found that alcohol and cannabis use in the everyday life of college students were associated with sleep-inducing effects, and that alcohol use was associated with disturbed sleep continuity. The results suggest that cannabis may curb alcohol's detrimental effect on the number of awakenings and may reduce the incidence of early awakenings. Yet, due to lack of control for potentially important confounders (e.g., quantity of cannabis/alcohol consumed, withdrawal) the current results may be best seen as preliminary and further research is needed before causal inferences can be reached.


Differential effects of syntactic and semantic processing on the subregions of Broca's area.
This study attempts to specify the contribution of two subregions of Broca's area during syntactic and semantic processing of sentences by examining brain activation in a grammaticality judgment task. The processing of two types of ungrammatical sentences was examined. One type leaves the thematic interpretation generally unaffected, by violating the noun-verb agreement in number, while the other type introduces an extraneous verb, which cannot be incorporated into the developing thematic structure. Pars triangularis was more sensitive to the extra verb violation, whereas pars opercularis was more sensitive to the noun-verb agreement violation. The current study adds to the growing literature that suggests there are separable functional subregions of Broca's area, with pars triangularis more involved in thematic processing and pars opercularis more involved in syntactic processing. The posterior left temporal area was also involved in both types of processing.


Regulation of adrenergic receptor function by phosphorylation. I. Agonist-promoted desensitization and phosphorylation of alpha 1-adrenergic receptors coupled to inositol phospholipid metabolism in DDT1 MF-2 smooth muscle cells.
Continuous exposure of DDT1 MF-2 smooth muscle cells to 10-100 microM norepinephrine results in a dramatic attenuation of the ability of norepinephrine to stimulate inositol phospholipid hydrolysis via alpha 1-adrenergic receptors (alpha 1-AR). In addition to the functional desensitization, norepinephrine exposure also reduces the number of accessible cell surface alpha 1-AR as assayed by [3H]prazosin binding at 4 degrees C. Desensitization of the cells with norepinephrine results in an increase in the phosphorylation of the Mr 80,000 alpha 1-AR ligand binding peptide (2.4 +/- 0.2 mol of 32P per mol of alpha 1-AR; n = 5) when compared to control cells (1.1 +/- 0.1 mol of 32P per mol of alpha 1-AR; n = 5). The time courses of these three processes are all comparable being half-maximal within 1-2 min. These norepinephrine-promoted effects can be prevented by the alpha 1-AR receptor antagonist phentolamine indicating that they are mediated via the alpha 1-AR. Treatment of cells with the vasoactive peptide bradykinin (10 microM) induces desensitization of alpha 1-AR function similar to that induced by tumor-promoting phorbol ester treatment (Leeb-Lundberg, L. M. F., Cotecchia, S., Lomasney, J. W., DeBernardis, J. F., Lefkowitz, R. J., and Caron, M. G. (1985) Proc. Natl. Acad. Sci. USA 82, 5651-5655). Both treatments also result in phosphorylation of the alpha 1-AR, with stoichiometries of 1.7 +/- 0.1 (bradykinin; n = 5) and 3.6 +/- 0.1 (PMA; n = 5) mol of 32P/mol of alpha 1-AR. However, neither phorbol esters nor bradykinin reduce the number of accessible cell surface alpha 1-AR. Similar phosphopeptide maps are obtained from tryptic phosphopeptides generated from phosphorylated alpha 1-AR derived from cells treated with norepinephrine, phorbol 12-myristate 13-acetate, and bradykinin. Phosphoamino acid analysis reveals that the various agents induce phosphorylation on both serine and threonine residues. Thus, phosphorylation of receptors linked to the inositol phospholipid/Ca2+ signaling pathway may represent an important mechanism of regulation of receptor responsiveness.


Parasitic Resilience: The Next Phase of Public Health Preparedness Must Address Power Imbalances Between Communities.
Community resilience, a system's ability to maintain its essential functions despite disturbance, is a cornerstone of public health preparedness. However, as currently practiced, community resilience generally focuses on defined neighborhood characteristics to describe factors such as vulnerability or social capital. This ignores the way that residents of some neighborhoods (as "essential workers") were required during the COVID-19 pandemic to sacrifice their wellbeing for the sake of others staying at home in more affluent neighborhoods. Using the global care chain theory, we analyze the way that the resilience of affluent neighborhoods depends on siphoning off the labor of other, less affluent neighborhoods, creating what we call the parasitic nature of resilience. We argue that understanding this neighborhood interdependence-and accounting for its parasitic nature-should be prioritized by public health authorities to prevent unintentional harm in future pandemics. Otherwise, any public health emergency response that relies on this labor (as did the COVID-19 pandemic response) depends on exploitative practices that produce the very disparities the response is trying to address. We explore the theoretical grounding and practical effects of this idea to provide the preparedness enterprise with an initial set of theoretical tools to move from a model of community resilience to one of community renewal. The community renewal model is based on an underlying ethics of care, in which systems are redesigned to become more prosocial during a public health response. We believe this model can more successfully address the tragic inequities in labor and health outcomes that we see during public health emergencies.


Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats.
To characterize an alcohol and high fat diet induced chronic pancreatitis rat model that mimics poor human dietary choices. Experimental rats were fed a modified Lieber-DeCarli alcohol (6%) and high-fat (65%) diet (AHF) for 10 wk while control animals received a regular rodent chow diet. Weekly behavioral tests determined mechanical and heat sensitivity. In week 10 a fasting glucose tolerance test was performed, measuring blood glucose levels before and after a 2 g/kg bodyweight intraperitoneal (i.p.) injection of glucose. Post mortem histological analysis was performed by staining pancreas and liver tissue sections with hematoxylin and eosin. Pancreas sections were also stained with Sirius red and fast green to quantify collagen content. Insulin-expressing cells were identified immunohistochemically in separate sections. Tissue staining density was quantified using Image J software. After mechanical and heat sensitivity became stable (weeks 6-10) in the AHF-fed animals, three different drugs were tested for their efficacy in attenuating pancreatitis associated hypersensitivity: a Group II metabotropic glutamate receptor specific agonist (2R,4R)-4-Aminopyrrolidine-2,4-dicarboxylate (APDC, 3 mg/kg, ip; Tocris, Bristol, United Kingdom), nociceptin (20, 60, 200 nmol/kg, ip; Tocris), and morphine sulfate (3 mg/kg, μ-opioid receptor agonist; Baxter Healthcare, Deerfield, IL, United States). Histological analysis of pancreas and liver determined that unlike control rats, AHF fed animals had pancreatic fibrosis, acinar and beta cell atrophy, with steatosis in both organs. Fat vacuolization was significantly increased in AHF fed rats (6.4% ± 1.1% in controls vs 23.8% ± 4.2%, P < 0.05). Rats fed the AHF diet had reduced fasting glucose tolerance in week 10 when peak blood glucose levels reached significantly higher concentrations than controls (127.4 ± 9.2 mg/dL in controls vs 161.0 ± 8.6 mg/dL, P < 0.05). This concurred with a 3.5 fold higher incidence of single and small 2-10 cell insulin-positive cell clusters (P < 0.05). Insulin expressing islet of Langerhans cells appeared hypertrophied while islet number and area measurements were not different from controls. Weekly behavioral tests determined that mechanical and heat sensitivities were significantly increased by 4 wk on AHF diet compared to controls. Hypersensitivity was attenuated with efficacy similar to morphine with single dose treatment of either metabotropic glutamate receptor 2/3 agonist APDC, or nociceptin, the endogenous ligand for opioid-receptor-like 1 receptor. The AHF diet induces a chronic alcoholic pancreatitis in rats with measurable features resembling clinical patients with chronic pancreatitis and type 3c diabetes mellitus.


[Radiosensitivity of different ploidy pollen in poplar and its application].
Through investigation on germinating rate and process of unreduced diploidy pollen and monoploid pollen in Populus tomentosa x P. alba and P. tomentosa, it was proved that there were different radiosensitivities to 60Co gamma-ray among different ploidy pollen, i.e. the radiosensitivity of monoploidy pollen was two times higher than diploidy pollen. To overcome the problems of late germination and poor compatibility of diploidy pollen during fertilization, a certain dose of radiation can be applied to stimulating the diploidy pollen germination, meanwhile to restrain of kill some monoploidy pollen based on their different radiosensibilities. Therefore the rate of germination and faster germinating process of diploidy pollen on stigmas can be increased relatively to certain extent. The efficiency of radiation was proved by breeding practice. In the hybidization of (P. alba x P. glandulosa) x (P. tomentosa x P. bolleana), 3.8% of triploid could be produced by 1,470 rad treatment; while no triploid is examined in the control. 12.9% of triploids were produced by the treatment of 1,680 rad from the above cross.


Socioeconomic factors, rather than diabetes mellitus per se, contribute to an excessive use of antidepressants among young adults with childhood onset type 1 diabetes mellitus: a register-based study.
Mood disorders, including depression, are suggested to be prevalent in persons with type 1 diabetes and may negatively affect self-management and glycaemic control and increase the risk of diabetic complications. The aim of this study was to analyse the prevalence of antidepressant (AD) use in adults with childhood onset type 1 diabetes and to compare risk determinants for AD prescription among diabetic patients and a group of matched controls. Young adults ≥ 18 years on 1 January 2006 with type 1 diabetes (n = 7,411) were retrieved from the population-based Swedish Childhood Diabetes Registry (SCDR) and compared with 30,043 age- and community-matched controls. Individual level data were collected from the Swedish National Drug Register (NDR), the Hospital Discharge Register (HDR) and the Labor Market Research database (LMR). ADs were prescribed to 9.5% and 6.8% of the type 1 diabetes and control subjects, respectively. Female sex, having received economic or other social support, or having a disability pension were the factors with the strongest association with AD prescription in both groups. Type 1 diabetes was associated with a 44% (OR 1.44, 95% CI 1.32, 1.58) higher risk of being prescribed ADs in crude analysis. When adjusting for potential confounders including sex, age and various socioeconomic risk factors, this risk increase was statistically non-significant (OR 1.11, 95% CI 0.99, 1.21). The risk factor patterns for AD use are similar among type 1 diabetic patients and controls, and socioeconomic risk factors, rather than the diabetes per se, contribute to the increased risk of AD use in young adults with type 1 diabetes.


Genetic alterations in B cell lymphoma subtypes as potential biomarkers for noninvasive diagnosis, prognosis, therapy, and disease monitoring.
Neoplastic transformation of germinal center B (GCB) cells may give rise to a variety of different B cell lymphoma subtypes, most of which show substantial heterogeneity in terms of genetic alterations and clinical features. The mutations observed in cancer-related genes in GCB cells are related to abnormalities in the immunogenetic mechanisms associated with germinal center reaction. Recent studies have rapidly identified genomic alterations in B cell lymphomas that may be useful for better subclassification, noninvasive diagnosis, and prediction of response to therapy. The WHO recognizes different lymphoma subsets classified within 2 major categories of B cell lymphoma: Hodgkin's lymphoma (HL) and B cell non-Hodgkin's lymphoma (NHL), each with distinct genetic aberrations, including chromosomal translocations, copy number abnormalities, or point mutations. Next-generation sequencing-based technologies have allowed cancer researchers to identify somatic mutations and gene expression signatures at a rapid pace so that novel diagnostic or prognostic biomarkers, as well as therapeutic targets, can be discovered much faster than before. Indeed, deep sequencing studies have recently revealed that lymphoma-specific somatic mutations may be detected in cell-free circulating DNA obtained from the peripheral blood of B cell lymphoma patients, suggesting the possibility of minimally invasive diagnosis, monitoring, and predicting response to therapy of B cell lymphoma patients. In this study, the current status of the recurrent genetic aberrations observed during diagnosis and/or relapse in HL and the major subtypes of B cell NHL (i.e. diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Burkitt lymphoma) are discussed to shed light on their potential use as noninvasive diagnostic or prognostic biomarkers and to reveal their role in lymphomagenesis as a target in therapy for newly diagnosed and chemotherapy-resistant cases.


A new respiratory monitor that enables accurate measurement of work of breathing: a validation study.
Computerized, yet portable, bedside pulmonary monitors that can measure work of breathing (WOB) are now commercially available; however, none accurately measures WOB. The purpose of this study was to evaluate new software designed to measure WOB by means of the Campbell diagram and to test the agreement between a monitor (Model CP-100, Bicore, Irvine CA) programmed with the new software and the conventional method of measuring WOB. Using a lung model of our own devising, we compared WOB measurements between the monitor and conventional laboratory equipment. Inspiratory flow-rate, tidal volume (VT), and resistance of the model were adjusted to produce WOB ranging from 0.80 to 3.25 J/L. Regression analysis and calculation of bias and precision were performed for these data. For total, elastic, and resistive WOB, the two methods of measurement correlated strongly and positively. For all values of WOB, the correlation coefficients (r) and coefficients of determination (r2) were close to 0.99 (p < 0.0001); bias was minimal (-0.05 J/L) and precision acceptable (0.06 J/L). Data from a lung model reveal that a respiratory monitor programmed with appropriate software can accurately measure total, elastic, and resistive WOB. The monitor may eventually prove useful for clinically assessing WOB, which then can be used to adjust the ventilator to optimize respiratory muscle loads.


Two-dimensional gel electrophoresis of cattle plasma proteins: genetic polymorphism of an alpha 1-protease inhibitor.
Two-dimensional electrophoretic analysis of cattle plasma proteins was done by a first dimension separation in agarose gel (pH 5.0), followed by a second dimension in horizontal polyacrylamide gel (pH 9.0). This method resulted in improved and reproducible separation of many alpha- and beta-globulins. Three groups of alpha-globulins, designated Pi-1, Pi-2 and Pi-3, were found to inhibit the esterolytic activity of bovine trypsin and bovine chymotrypsin. Pi-2 showed appreciable inhibition only for trypsin and genetic polymorphism was observed for this protein. Family data supported the hypothesis that the three Pi-2 types observed were controlled by two codominant, autosomal alleles. The occurrence of a third Pi-2 allele was also postulated in some animals studied. The frequency of the most common allele, Pi-2s, ranged from 0.5-0.8 in the different breeds of cattle studied (Swedish Red and White, Friesian, Jersey, Charolais and Simmental). The post-transferrins Ptf-1 and Ptf-2 in cattle plasma were shown to be two different genetic systems.


[Interaction of SENP6 with PINK1 Promotes Temozolomide Resistance in Neuroglioma Cells via Inducing the Mitophagy].
Temozolomide resistance is a major cause of recurrence and poor prognosis in neuroglioma. Recently, growing evidence has suggested that mitophagy is involved in drug resistance in various tumor types. However, the role and molecular mechanisms of mitophagy in temozolomide resistance in glioma remain unclear. In this study, mitophagy levels in temozolomide-resistant and -sensitive cell lines were evaluated. The mechanisms underlying the regulation of mitophagy were explored through RNA sequencing, and the roles of differentially expressed genes in mitophagy and temozolomide resistance were investigated. We found that mitophagy promotes temozolomide resistance in glioma. Specifically, small ubiquitin-like modifier specific protease 6 (SENP6) promoted temozolomide resistance in glioma by inducing mitophagy. Protein-protein interactions between SENP6 and the mitophagy executive protein PTEN-induced kinase 1 (PINK1) resulted in a reduction in small ubiquitin-like modifier 2 (SUMO2)ylation of PINK1, thereby enhancing mitophagy. Our study demonstrates that by inducing mitophagy, the interaction of SENP6 with PINK1 promotes temozolomide resistance in glioblastoma. Therefore, targeting SENP6 or directly regulating mitophagy could be a potential and novel therapeutic target for reversing temozolomide resistance in glioma.


[Education about dementia. Effectiveness of a public lecture].
Memory and dementia are often topics of educational activities, however there is only limited information about the effectiveness of this education. In this study the effectiveness of a lecture, as part of a series of lectures about dementia, has been evaluated. The results showed an improvement in knowledge after the lecture and the participants were satisfied afterwards. Finally, it showed that there is a need for this kind of education; for professionals and for people who were worried about their memory or their partners' memory.


Dissection technique for cochleas prepared for scanning electron microscopy.
Scanning electron microscopy (SEM) permits a three-dimensional study of the surface morphology of the organ of Corti that is very useful in evaluating the condition of the apical end of the hair cells and the stereocilia. However, some laboratories have experienced problems with curling of the basilar membrane during critical point drying of cochlear specimens prepared for SEM evaluation using the Murakami or osmium thiocarbohydrazide-procedures. This curling of the basilar membrane can obstruct the view of the reticular lamina and the ciliary ends of the hair cells. We have used a dissection method, referred to as the anchor technique, to overcome basilar membrane curling. This technique removes all the structures above the reticular lamina but leaves the basilar membrane attached to the spiral ligament and the lateral bone to which the spiral ligament is anchored. Individual cochlear turns are dissected in this manner and mounted on the same examination stub for SEM evaluation. Maintenance of the lateral attachment of the basilar membrane requires additional dissection time but eliminates the problem of curling during critical point drying. An additional benefit is that mounting the individual turns on the same examination stub facilitates evaluation and photomicroscopy of the surface morphology. The anchor technique has been used successfully on the guinea pig and should be appropriate for most mammalian cochleas.


Anthropological studies among Libyans. Erythrocyte genetic factors, serum haptoglobin phenotypes and anthropometry.
Anthropological studies were done on 1276 Libyans from the Mediterranean cities of Tripoli and Benghazi, and from Sabha southward in The Sahara. The incidences of hemoglobin (Hb)-S and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency were low in the coastal areas and significantly high in Sabha. Hb-C occurred sporadically in Tripoli and Sabha, and was absent from Benghazi in the east. One case of Hb-J Benghazi was noted. There were no sigificant differences in the ABO blood group and Rh0 (D) type distributions in the three localities. G-6-PD gene GdAfrequency was significantly high in Sabha. The lowest value of 6-phosphogluconate dehydrogenase (6-PGD) gene PGDA frequency and highest value of the gene PGDC were in Sabha. Adenylate kinase (AK) gene AK2 was only detectable in Tripoli. Acid phosphatase (AP) gene Pa frequency in Sabha was more than twice that in Tripoli and Benghazi, while pc was distinctly lower in Sabha than in the northern cities. Haptoglobin gene Hp1 frequency was almost identical in all areas. Anthropometric measurements revealed overall homogeneity of the three samples, closer similarity in the coastal region to adjacent North African populations, and Negroid influence in the Sahara Libyans. Anthropometry substantiated findings from blood markers.


[Triple biphasic chemotherapy in the treatment of small-cell bronchial cancer].
Forty-three patients with small-cell bronchial carcinoma were treated with sequential combination chemotherapy of the CMC-VAP type alternating every 6 weeks. Toxicity affected mostly blood cells and occurred during induction. The response rate was 60% in circumscribed forms with a median survival of 15 months, and 30% in diffuse forms with a median survival of 6 months. The value of alternating protocols and the place of radiotherapy are discussed in the light of these results.


Multifocal electroretinogram and optical coherent tomography: prediction of visual outcome after epiretinal membrane removal.
The aim was to evaluate the value of multifocal electroretinogram (mfERG) and optical coherence tomography (OCT) in predicting post-operative visual acuity (post-VA) after removal of an idiopathic epiretinal membrane (ERM). Fifty-one eyes of 51 patients with an idiopathic macular ERM were examined by OCT and mfERG before three-port pars plana vitrectomy with removal of the ERM. The parameters of the OCT images and mfERGs, pre-operative visual acuity (pre-VA) and the duration of symptoms (DS) were compared with the post-VA. The pre-VA (r = 0.570, p < 0.001) and the duration of the symptoms (r = 0.389, p < 0.035; n = 35) were significantly correlated with the post-VA. The central retinal thickness (CRT) was significantly correlated with the pre-VA (r = 0.379, p < 0.01) and the post-VA (r = 0.318, p < 0.03). The amplitudes of macular electroretinogram (amERGs) were not significantly correlated with the pre-VA or post-VA. The CRT to amERG ratio (CRT/amERG) was correlated with the post-VA (r = 0.429, p < 0.002) but not with the pre-VA (p > 0.1). Comparative analyses among groups of cases based on CRT/amERG showed significant differences in the post-VA but not in the pre-VA and the duration of symptoms. As with the large CRT/amERG, the pre-operative morphologically thickened and electroretinographically reduced retinas have a greater likelihood of being affected by the irreversible photoreceptor damages that could have been masked or modified by other factors before the removal of the ERM. Because the CRT/amERG values are obtained objectively, they should be valuable in predicting the post-operative visual function along with the pre-VA and the duration of symptoms.


Accumulation of Cu, Zn, Pb, and Cd in edible parts of four commonly grown crops in two contaminated soils.
Soil heavy metal pollution resulting from human activities is causing major concern due to its potential risk. In this study, four crop species with different cultivars were planted in 2 levels (heavily and slightly) of heavy metal contaminated soils, and the accumulation of Cu, Zn, Pb, and Cd in the edible parts of the crops were investigated. Metal concentrations in sesame seeds grown in both soils exceeded both the Chinese Food Hygiene Standard (CFHS) and Codex Alimentarius Commission Standard (CACS), while the metal concentrations in all pepper cultivars in the slightly contaminated soil were below the CFHS and CACS. Other crops were generally in between in both soils. Among the tested crops, the order of soil-plant transfer factor (TF) was: sesame > green soybean > cowpea > pepper. Additionally, old fruit of cowpea contained larger amounts of metals than young fruit. It suggests that sesame should not be planted in the metal contaminated area, while pepper cultivar "Chaobianjiao No.1" may be an alternative to be grown in the slightly contaminated soil. There were differences in individual human susceptibilities to metals. Therefore, a comprehensive risk assessment should consider the frequency, amount and species consumed by human besides metal concentrations in crops.


Gamma-ray bursts and cosmology.
I review the current status of the use of gamma-ray bursts (GRBs) as probes of the early Universe and cosmology. I describe the promise of long GRBs as probes of the high redshift (z>4) and very high redshift (z>5) Universe, and several key scientific results that have come from observations made possible by accurate, rapid localizations of these bursts by Swift. I then estimate the fraction of long GRBs that lie at very high redshifts and discuss ways in which it may be possible to rapidly identify-and therefore study-a larger number of these bursts. Finally, I discuss the ways in which both long and short GRBs can be made 'standard candles' and used to constrain the properties of dark energy.


Effect on Overall Health Status With Weightbearing at 2 Weeks vs 6 Weeks After Open Reduction and Internal Fixation of Ankle Fractures.
Ongoing controversy exists on postoperative weightbearing status after open reduction and internal fixation of an ankle fracture. This prospective randomized controlled trial aimed to compare patient-based and physician-based outcomes after early weightbearing at 2 vs 6 weeks postoperatively. Fifty patients with unstable rotational-type ankle fractures were treated operatively with subsequent immobilization in a below-the-knee cast for 2 weeks and were then randomly allocated to 2 groups. The first group had early weightbearing at 2 weeks postoperation and the second group at 6 weeks postoperation. Follow-up included subjective and objective evaluations performed at 2, 6, 12, and 26 weeks postoperatively. The primary outcome was the patient-based general health status as measured with the EuroQol-5D (EQ-5D) scoring system. Secondary outcome was the Olerud and Molander ankle score. Power analysis revealed a study group of 50 patients was needed to show a clinically relevant effect size of 10 points in both EQ-5D visual analog scale (VAS) score and Olerud and Molander score. Patients in the early weightbearing group had higher mean EQ-5D VAS scores at a 6-week follow-up (P = .014) of 77 ± 14 compared to 66 ± 15 for late mobilization. No difference was found at other follow-up points or between groups for physician-based outcome measures. At 26 weeks postoperatively, mean Olerud and Molander ankle scores were similar at 84 ± 16 and 81 ± 17 for mobilization at 2 and 6 weeks postoperation, respectively. Early weightbearing after operative fixation of rotational-type ankle fractures had a clinically relevant and statistically significant benefit in patient-based general health status, as quantified with EQ-5D VAS scores, at 6 weeks postoperation. These results contribute to our understanding of early weightbearing and may encourage consideration of weightbearing at 2 weeks postoperatively in standard protocols. Therapeutic Level I, prospective randomized controlled trial.


Structure-function based design of small molecule inhibitors targeting Rho family GTPases.
Rho GTPases of the Ras superfamily are involved in the regulation of multiple cell functions and have been implicated in the pathology of various human diseases including cancer. They are attractive drug targets in future targeted therapy. A wealth of structure-function information made available by high resolution structures and mutagenesis studies has laid out the foundation for the derivation of a mechanism-based targeting strategy. Here we describe the rational design and characterizations of a first generation Rac-specific small molecule inhibitor. Based on the structure-function information of Rac interaction with GEFs, in a computer based Virtual Screening we have identified NSC23766, a highly soluble and membrane permeable compound, as a specific inhibitor of a subset of GEF binding to Rac and therefore Rac activation. In fibroblast cells NSC23766 inhibited Rac1 GTP-loading without affecting Cdc42 or RhoA activity and suppressed the Rac-GEF, Tiam1, and oncogenic Ras induced cell growth and transformation. NSC23766 also potently inhibited the prostate PC-3 cancer cell proliferation and invasion induced by Rac hyperactivation. Intraperitoneal administration of NSC23766 to laboratory mice resulted in effective Rac GTPase suppression and hematopoietic stem cell mobilization from the bone marrow to the peripheral blood, similar to the effects of genetically targeted disruption of Rac GTPases in the animals. A co-crystal structure of NSC23766 bound to Rac1 provided further insight for future medicinal chemistry modification and improvement of this lead Rac-specific inhibitor. Thus, structure-function based rational design may represent a new avenue for generating lead small molecule inhibitors of Ras superfamily GTPases that are useful for modulating pathological conditions in which the small GTPase deregulation may play a role.


[Pulmonary allergic responses were drived by atomization with ovalbumin in BALB/c mice with intestinal microflora disruption].
The mice in which the intestinal microflora disruption resulted from antibiotic therapy are challenged by atomization with ovalbumin (OVA) to investigate the relation of allergic airway response and intestinal microflora disruption. One hundred and twelve female BALB/c mice were divided at random into 6 groups. They were microbiota disruption I group, control I group, microbiota disruption II group, microbiota disruption and challenge group, challenge group and control II group. Cecal contents were collected for quantitative analysis of the intestinal microflora in mice in the former two groups and in mice in the latter four groups on day 6 and day 14, respectively. On day 14, the bronchoalveolar lavage fluid (BALF) was collected for cells counting. OVA-specific IgE in BALF and sera was detected by ELISA. Parts of lungs were collected for histopathology and detection of Th1 and Th2 cell levels by flow of cytometry. The mice which were given antibiotics suffered from intestinal microbiota disruption. In microbiota disruption and challenge group, eosinophil and lymphocyte infiltration was significant and mucus secretion was increased in lung. The number of total cells, eosinophils, lymphocytes, neutrophils and OVA-specific IgE level were increased in BALF in microbiota disruption and challenge group. Th2 cell levels were increased and Th1 cell levels were not significantly different in microbiota disruption and challenge group compared with those in the control II group. The allergic (Th2) immune response can be induced by atomization with ovalbumin in the mice in which the intestinal microflora disruption is resulted from antibiotic therapy. The result suggests that the intestinal microflora disruption is a risk factor for allergy and asthma.


Robust combination of neural networks and hidden Markov models for speech recognition.
Acoustic modeling in state-of-the-art speech recognition systems usually relies on hidden Markov models (HMMs) with Gaussian emission densities. HMMs suffer from intrinsic limitations, mainly due to their arbitrary parametric assumption. Artificial neural networks (ANNs) appear to be a promising alternative in this respect, but they historically failed as a general solution to the acoustic modeling problem. This paper introduces algorithms based on a gradient-ascent technique for global training of a hybrid ANN/HMM system, in which the ANN is trained for estimating the emission probabilities of the states of the HMM. The approach is related to the major hybrid systems proposed by Bourlard and Morgan and by Bengio, with the aim of combining their benefits within a unified framework and to overcome their limitations. Several viable solutions to the "divergence problem"-that may arise when training is accomplished over the maximum-likelihood (ML) criterion-are proposed. Experimental results in speaker-independent, continuous speech recognition over Italian digit-strings validate the novel hybrid framework, allowing for improved recognition performance over HMMs with mixtures of Gaussian components, as well as over Bourlard and Morgan's paradigm. In particular, it is shown that the maximum a posteriori (MAP) version of the algorithm yields a 46.34% relative word error rate reduction with respect to standard HMMs.


The diagnostic accuracy of routine clinical findings for detection of esophageal varices in rural sub-Saharan Africa where schistosomiasis is endemic.
Variceal upper gastrointestinal bleeding (UGIB) is common in sub-Saharan Africa (SSA). However, poor access to endoscopy services precludes the diagnosis of varices. We determined the diagnostic accuracy of routine clinical findings for detection of esophageal varices among patients with UGIB in rural SSA where schistosomiasis is endemic. We studied patients with a history of UGIB. The index tests included routine clinical findings and the reference test was diagnostic endoscopy. Multivariable regression with post-estimation provided measures of association and diagnostic accuracy. We studied 107 participants with UGIB and 21% had active bleeding. One hundred and three (96%) had liver disease and 86(80%) varices. Factors associated with varices (p-value <0.05) were ≥ 4 lifetime episodes of UGIB, prior blood transfusion, splenomegaly, liver fibrosis, thrombocytopenia, platelet count spleen diameter ratio <909, and a dilated portal vein. Two models showed an overall diagnostic accuracy of > 90% in detection of varices with a number needed to misdiagnose of 13(number of patients who needed to be tested in order for one to be misdiagnosed by the test). Where access to endoscopy is limited, routine clinical findings could improve the diagnosis of patients with UGIB in Africa. The diagnostic accuracy of routine clinical findings for detection of esophageal varices in rural sub-Saharan Africa where schistosomiasis is endemic.


Iodine/palladium approaches to the synthesis of polyheterocyclic compounds.
A simple, straightforward strategy for the synthesis of polyheterocyclic compounds (PHCs) is reported, which involves iterative cycles of palladium-catalyzed Sonogashira coupling, followed by iodocyclization using I(2) or ICl. A variety of heterocyclic units, including benzofurans, benzothiophenes, indoles, and isocoumarins, can be efficiently incorporated under mild reaction conditions. In addition, variations of this strategy afford a variety of linked and fused PHCs.


Suspected malignant transformation of B lymphocytes in the equine cornea from immune-mediated keratitis.
To describe clinical, in vivo confocal microscopic, histopathologic, polymerase chain reaction assay for antigen receptor rearrangement (PARR) and immunohistochemical features of a horse with suspected malignant transformation of corneal B lymphocytes in immune-mediated keratitis (IMMK) and to also report surgical management and adjunctive treatment including topical and radiation therapies. A 15-year-old Oldenburg gelding was examined for presumptive progressive stromal IMMK of the right eye which became refractory to medical management. Corneal in vivo confocal microscopy revealed a marked infiltration of neovascularization, leukocytes, and dendritic cells. Superficial keratectomy was performed. Histopathologic and immunohistopathologic abnormalities of the cornea were restricted to the anterior and mid-stroma and included sheets of medium-size atypical lymphocytes which stained positively for CD79a and CD20 and also demonstrated clonal rearrangements of immunoglobulin heavy chain 2 (IGH2) and 3 (IGH3) confirming B-cell lymphoma. Complete physical examination, complete blood count, serum chemistry, thoracic radiographs, and thoracic ultrasound were performed. No evidence of systemic metastasis was found. Adjunctive local therapy included topical dexamethasone, mitomycin C, and radiation therapy using electronic surface brachytherapy. Follow-up at 16 months revealed a lack of corneal infiltrate and progressive clearing of corneal fibrosis and superficial pigment. This case represents a unique presentation of primary corneal lymphoma in the horse. Tumor development was associated with chronic IMMK and chronic topical anti-inflammatory therapy. Surgical excision with adjunctive therapy using mitomycin C and electronic surface brachytherapy was well tolerated and considered curative. Future immunohistochemistry and PARR will be important in characterizing the IMMK syndrome and its variations.


Ablative liver radiotherapy for unresected intrahepatic cholangiocarcinoma: Patterns of care and survival in the United States.
Single-institution studies have shown the oncologic benefit of ablative liver radiotherapy (A-RT) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, adoption of A-RT across the United States and its associated outcomes are unknown. We queried the National Cancer Data Base for nonsurgically managed patients with ICC diagnosed between 2004 and 2018. Patients were labeled A-RT for receipt of biologically effective doses (BED10 ) ≥ 80.5 Gy and conventional RT (Conv-RT) for lower doses. Associations with A-RT use and overall survival were identified using logistic and Cox regressions, respectively. Of 27,571 patients, the most common treatments were chemotherapy without liver RT (45%), no chemotherapy or liver RT (42%), and liver RT ± chemotherapy (13%). Use of liver RT remained constant over time. Of 1112 patients receiving liver RT with known doses, RT was 73% Conv-RT (median BED10 , 53 Gy; median, 20 fractions) and 27% A-RT (median BED10 , 100 Gy; median, 5 fractions). Use of A-RT increased from 5% in 2004 to 48% in 2018 (Ptrend < .001). With a median follow-up of 52.3 months, median survival estimates for Conv-RT and A-RT were 12.8 and 23.7 months (P < .001), respectively. On multivariable analysis, stage III and IV disease correlated with a higher risk of death, whereas chemotherapy and A-RT correlated with a lower risk. Although A-RT has been increasingly used, use of liver RT as a whole in the United States remained constant despite growing evidence supporting its use, suggesting continued unmet need. A-RT is associated with longer survival versus Conv-RT. Bile duct cancer is a rare, deadly disease that often presents at advanced stages. Single-institution retrospective studies have demonstrated that use of high-dose radiotherapy may be associated with longer survival, but larger studies have not been conducted. We used a large, national cancer registry of patients diagnosed between 2004 and 2018 to show that liver radiotherapy use remains low in the United States, despite growing evidence that patients who receive it live longer. Furthermore, we showed that patients who received high-dose radiotherapy lived longer than those who received lower doses. Greater awareness of the benefits of liver radiotherapy is needed to improve patient outcomes.


Postoperative choledochoscopy through the T-tube tract.
The present management of retained biliary calculi utilizing irrigation with heparin and other agents through the T tube has proved disappointing. The use of basket catheters under fluoroscopy is more successful but has limited usefulness in extraction of impacted and certain other stones. The preliminary use of postoperative choledochoscopy utilizing a choledochofiberscope passed through the T-tube tract has been consistently effective in 17 patients for evaluation of filling defects on the postoperative cholangiogram and for the removal of difficult or multiple retained stones. Introduction of the endoscope may require dilation of the T-tube tract. This is accomplished with ease. Use of the recently available T tube with a larger external limb will improve postoperative access to the common bile duct for direct visual examination and removal of stones.


Patient and Caregiver Perspectives on Telehealth Use in a Multidisciplinary Huntington's Disease Clinic: A Single-Institution Experience.
The coronavirus pandemic saw technology evolve as outpatient clinics faced restriction of in-person visits. Reliance on telemedicine using two-way audio-video communication significantly increased. Telemedicine was observed to be convenient, cost-effective, reduced no-show rates, and fostered sustained engagement. Enhanced flexibility from short notice scheduling benefitted patients and their caregivers. Greater time value was perceived by patients, and reduced reliance on caregivers. Disadvantages included barriers of access to internet connectivity or equipment. We aimed to retrospectively survey patients with Huntington's disease (HD) seen via telehealth in our HDSA Center for Excellence Multidisciplinary clinic. We evaluated usability, learnability, interface quality, reliability, and future use. This qualitative survey used the 21-item Telehealth Usability Questionnaire. Close-ended responses ranged from strongly disagree to strongly agree scored on Likert scale (1 through 7). Averages were calculated to examine attitudes towards telemedicine. Spearman correlation test was performed to detect attitude biases between patients and caregivers. Respondents were more likely than not to strongly agree with survey statements. Average attitude score of 5.92 (range 2.95-7.00) suggested favorability and improved convenience when telehealth was used in complement to in-person visits, without detriment to patient-provider communication. Spearman correlation coefficient between patient and family/caregiver groups was 0.023, which is below the cutoff of 0.344 for a = 0.05 at N = 24. This suggests there was no bias between patient and caregiver attitudes. This study demonstrated telehealth is favored by caregivers and patients with HD. This population with specific physical, cognitive and psychiatric needs can benefit from adaptive systems that enhance compliance.


Psychological health among Chinese college students: a rural/urban comparison.
The literature on suicide among the Chinese indicates that younger individuals from rural areas are at higher risk of suicide than their urban counterparts. While earlier studies have investigated the relationship between psychological health and major demographic variables, the relationship of psychological health as it relates to suicide by those from urban and rural areas have been rare. Studying the psychological health of college students from rural China in comparison with students who originate from urban areas may shed light on the mental health disparities of the two populations. This study examined the relationship of psychological health and rural/urban origins of college students in China. Data was obtained from 2 400 college students who completed a survey questionnaire while in attendance at a key university in Beijing China in 2013. Four standardised psychological health scales were administered to obtain measures of participants' self-esteem, depression, social support, and suicide ideation. Findings indicated that urban students had significantly higher scores than their rural counterparts on self-esteem and social support. However, there was no statistically significant difference between the groups on measures of depression and suicide ideation.


Abelmoschus esculentus subfractions improved nephropathy with regulating dipeptidyl peptidase-4 and type 1 glucagon-like peptide receptor in type 2 diabetic rats.
Abelmoschus esculentus (AE) has been used in traditional medicine to ameliorate hyperglycemia, but its mucilage increased bioassay difficulties. We have obtained a series of AE subfractions. Among them F1 and F2 regulated dipeptidyl peptidase-4 (DPP-4) and type 1 glucagon-like peptide receptor (GLP-1R), the treatment targets for type 2 diabetes. F1, F2 and fraction residues (FR) showed advantage on different aspects, which attenuates insulin resistance and metabolic disorder in vivo, and prevents renal-tubular change in vitro. In the present study, using type 2 diabetes model induced by high fat diet (HFD) and streptozotocin (STZ), we aim to investigate whether AE prevent diabetic nephropathy by regulating the putative markers. The results showed that all the subfractions ameliorated albuminuria and renal hyperfiltration (measured by creatinine clearance rate; CCr) accompanied with diabetes, while F2 acted most promptly and consistently. Histologically AE reduced renal tubular change, fibrosis and fat deposition. F2 and FR exerted significant effects to decrease DPP-4 while increase GLP-1R. Although all the subfractions were effective to reduce oxidative stress, only F2 acted on kidneys specifically. In conclusion, we have demonstrated AE has benefits to regulate DPP-4 and GLP-1R, to reduce oxidative stress and renal fibrosis, with resultant to improve renal function and prevent diabetic renal damage. Taken together, F2 could be more promising to be developed as adjuvant for diabetic nephropathy.


Effects of green and black tea consumption on brain wave activities in healthy volunteers as measured by a simplified Electroencephalogram (EEG): A feasibility study.
Tea has been associated with many mental benefits, such as attention enhancement, clarity of mind, and relaxation. These psychosomatic states can be measured in terms of brain activity using an electroencephalogram (EEG). Brain activity can be assessed either during a state of passive activity or when performing attention tasks and it can provide useful information about the brain's state. This study investigated the effects of green and black consumption on brain activity as measured by a simplified EEG, during passive activity. Eight healthy volunteers participated in the study. The EEG measurements were performed using a two channel EEG brain mapping instrument - HeadCoach™. Fast Fourier transform algorithm and EEGLAB toolbox using the Matlab software were used for data processing and analysis. Alpha, theta, and beta wave activities were all found to increase after 1 hour of green and black tea consumption, albeit, with very considerable inter-individual variations. Our findings provide further evidence for the putative beneficial effects of tea. The highly significant increase in theta waves (P < 0.004) between 30 minutes and 1 hour post-consumption of green tea may be an indication of its putative role in cognitive function, specifically alertness and attention. There were considerable inter-individual variations in response to the two teas which may be due genetic polymorphisms in metabolism and/or influence of variety/blend, dose and content of the selected products whose chemistry and therefore efficacy will have been influenced by 'from field to shelf practices'.


Patient education, nudge, and manipulation: defining the ethical conditions of the person-centered model of care.
Patient education (PE) is expected to help patients with a chronic disease to manage their lives and give them the possibility of adopting, in an appropriate manner, beneficial changes in health behaviors that are prescribed by their physicians. It is aimed at delineating, agreeing on, and implementing a patient's personal action plan and is therefore an essential constituent of the person-centered model of care. The aim of this article is to examine the idea that PE may sometimes be a manipulation that is organized for the good of patients in a paternalistic framework. Theoretically, PE differs from manipulation by addressing the reflective intelligence of patients in full light and helping them make autonomous choices. In this article, we examined some analogies between PE and nudge (ie, techniques used to push people to make good choices by organizing their environment). This analysis suggests that PE is not always as transparent and reflective as it is supposed to be and that unmasking these issues may be useful for improving the ethical quality of educational practice that must be performed in a framework of a trusting patient-doctor relationship. Under this condition, PE may sometimes represent a form of persuasion without being accused of patient deception and manipulation: trust is therefore the core of the person-centered model of care.


Rapid improvements in charge carrier mobility at ionic liquid/pentacene single crystal interfaces by self-cleaning.
We report the rapid improvement in the carrier mobility of the electric double layer field-effect transistor based on the ionic liquid (IL)/pentacene single crystal interface. Generally, the surface oxidation of the pentacene single crystal is unavoidable, and the considerable degradation restricts the performance of the field-effect transistor. However, the formation of the IL/pentacene single crystal interface resolves this problem by increasing the carrier mobility by approximately twice the initial value within a few hours. Furthermore, frequency-modulation atomic force microscopy revealed that the aforementioned rapid improvement is attributed to the appearance of a clean and flat surface of the pentacene single crystal via the defect-induced spontaneous dissolution of pentacene molecules into the IL.


Clinical and serologic markers of periodontal infection and chronic kidney disease.
Chronic kidney disease and its concomitant sequelae represent a major public health problem. Recent data suggest periodontal infection contributes to chronic kidney disease. This United States population-based study of 4,053 adults > or =40 years of age investigated the association between chronic kidney disease and clinical measures and serologic markers of periodontal infection. Chronic kidney disease was defined as moderate-to-severe reduction of kidney function with glomerular filtration rate of 15 to 59 ml/minute/1.73 m(2) based on stages 3 and 4 of the Kidney Disease Outcome Quality Initiative. Chronic oral inflammatory burden was measured as 1) clinical periodontal infection categorized as no periodontal disease, periodontal disease (at least one tooth with > or =4 mm loss of attachment and bleeding on probing as an indicator of inflammation), or edentulism and 2) serum immunoglobulin G antibody response to Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) and Porphyromonas gingivalis. Multiple logistic regression modeling quantified the association between chronic kidney disease and chronic inflammatory burden and other risk factors. Nine percent of the study population had chronic kidney disease, 22% had high A. actinomycetemcomitans antibody titer, 24% had high P. gingivalis antibody titer, 9% had periodontal disease, and 17% were edentulous. After simultaneously adjusting for recognized risk factors, adults with a high A. actinomycetemcomitans titer were less likely to have chronic kidney disease (adjusted odds ratio [OR(Adj)] = 0.67; 95% confidence interval [CI]: 0.46 to 0.98), and adults with edentulism were more likely to have chronic kidney disease (OR(Adj) = 1.64; 95% CI: 1.11 to 2.44). These results support considering edentulism and low serum titer to A. actinomycetemcomitans as risk indicators for chronic kidney disease.


Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects.
Nigella sativa seeds have wide therapeutic effects and have been reported to have significant effects against many ailments such as skin diseases, jaundice, gastrointestinal problems, anorexia, conjunctivitis, dyspepsia, rheumatism, diabetes, hypertension, intrinsic hemorrhage, paralysis, amenorrhea, anorexia, asthma, cough, bronchitis, headache, fever, influenza and eczema. Thymoquinone (TQ) is one of the most active constituent and has different beneficial properties. Focus on antimicrobial effects, different extracts of N. sativa as well as TQ, have a broad antimicrobial spectrum including Gram-negative, Gram-positive bacteria, viruses, parasites, schistosoma and fungi. The effectiveness of N. sativa seeds and TQ is variable and depends on species of target microorganisms. The present review paper tries to describe all antimicrobial activities that have been carried out by various researchers.


Role of histopathology and molecular markers in the active surveillance of prostate cancer.
Surgery or radiation therapy remain the standard curative treatments for newly diagnosed prostate cancer patients. Nonetheless, these aggressive treatments are associated with decreased quality of life with altered sexual and urinary functions. The objective was a systematic review of active surveillance protocols to investigate the role of histopathology and molecular markers in the active surveillance of prostate cancer. Medline was searched using the following terms: prostate cancer, active surveillance and expectant management. Selection criteria, follow-up strategies and outcomes. Using modern risk stratification, several centres have gained significant experience in identifying patients with a low risk of prostate cancer progression and have adopted an active surveillance program with delayed curative therapy. Interestingly, only limited numbers of patients under active surveillance require additional treatment. Recent data suggest that delayed treatment does not appear to alter the clinical outcome among those highly selected patients. The future and conclusions. A better understanding of the molecular determinants of prostate cancer behaviour would not only enable healthcare professionals to identify which cases need aggressive treatment but, perhaps more importantly, would also indicate potential targets for the development of novel therapeutic strategies.


Alpha lipoic acid treatment improved endothelium-dependent relaxation in diabetic rat aorta.
The aim of this study was to ascertain the effects of α-lipoic acid (ALA) treatment on relaxant responses of acetylcholine (ACh) and isoprenaline (ISO) in aortic rings precontracted with serotonin (5-HT, 10(-6) M) obtained from streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in the rats by 50 mg/kg streptozotocin (STZ) via an intraperitoneal injection. Rat body and aorta weights were measured. The isometric tension to ACh (10(-9)-3×10(-6) M) and ISO (10(-9)-10(-4) M) of 5-HT-precontracted diabetic and non-diabetic rat (control), diabetic-ALA-treated, and ALA-treated aortas, in organ baths were recorded. Six weeks after STZ treatment blood glucose was elevated compared to control rats. In aortic rings from diabetic rats ACh and ISO-induced relaxations were impaired whereas endothelium-independent relaxation to sodium nitroprusside (SNP) was unaffected. ALA (100 mg/kg/day) treatment for 5 weeks enhanced ACh and ISO-induced relaxation in diabetic aortas. This recovering effect was via NO because prevented by incubating the vessels with N(G)-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). It may be assumed that ALA treatment in vivo, can protect against impaired vascular responsiveness in STZ-induced diabetic rats.


Feedback regulation of thyrotropin-releasing hormone (TRH): mechanisms for the non-thyroidal illness syndrome.
Regulation of the hypothalamic-pituitary-thyroid (HPT) axis is dependent upon the secretion of thyrotropin-releasing hormone (TRH), a tripeptide originating in the hypothalamic paraventricular nucleus (PVN). These so-called hypophysiotropic neurons are under feedback inhibition by circulating levels of thyroid hormone, mediated through interactions with the beta2 thyroid hormone receptor (TRbeta2) and competition with the phosphorylated form of cyclic adenosine 5'-monophosphate response element binding protein (CREB) for a multifunctional binding site in the TRH gene. The non-thyroidal illness syndrome, characterized by low circulating thyroid hormone levels yet suppression of TRH gene expression in hypophysiotropic neurons, is due to alteration in the regulatory factors that modulate TRH gene expression to result in central hypothyroidism. These factors include alpha melanocyte-stimulating hormone (alphaMSH) and cocaine- and amphetamine-regulated transcript (CART), and agouti-related protein (AGRP) and neuropeptide Y (NPY), substances co-produced by distinct populations of leptin-responsive neurons in the hypothalamic arcuate nucleus. Through monosynaptic projections from arcuate nucleus neurons to hypophysiotropic TRH neurons, these factors contribute to suppression of HPT axis during fasting and starvation by exerting opposing actions on the TRH gene, altering the sensitivity for feedback inhibition by thyroid hormone. In contrast, central hypothyroidism associated with infection may be due to upregulation of type 2 deiodinase activity in tanycytes, specialized glial cells that line the infralateral walls and floor of the third ventricle. Through tanycyte-cerebrospinal fluid, -vascular or -neuronal associations, these cells may lead to inhibition of TRH gene expression in hypophysiotropic neurons by increasing local triiodothyronine production.


Automatic ultrasound determination of thermal coagulation front during laser tissue heating.
Thermal therapies using laser, microwaves, radio frequency radiation, and high intensity focused ultrasound have shown great promise for minimally invasive treatment of benign and malignant lesions. To treat tissue effectively and safely, techniques that could monitor the advancement of coagulation front during treatment are highly desirable. This paper presents a noninvasive ultrasound technique for automatically determining the propagation of coagulation damage front during laser tissue heating. The basic assumption underlying this technique is that when coagulation is taking place in a tissue, owing to thermally induced structure changes in tissue, the waveform of echo signal scattered from that treated region should be changing accordingly. We first track echoes scattered from many small tissue regions during heating using a cross-correlation echo-tracking technique. We then use the waveform-change information to determine the position of coagulation front via an automatic calculation procedure. To test our technique, we carried out 35 experiments in which we irradiated fresh canine liver samples with a Nd:YAG laser (1064-nm wavelength) at various light fluence (62 to 167 W/cm(2)) and exposure time (20 to 350 s). A 13-mm diameter 10-MHz broadband single-element spherical focused ultrasound transducer was used to detect the thermal coagulation front. The root mean square difference between ultrasonically and visually determined coagulation depths was 0.77 mm. This good agreement between visually inspected and ultrasonically determined coagulation depths shows the potential of our technique for monitoring coagulative tissue damage during thermal therapy.


Impact of COVID-19 pandemic on sleep quality among medical and general science students: King Saud University Experience.
Sleep is a vital component for overall health and well-being, and it plays an essential role in social, physical, psychological, and cognitive health. This study aimed to appraise the sleep quality in medical and science students during the COVID-19 pandemic. This questionnaire-based cross sectional study was conducted in the Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia, during September-December 2020. In this study, a validated self-administered electronic questionnaire was distributed to 1000 students, 782 (78.2%) of whom completed the study. The selection of students was based on using the stratified random sampling. The Pittsburgh Sleep Quality Index (PSQI) instrument scale was used to assess the sleep quality among medical and general sciences students. Out of 782 respondents, 410 (52.4%) were medical students, and 372 (47.6%) were science students, including Physics, Chemistry, Mathematics, Statistics, Botany, and Zoology. Among the medical students, 143 (34.9%) were in pre-clinical years (1st and 2nd), while 266 (64.9%) of them were in clinical years (3rd, 4th, and 5th). Among all medical and general sciences students, it was found that 669 (85.5%) had poor sleep quality with a mean PSQI global score (mean 8.356) among them 336 (50.2%) were medical, and 333 (49.8%) were science students. Science students' sleep quality was poorer (mean 8.78) than their medical counterparts (mean= 7.93). The COVID-19 pandemic has a significant negative impact on students' mental health and sleep quality. Both medical and general science students showed alarming levels of sleep deprivation and concerning low sleep quality during the COVID-19 pandemic. The sleep deprivation among students may be due to the sudden change of pedagogy in education driven by the COVID-19 pandemic. Sleep quality is quite a critical issue to be evaluated and addressed nationally and globally.


Internal carotid artery aneurysm. A case report.
This case report documents the diagnosis and treatment of a large carotid artery aneurysm (4 cm) associated with fibromuscular hyperplasia of the internal carotid artery. This patient underwent replacement of the section of internal carotid artery using a segment of the proximal greater saphenous (from the groin to upper thigh). She did well postoperatively with the exception of some difficulty with swallowing, which rapidly cleared. At one year she was neurologically intact with no complaints.


Prevalence of HIV-1 drug resistance amongst newly diagnosed HIV-infected infants age 4-8 weeks, enrolled in three nationally representative PMTCT effectiveness surveys, South Africa: 2010, 2011-12 and 2012-13.
South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. Three nationally representative surveys were conducted in 2010, 2011-12 and 2012-13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4-8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45-58%]) of HIV PCR positive infants, 37% (95% CI [28-47%]) in 2010, 64% (95% CI [53-74%]) in 2011 and 63% (95% CI [47-77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years.


The Three-dimensional Spatial Distribution of Interstellar Gas in the Milky Way: Implications for Cosmic Rays and High-energy Gamma-ray Emissions.
Direct measurements of cosmic ray (CR) species combined with observations of their associated γ-ray emissions can be used to constrain models of CR propagation, trace the structure of the Galaxy, and search for signatures of new physics. The spatial density distribution of interstellar gas is a vital element for all these studies. So far, models have employed the 2D cylindrically symmetric geometry, but their accuracy is well behind that of the available data. In this paper, 3D spatial density models for neutral and molecular hydrogen are constructed based on empirical model fitting to gas line-survey data. The developed density models incorporate spiral arms and account for the warping of the disk, and the increasing gas scale height with radial distance from the Galactic center. They are employed together with the GALPROP CR propagation code to investigate how the new 3D gas models affect calculations of CR propagation and high-energy γ-ray intensity maps. The calculations reveal non-trivial features that are directly related to the new gas models. The best-fit values for propagation model parameters employing 3D gas models are presented and they differ significantly from those derived with the 2D gas density models that have been widely used. The combination of 3D CR and gas density models provide a more realistic basis for the interpretation of non-thermal emissions from the Galaxy.


Association of Non-Cigarette Tobacco Advertisements and Racial Discrimination With Non-Cigarette Tobacco Product Use Among Black Adults.
Black communities are targeted by more cigarette advertisements than White communities and racial discrimination among Black people is related to cigarette use. However, little is known about these factors with non-cigarette tobacco product use among Black adults. Therefore, this study assessed the association of non-cigarette advertisement exposure and racial discrimination with use of non-cigarette tobacco products among Black adults. Black adults (n = 533) from The Family and Community Health Study in 2016 were asked if they had seen advertisements for e-cigarettes, snus pouches, filtered cigars, large cigars, cigarillos, dissolvable tobacco, smokeless tobacco, hookah, and tobacco pipe and if they used these in the past month. For products with the highest past month use and significant correlations with advertisement exposure, separate logistic regression models were performed that evaluated the association between advertisement exposure, racial discrimination, and non-cigarette tobacco product use while controlling for cigarette use, sex, socioeconomic status, and age. Use of cigarillos, large cigars, and hookah were higher than other non-cigarette tobacco products assessed. Logistic regressions revealed that more advertisement exposure in the past month was associated with higher odds of using cigarillos, large cigars, and hookah (p < .01). More experiences of racial discrimination were associated with past month cigarillo use, but not hookah or large cigars (p < .01). Non-cigarette tobacco advertisement exposure was associated with the use of non-cigarette tobacco products. Experiences of racial discrimination were associated with the most used non-cigarette tobacco product among Black adults, cigarillos. This is the first time that a specific type of cigar (ie cigarillos) has been associated with experiences of racial discrimination among Black adults. Efforts to reduce non-cigarette tobacco marketing and eradicate exposure to racial discrimination among Black adults may aid in eliminating tobacco-related health disparities.


Factors influencing self-management in patients with type 2 diabetes: a quantitative systematic review protocol.
To describe a protocol for a quantitative systematic review, to identify critique and summarize factors that influence self-management education. Self-management education enables patients to manage their condition successfully and it is associated with better self-care, good control over lifestyle and leading the best possible quality of life, notwithstanding the presence of a chronic disease. Type II Diabetes is a chronic disease that requires lifestyle adjustments and disease management to keep glycaemia and long-term complications under control. Education has to be customized and based on an assessment that includes factors influencing self-management, such as personal characteristics that can optimize the educational intervention. The protocol for the systematic review was conducted according to the guidelines of the Centre for Reviews and Dissemination, York (UK). The review question was defined in terms of population, interventions, comparators, outcomes and study designs. The protocol included decisions about the review question, inclusion criteria, search strategy, study selection, data extraction, quality assessment, data synthesis and plans for dissemination. Funding for the review was confirmed on January 2011 by the Centre of Excellence for Nursing Scholarship in Rome. An initial summary will be made by tabulating the data; the review will be reported in a narrative style and be developed according to the PRISMA guidelines. The protocol for the systematic review will allow us to identify, among the factors influencing self-management in people with Type II diabetes, the personal characteristics most relevant to the factors of motivation and empowerment. In addition, the systematic review will also identify an appropriate self-management model.


Long-Term Yoga and Aerobic/Strength Exercise Adherence in Older Women with Knee Osteoarthritis: A Mixed Methods Approach.
Hatha yoga (HY) and aerobic and strengthening exercise (ASE) programs are recommended for optimal management of osteoarthritis. However, evidence on long-term adherence to these programs and factors that influence it is lacking in older adults. The purposes of this study were to (1) describe and compare long-term HY and ASE adherence in community-dwelling older women with knee osteoarthritis 12 months post-HY/ASE intervention programs; (2) identify benefits and facilitators of, and barriers to, long-term adherence; and (3) examine other self-care interventions used after completing HY or ASE programs. Adherence was defined as following the prescribed HY/ASE program or incorporating the practice into daily habits. Five semistructured focus group interviews and 12 months of exercise diaries were obtained from 28 women (mean age 71.2 years). Long-term adherence to the prescribed HY or ASE regimen was relatively high, albeit adapted to individual needs, priorities, and preferences. Over the 12-month follow-up period, participants spent on average 3.5 days/3.1 hours per week on exercise. Most participants remained physically active by modifying their prescribed programs and integrating elements of the interventions into their own exercise regimens. Facilitators to long-term adherence were perceived benefits, having an exercise routine/habit, and program structure/instruction. Poor health status, lack of time, and exercise preferences were identified as barriers. Participants used a variety of self-care interventions including oral supplements and alternative diets for managing their osteoarthritis. This work suggests that exercise programs for osteoarthritis that incorporate individual preferences, flexible hours, and easy-to-follow instructions are most likely to result in long-term adherence.


Interactive microbial distribution analysis using BioAtlas.
Massive amounts of 16S rRNA sequencing data have been stored in publicly accessible databases, such as GOLD, SILVA, GreenGenes (GG), and the Ribosomal Database Project (RDP). Many of these sequences are tagged with geo-locations. Nevertheless, researchers currently lack a user-friendly tool to analyze microbial distribution in a location-specific context. BioAtlas is an interactive web application that closes this gap between sequence databases, taxonomy profiling and geo/body-location information. It enables users to browse taxonomically annotated sequences across (i) the world map, (ii) human body maps and (iii) user-defined maps. It further allows for (iv) uploading of own sample data, which can be placed on existing maps to (v) browse the distribution of the associated taxonomies. Finally, BioAtlas enables users to (vi) contribute custom maps (e.g. for plants or animals) and to map taxonomies to pre-defined map locations. In summary, BioAtlas facilitates map-supported browsing of public 16S rRNA sequence data and analyses of user-provided sequences without requiring manual mapping to taxonomies and existing databases. http://bioatlas.compbio.sdu.dk/.