Combined effect of medical therapy and rehabilitation in Chronic Ataxic Neuropathy with anti-Disialosyl IgM Antibodies (CANDA): a case report.
Chronic Ataxic Neuropathy with anti-Disialosyl IgM Antibodies (CANDA) is a rare form of immune-mediated sensory ataxic neuropathy. We describe the case of a 45-year-old man, who was diagnosed with CANDA in October 2018. Since then, he has been treated with monthly courses of intravenous immunoglobulin administration (IV Ig) and, in October 2022, he underwent plasmapheresis, reporting a sudden worsening of clinical and motor picture. After a new IV Ig cycle admission, the patient was hospitalized to perform intensive rehabilitation, involving two individual sessions per day (90 minutes each) for 5 days a week. During hospitalization it was registered a relevant improvement in the muscle strength of the lower limbs (LLs). Furthermore, progressive improvements were recorded both in patient's motor performance and in his level of autonomy in activities of daily living. These results had a positive impact on his quality of life and made it possible to reduce the frequency of IV Ig treatments. This is the first case in literature reporting the combined effect of rehabilitation treatment and medical therapy in CANDA neuropathy.


Pathologic staging of white matter lesions in adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids.
The pathologic features of adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids (ALAS) are variable, and this has led to different hypotheses as to whether primarily demyelination or axonopathy may underlie this disorder. Typical ALAS pathology is rarely accompanied by focal multiple sclerosis (MS)-like plaques. In ALAS pathology accompanied by focal multiple sclerosis (MS)-like plaques cases, the pathologic features cannot be distinguished from those of progressive MS with diffusely abnormal white matter. To clarify these issues, we examined neuropathologic features in 159 representative samples from 5 ALAS cases (3 men and 2 women aged 39-61 years) and in 95 representative samples from 3 chronic MS cases (1 man and 2 women aged 50-73 years). The white matter abnormalities in ALAS cases were characterized by 3 evolving stages: 1) white matter with numerous spheroids in a background of well-myelinated fibers; 2) moderate loss of myelinated fibers with sparse to moderate number of spheroids; and 3) leukodystrophy-like pattern of confluent axonal and myelin loss. The application of this staging system suggests that myelin loss in ALAS is preceded by axonopathy. In progressive MS cases, the diffusely abnormal white matter pathology could be attributed to both primary demyelination and axonopathy. Some cases with predominant axonopathy are difficult to distinguish from cases with ALAS.


[Local immunotherapy].
Specific immunotherapy, together with avoidance of the allergen and symptomatic treatment, forms part of the treatment of allergic pathology. The oldest, best known and most studied form is subcutaneous immunotherapy (SCIT), whose efficacy, both in the short and the long term, has been widely demonstrated in numerous studies. However, in spite of having been shown to be safe, it is not free of adverse effects and must be administered under the supervision of medical personnel. This has encouraged the search for new ways of administration of similar efficacy, with a good safety profile and good adherence on the patient's side. Sublingual immunotherapy (SLIT) is the most relevant of the different alternatives studied. In this alternative the antigen is administered in the form of drops under the tongue. There are different dosages of administration depending on the allergen involved. The optimum treatment dose has still to be determined, at present a wide range of dosages are found in comparison with subcutaneous immunotherapy. Its mechanism of action is little known although immunological changes have been observed in different studies. SLIT has shown a good safety profile with scarce secondary effects, normally of a local character. Similarly, different clinical tests have been carried out in which its efficacy has been shown in the treatment of respiratory allergy both in children and in adults. For this reason, although there are still unresolved data concerning this way of administering the immunotherapy, it has been proposed by the WHO as a valid alternative to SCIT.


Interaction of the N-methyl-D-aspartic acid receptor NR2D subunit with the c-Abl tyrosine kinase.
The COOH-terminal domain of the NR2D subunit of the NMDA receptor contains proline-rich regions that show striking homology to sequences known to bind to Src homology 3 (SH3) domains. To determine whether the proline-rich region of the NR2D subunit interacts with specific SH3 domains, in vitro SH3 domain binding assays were performed. A proline-rich fragment of the NR2D subunit (2D(866-1064)) bound to the Abl SH3 domain but not to the SH3 domains from Src, Fyn, Grb2, GAP, or phospholipase C-gamma (PLCgamma). Co-immunoprecipitation of NR2D with Abl suggests stable association of NR2D and Abl in transfected cells. The SH3 domain plays an important role in the negative regulation of Abl kinase activity. To determine whether the interaction of NR2D with the Abl SH3 domain alters Abl kinase activity, Abl was expressed alone or with NR2D in 293T cells. Autophosphorylation of Abl was readily observed when Abl was expressed alone. However, co-expression of Abl with 2D(866-1064) or full-length NR2D inhibited autophosphorylation. 2D(866-1064) did not inhibit DeltaSH3 Abl, indicating a requirement for the Abl SH3 domain in the inhibitory effect. Similarly, 2D(866-1064) did not inhibit the catalytic activity of Abl-PP, which contains two point mutations in the SH2-kinase linker domain that release the negative kinase regulation by the SH3 domain. In contrast, the full-length NR2D subunit partially inhibited the autokinase activity of both DeltaSH3 Abl and Abl-PP, suggesting that NR2D and Abl may interact at multiple sites. Taken together, the data in this report provide the first evidence for a novel inhibitory interaction between the NR2D subunit of the NMDA receptor and the Abl tyrosine kinase.


Phakic intraocular lens correction of high ametropia in children with neurobehavioral disorders.
A subset of children with high ametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral phakic intraocular lenses (IOLs) for ametropia >10 D. Clinical course and outcome data were collated prospectively in a group of 12 children (mean age, 10.1 years; range, 4-17 years) with neurobehavioral disorders exacerbated by poor compliance with spectacles. Myopia in 18 eyes ranged from -10.0 to -22.75 D (mean, -15.2 D) and in 2 hyperopic eyes from +10.25 to +10.75 (mean, +10.5 D). Goal refraction was approximately 0 to +1 D. Correction was achieved by implantation of an iris-enclaved phakic IOL under general anesthesia. Mean follow-up was 9.1 months (range, 3-15 months). Myopia correction averaged 14.5 D and hyperopia correction 9.4 D. Eighty-six percent of eyes (17/20 eyes) were corrected to within +/- 1 D of emmetropia and the remaining 14% (3 eyes) to within +/- 2 D. Uncorrected visual acuity improved substantially in all 20 eyes (60-fold; from a mean of 20/3400 to a mean of 20/57). Ocular comorbidities in each child accounted for residual postoperative, subnormal visual acuity (eg, amblyopia, nystagmus, albinism, regressed retinopathy of prematurity). Visual functions (measured using a 23-item validated survey) improved. One eye required IOL exchange; no other clinically significant complications have been encountered. Phakic IOL implantation improves visual function substantially in neurobehaviorally impaired children who have high ametropia and difficulties wearing glasses.


Two-photon-absorption line strengths for nitric oxide: Comparison of theory and sub-Doppler, laser-induced fluorescence measurements.
We discuss the results of high-resolution, sub-Doppler two-photon-absorption laser-induced fluorescence (TPALIF) spectroscopy of nitric oxide at low pressure and room temperature. The measurements were performed using the single-longitudinal mode output of a diode-laser-seeded optical parametric generator (OPG) system with a measured frequency bandwidth of 220 MHz. The measurements were performed using a counter-propagating pump beam geometry, resulting in sub-Doppler TPALIF spectra of NO for various rotational transitions in the (0,0) vibrational band of the A2Σ+ - X2Π electronic transition. The experimental results are compared with the results of a perturbative treatment of the rotational line strengths for the 20 different rotational branches of the X2Π(v″ = 0) → A2Σ+(v' = 0) two-photon absorption band. In the derivation of the expressions for the two-photon transition absorption strength, the closure relation is used for rotational states in the intermediate levels of the two-photon transition in analogy with the Placzek treatment of Raman transitions. The theoretical treatment of the effect of angular momentum coupling on the two-photon rotational line strengths features the use of irreducible spherical tensors and 3j symbols. The final results are expressed in terms of the Hund's case (a) coupling coefficients aJ and bJ for the X2Π(v″ = 0) rotational level wavefunctions, which are intermediate between Hund's case (a) and case (b). Considerable physical insight is provided by this final form of the equations for the rotational line strengths. Corrections to the two-photon absorption rotational line strength for higher order effects such as centrifugal stretching can be included in a straightforward fashion in the analysis by incorporating higher order terms in these coupling coefficients aJ and bJ, although these corrections are essentially negligible for J < 50. The theoretical calculations of relative line intensities are in good agreement both with our experiment and with published experimental results. In addition, the calculated line shapes and relative intensities for closely spaced main branch and satellite transitions are in excellent agreement with our experimental measurements.


Outcome of liver retransplantation in children.
Irreversible liver graft failure is a life-threatening complication. We reviewed the first 200 pediatric liver transplantations in Birmingham. Forty-one children developed primary graft failure, 9 of whom developed secondary graft failure. The main indications for graft failure were primary nonfunction (PRNF; 8 patients), vascular complications (VASC; 23 patients), and chronic rejection (CHRE; 19 patients). Thirty-two children underwent retransplantation (ReTx) (21 children received reduced grafts; 11 children, whole hepatic grafts). Patient survival was significantly worse for retransplant recipients compared with children receiving a single graft (63% v 76. 5% actuarial patient survival at 1 year; P <.05). Primary graft 1-year actuarial survival was 74% in first grafts compared with 47% for regrafts (P <.05), but improved with time. The graft 1-year survival rate was 55% for whole grafts and 45% for reduced and/or split grafts in the first 100 grafts compared with 83% and 66% in the second 100 grafts, respectively (P <.01). Emergency ReTx within a month of transplantation was associated with more complications and a worse outcome (1-year survival rate, 37%) compared with patients who underwent ReTx later (1-year survival rate, 72%; P <. 01). The incidence of primary graft failure decreased from 33% in the first 100 grafts to 16% in the second 100 grafts (P <.01), as did the incidence of PRNF, which decreased from 8% to 0% (P <.05). Although the rates of graft failure from VASC decreased from 15% to 8% (P =.2) and CHRE decreased from 11% to 8% (P =.6), neither reached statistical significance. The improved results overall are because of advances in surgical techniques, intensive care management, and graft preservation and refinements in immunosuppression. We conclude that ReTx for a child with primary graft failure is justified.


Generic and patient-specific models of the arterial tree.
Recent advance in imaging modalities used frequently in clinical routine can provide description of the geometrical and hemodynamical properties of the arterial tree in great detail. The combination of such information with models of blood flow of the arterial tree can provide further information, such as details in pressure and flow waves or details in the local flow field. Such knowledge maybe be critical in understanding the development or state of arterial disease and can help clinicians perform better diagnosis or plan better treatments. In the present review, the state of the art of arterial tree models is presented, ranging from 0-D lumped models, 1-D wave propagation model to more complex 3-D fluid-structure interaction models. Our development of a generic and patient-specific model of the human arterial tree permitting to study pressure and flow waves propagation in patients is presented. The predicted pressure and flow waveforms are in good agreement with the in vivo measurements. We discuss the utility of these models in different clinical application and future development of interest.


[Risk approach in the diagnosis of malaria in high altitude regions].
Sixteen cases of malaria are reported per thousand inhabitants per year in Kayanza, a province in the High Plateaux of Burundi. A case control study was conducted between October 1990 and March 1991 to better document this phenomenon. The majority of confirmed cases presented in persons who had recently sojourned in an endemic area (relative risk = 18). All except one of the other patients were carriers of plasmodium species that can cause late recurrences, which is compatible with the absence of local transmission. The presumptive diagnosis of malaria, as it is routinely made in the health centres, is not very specific (60%) and it has a positive predictive value of only 10%. This implies that an anti-malaria treatment is useless for 90% of the patients who receive it. It also means that the true malaria incidence rate in Kayanza can be estimated at less than 1 per thousand per year. We propose an alternative diagnostic strategy based on the risk differences between population sub-groups. It should permit an adequate patient management and a satisfactory surveillance of malaria in non-endemic epidemiological strata.


[High-dose treatment of systemic AL-amyloidosis with autologous stem cell support].
AL-amyloidosis is a serious disease with a short median survival without treatment. Treatment with high-dose melphalan with autologous stem cell support (HMAS) has a potential to increase survival, but is associated with toxicity and mortality. In this paper we report the Norwegian results retrospectively. We used questionnaires and had personal contact with a local physician from each hospital with HMAS experience. Diagnosis and treatment were evaluated according to the guidelines at the time of treatment, and the results were compared to internationally published reports. Stem cell harvesting was attempted in 18 patients from 1997 to 2006. 15 of these received HMAS treatment. Treatment-related mortality was 20%, and 5 of 11 (45%) had an organ response. Median survival was not reached within the 55-month median observation time. The course of the disease was more complicated when known risk factors for HMAS treatment were present, such as reduced kidney function, advanced heart involvement, reduced performance status, and multiorgan disease. Three of 18 patients were not diagnosed according to relevant guidelines. In seven of 12 patients the response to treatment was not evaluated adequately with respect to haematology. AL-amyloidosis is a difficult diagnosis and the condition is probably under-diagnosed in Norway. The results of HMAS treatment in Norway are comparable with those in published reports from centres abroad. The follow-up of patients should be improved.


LRP-1 Promotes Colon Cancer Cell Proliferation in 3D Collagen Matrices by Mediating DDR1 Endocytosis.
Low density lipoprotein receptor related protein-1 (LRP-1) is a large ubiquitous endocytic receptor mediating the clearance of various molecules from the extracellular matrix. Several studies have shown that LRP-1 plays crucial roles during tumorigenesis functioning as a main signal pathway regulator, especially by interacting with other cell-surface receptors. Discoïdin Domain Receptors (DDRs), type I collagen receptors with tyrosine kinase activity, have previously been associated with tumor invasion and aggressiveness in diverse tumor environments. Here, we addressed whether it could exist functional interplays between LRP-1 and DDR1 to control colon carcinoma cell behavior in three-dimensional (3D) collagen matrices. We found that LRP-1 established tight molecular connections with DDR1 at the plasma membrane in colon cancer cells. In this tumor context, we provide evidence that LRP-1 regulates by endocytosis the cell surface levels of DDR1 expression. The LRP-1 mediated endocytosis of DDR1 increased cell proliferation by promoting cell cycle progression into S phase and decreasing apoptosis. In this study, we identified a new molecular way that controls the cell-surface expression of DDR1 and consequently the colon carcinoma cell proliferation and apoptosis and highlighted an additional mechanism by which LRP-1 carries out its sensor activity of the tumor microenvironment.


Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction.
Mammalian heart is capable to regenerate almost completely early after birth through endogenous cardiomyocyte proliferation. However, this regenerative capacity diminishes gradually with growth and is nearly lost in adulthood. Cannabidiol (CBD) is a major component of cannabis and has various biological activities to regulate oxidative stress, fibrosis, inflammation, and cell death. The present study was conducted to investigate the pharmacological effects of CBD on heart regeneration in post-MI mice. MI models in adult mice were constructed via coronary artery ligation, which were administrated with or without CBD. Our results demonstrate that systemic administration (10 mg/kg) of CBD markedly increased cardiac regenerative ability, reduced infarct size, and restored cardiac function in MI mice. Consistently, in vitro study also showed that CBD was able to promote the proliferation of neonatal cardiomyocytes. Mechanistically, the expression of miR-143-3p related to cardiomyocyte proliferation was significantly down-regulated in CBD-treated cardiomyocytes, while the overexpression of miR-143-3p inhibited cardiomyocyte mitosis and eliminated CBD-induced cardiomyocyte proliferation. Moreover, CBD enhanced the expression of Yap and Ctnnd1, which were demonstrated as the target genes of miR-143-3p. Silencing of Yap and Ctnnd1 hindered the proliferative effects of CBD. We further revealed that inhibition of the cannabinoid receptor 2 impeded the regulatory effect of CBD on miR-143-3p and its downstream target Yap/Ctnnd1, which ultimately eliminated the pro-proliferative effect of CBD on neonatal and adult cardiomyocytes. Taken together, CBD promotes cardiomyocyte proliferation and heart regeneration after MI via miR-143-3p/Yap/Ctnnd1 signaling pathway, which provides a new strategy for cardiac repair in adult myocardium.


[Influenza vaccination in the elderly: effectiveness not in doubt].
In a recent review the effectiveness of influenza vaccination in the elderly was brought into question. Selection bias, which would occurr if healthy people were more likely to be vaccinated than their infirm peers, and the use of non-specific outcomes, such as death from all causes, were considered to have contributed to the effectiveness of the vaccine as to morbidity and mortality being overestimated. However, a recent study has shown that even when potential bias and residual confounding were addressed, influenza vaccination was associated with a significant reduction in the risk of influenza-related morbidity and mortality among community-dwelling elderly persons. Direct estimates of influenza-related morbidity were hampered by delayed and insufficiently sensitive diagnostics. Excess studies, however, comparing morbidity and mortality during periods with and without influenza predominance, present reliable indirect estimates in favour of vaccination. While the vaccination rate of high-risk subjects in The Netherlands is traditionally high, the age limit for influenza vaccination was lowered from 65 to 60 in 2008, taking into account influenza-related morbidity and mortality in healthy people aged 60 to 65 years and the undisputed effectiveness of vaccination against influenza.


Cell-Based Therapies in Vascularized Composite Allotransplantation.
Dendritic cells (DCs) are bone marrow-derived, professional antigen-presenting cells with tolerogenic function. The ability of DCs to regulate alloantigen-specific T cell responses and to promote tolerance has aligned them ideally for a role in vascularized composite allotransplantation (VCA). In this study, we summarize the current evidence for DC therapies for tolerance induction to alleviate the requirement for chronic immunosuppression. A comprehensive and structured review of manuscripts published on VCA was performed using the MEDLINE and PubMed databases. All eligible studies published from the year 2000 to 2017 were included in the final results. Nineteen original preclinical and clinical studies that employed cell therapy for VCA were included in this review. In vivo DC therapy was found to direct the alloimmune response toward either transplant rejection or tolerance in VCA models. While injection of mature DCs rapidly increases T-cell activity in humans and promotes transplant rejection, the injection of immature DCs acts as an immunosuppressant and inhibits T-cell activity. In addition to immature DCs, mesenchymal stem cells were also found to have a positive effect on allotransplantation of solid organs and bone marrow via cytokine expression which decreases the alloreactive effector lymphocytes and increases CD4+/CD25+/FoxP3 Tregs. Despite the promising findings, the efficacy of cell-based therapies varies greatly across studies, partly due to different methods of cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. Additional research is needed to evaluate the efficacy and safety of DC and other cell-based therapeutic measures in human allotransplant recipients. Future direction will focus on the development of novel methods to reduce immunosuppression and develop more individualized management, as well as the clinical application of basic research in the mechanisms of immunologic tolerance.


Transient protein-losing enteropathy and enlarged gastric rugae in childhood.
Data on two patients with massive but transient protein-losing enteropathy due to gastric disease suggest that antibody-mediated allergic reactions may have been responsible for the clinical picture. The majority of patients described in the literature have had evidence of a preceding or concomitant viral infection, and three of these have had evidence of infection with cytomegalovirus. Recovery occurred relatively rapidly in all patients without sequelae. The syndrome may be a variant of eosinophilic gastroenteritis.


Exploring drug cost and disease outcome in rheumatoid arthritis patients treated with biologic and targeted synthetic DMARDs in Norway in 2010-2019 - a country with a national tender system for prescription of costly drugs.
In Norway, an annual tender system for the prescription of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has been used since 2007. This study aimed to explore annual b/tsDMARDs costs and disease outcomes in Norwegian rheumatoid arthritis (RA) patients between 2010 and 2019 under the influence of the tender system. RA patients monitored in ordinary clinical practice were recruited from 10 Norwegian centers. Data files from each center for each year were collected to explore demographics, disease outcomes, and the prescribed treatment. The cost of b/tsDMARDs was calculated based on the drug price given in the annual tender process. The number of registered RA patients increased from 4909 in 2010 to 9335 in 2019. The percentage of patients receiving a b/tsDMARD was 39% in 2010 and 45% in 2019. The proportion of b/tsDMARDs treated patients achieving DAS28 remission increased from 42 to 67%. The estimated mean annual cost to treat a patient on b/tsDMARDs fell by 47%, from 13.1 thousand euros (EUR) in 2010 to 6.9 thousand EUR in 2019. The mean annual cost to treat b/tsDMARDs naïve patients was reduced by 75% (13.0 thousand EUR in 2010 and 3.2 thousand EUR in 2019). In the period 2010-2019, b/tsDMARD treatment costs for Norwegian RA patients were significantly reduced, whereas DAS28 remission rates increased. Our data may indicate that the health authorities' intention to reduce treatment costs by implementing a tender system has been successful.


Dosimetric study of fetal exposure to uniform magnetic fields at 50 Hz.
In this paper, fetal exposure to uniform magnetic fields (MF) with different polarizations is quantified at 50 Hz. Numerical computations were performed on high-resolution pregnant models at 3, 7, and 9 months of gestational age (GA), that distinguish a high number of fetal tissues. Fetal whole-body and tissue-specific induced electric fields (E) and current densities (J) were analyzed as a function of both the extremely low frequency magnetic field (ELF-MF) polarization and GA. Additionally, the induced field variation due to changes in fetal position was analyzed by means of two new pregnant models. The uncertainty budget due to the grid resolution was also calculated. Finally, the compliance of the fetal exposure to the ICNIRP Guidelines was checked. A fetal exposure matrix was built at 50 Hz, which could be used to further investigate possible interaction mechanisms between ELF-MF and the associated health risk. Some specific findings were: (1) the induced fields increased with GA; (2) the maxima E were found in skin and fat tissues at each GA; (3) fetal tissue-specific exposure was modified as a function of GA and polarization; (4) the change of the fetal position in the womb significantly modified the induced E in some fetal tissues; (5) the induced fields were in compliance with ICNIRP Guidelines and the results were quite below the permitted threshold limit.


Healers Need Healing Too: Results from the Good Road of Life Training.
Mental health professionals that work with American Indian and Alaska Native (AI/AN) populations are often viewed as ineffective because their professional training is based on a Western model of service delivery that is an extension of Western colonization. Research on effective training approaches for AI/AN mental health providers or mental health professionals that work with AI/AN populations is limited. The purpose of this study is to document the experiences and impact of the Good Road of Life (GRL) training on mental health professionals that work with AI/AN populations. A cross sectional mixed-methods design was used to answer the primary research question, "What is the impact of GRL training on mental health professionals who work in American Indian communities?" We used GRL ratings, self-reported impacts, knowledge gains, and pre-post Sources of Strength scores. Self-reported mean knowledge scores increased for all topics. Daily evaluations indicate that most participants felt more positive, knew more about the impacts of sobriety, and knew how to help a suicidal person. Sources of Strength mean scores increased in the following areas: confidence, belonging, historical trauma, using strengths to overcome difficulties, spiritual practices, resolved unhealthy relationships, and use of cultural resilience. Results indicate that GRL is an effective short-term training for professionals working in the mental health field throughout Indian Country.


Effect of long-term application of snuff on the oral mucosa: an experimental study in the rat.
The long-term effect of snuff exposure was studied in Sprague-Dawley rats using a surgically-created test canal in the lower lip to retain snuff. The rats received standard snuff (n = 42) and highly alkaline snuff (n = 10) for 9-22 months, whereupon they were killed. Untreated rats with identical test canals (n = 15) served as controls. A complete post-mortem examination was performed. One rat exposed to standard snuff for 9 months developed a squamous cell carcinoma of the oral cavity. However, exposure to standard snuff usually resulted in a mild to moderate hyperplasia of the epithelium, hyperorthokeratosis and acanthosis. Rats exposed to snuff for 18-22 months showed vacuolated cells penetrating deeper into the epithelium with hyperplastic and atrophic lesions. In a few rats, severe dysplastic changes developed in the crevicular epithelium. Rats exposed to alkaline snuff differed little from the first group except that there was focally atrophic and ulcerated epithelium and less fibrosis. Pathological findings outside the oral cavity were rare. Squamous cell hyperplasia of the forestomach was found in rats exposed to snuff for 18-22 months, possibly caused by ingested snuff. In conclusion, this study has shown that exposure of rats to snuff for 10-16 hours per day 5 days a week for most of their life-span resulted in lesions mainly restricted to the epithelium and the underlying connective tissue of the surgically created test canal.


Tear Fluid Inflammatory Proteome Analysis Highlights Similarities Between Keratoconus and Allergic Conjunctivitis.
Keratoconus is characterized by the progressive thinning of the cornea, which leads to a cone-like appearance of the eye over time. Although conventionally defined as a noninflammatory condition, a number of recent studies have associated keratoconus (KC) with allergic conjunctivitis (AC) based on clinical parameters. This study aimed to consolidate this association by performing a proteomic analysis of tear fluid from patients with keratoconus and/or allergic conjunctivitis. Of 51 patients, 17 were diagnosed with KC, 17 were diagnosed with AC, and 17 were diagnosed with both KC and AC (combined). Nine of 34 patients with KC had a progressive form of the disease. Tear fluid samples (n = 51, one eye per patient) were collected by the Schirmer's strips. Tear proteins were extracted from the Schirmer's strips. Proteomic profiling of 384 inflammatory proteins was assessed by a multiplex proximity extension assay (Olink Explore 384 Inflammation Panel I). A total of 384 inflammatory proteins were measured. Two hundred seventy-two of the 384 proteins passed stringent data cleaning and were compared among the patient groups. Compared to the 2 other groups, LGALS9 was upregulated uniquely in KC, whereas FGF19, PDGFB, HPCAL1, OSM, and FCAR were downregulated in KC. Similarly, TNFRSF4 and CCL13 were specifically upregulated in AC, whereas ectodysplasin A receptor (EDAR) was uniquely downregulated in AC. High-throughput proteomic profiling of tear fluid confirms the association between KC and AC on a molecular level and raise the importance of redefining KC as an inflammatory condition.


Complementary roles of gasotransmitters CO and H2S in sleep apnea.
Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (H2S) as the major effector molecule driving apneas. Genetic ablation of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2-/- mice. Pharmacologic inhibition of CSE with l-propargyl glycine prevented apneas in both HO-2-/- mice and SH rats. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.


Characterization of CurcuEmulsomes: nanoformulation for enhanced solubility and delivery of curcumin.
Curcumin is a polyphenolic compound isolated from the rhizomes of the plant Curcuma longa and shows intrinsic anti-cancer properties. Its medical use remains limited due to its extremely low water solubility and bioavailability. Addressing this problem, drug delivery systems accompanied by nanoparticle technology have emerged. The present study introduces a novel nanocarrier system, so-called CurcuEmulsomes, where curcumin is encapsulated inside the solid core of emulsomes. CurcuEmulsomes are spherical solid nanoparticles with an average size of 286 nm and a zeta potential of 37 mV. Encapsulation increases the bioavailability of curcumin by up to 10,000 fold corresponding to a concentration of 0.11 mg/mL. Uptaken by HepG2 human liver carcinoma cell line, CurcuEmulsomes show a significantly prolonged biological activity and demonstrated therapeutic efficacy comparable to free curcumin against HepG2 in vitro - with a delay in response, as assessed by cell viability, apoptosis and cell cycle studies. The delay is attributed to the solid character of the nanocarrier prolonging the release of curcumin inside the HepG2 cells. Incorporation of curcumin into emulsomes results in water-soluble and stable CurcuEmulsome nanoformulations. CurcuEmulsomes do not only successfully facilitate the delivery of curcumin into the cell in vitro, but also enable curcumin to reach its effective concentrations inside the cell. The enhanced solubility of curcumin and the promising in vitro efficacy of CurcuEmulsomes highlight the potential of the system for the delivery of lipophilic drugs. Moreover, high degree of compatibility, prolonged release profile and tailoring properties feature CurcuEmulsomes for further therapeutic applications in vivo.


Protein intake and energy balance.
Maintaining energy balance in the context of body-weight regulation requires a multifactorial approach. Recent findings suggest that an elevated protein intake plays a key role herein, through (i) increased satiety related to increased diet-induced thermogenesis, (ii) its effect on thermogenesis, (iii) body composition, and (iv) decreased energy-efficiency, all of which are related to protein metabolism. Supported by these mechanisms, relatively larger weight loss and subsequent stronger body-weight maintenance have been observed. Elevated thermogenesis and GLP-1 appear to play a role in high protein induced satiety. Moreover, a negative fat-balance and positive protein-balance is shown in the short-term, whereby fat-oxidation is increased. Furthermore, a high protein diet shows a reduced energy efficiency related to the body-composition of the body-weight regained, i.e. favor of fat free mass. Since protein intake is studied under various energy balances, absolute and relative protein intake needs to be discriminated. In absolute grams, a normal protein diet becomes a relatively high protein diet in negative energy balance and at weight maintenance. Therefore 'high protein negative energy balance diets' aim to keep the grams of proteins ingested at the same level as consumed at energy balance, despite lower energy intakes.


Phylogenetic structure of Xanthomonas determined by comparison of gyrB sequences.
Previously, we have produced a phylogeny of species type strains from the plant-pathogenic genus Xanthomonas based on gyrB sequences. To evaluate this locus further for species and infraspecies identification, we sequenced an additional 203 strains comprising all the pathovar reference strains (which have defined plant hosts), 67 poorly characterized pathovars, currently classified as Xanthomonas campestris, and 59 unidentified xanthomonads. The well-characterized pathovars grouped either in clades containing their respective species type strain or in clades containing species related to Xanthomonas axonopodis. The Xanthomonas euvesicatoria, Xanthomonas perforans and Xanthomonas alfalfae species complex, Xanthomonas fuscans and Xanthomonas citri were discriminated as X. axonopodis-related clades and comprised a large proportion of unidentified strains as well as 80 pathovars representing all the X. axonopodis pathovars and many poorly characterized pathovars, greatly increasing the plant host ranges of the constituent species. Most xanthomonads from these three large clades were isolated from a taxonomically diverse range of plant hosts, including many weed species, from field systems in India, suggesting that these lineages became established and diversified in agricultural areas in this region. The majority of these xanthomonads had minimal sequence diversity, consistent with rapid and highly extensive pathovar diversification that has occurred in relatively recent times. Low-intensity farming practices may have provided conditions conducive to pathovar development, and evidence for pathovar diversification within other regional angiosperm floras is discussed. The gyrB locus was sufficiently discriminating to identify diversity within many species. Seven branches or clades were sufficiently distinct to be considered as potential novel species. This study has provided a comprehensive xanthomonad classification framework and has firmly established gyrB sequencing as a rapid and efficient identification tool.


[Several properties of beta-galactosidase from Artemisia annua L].
beta-Galactosidase was isolated from different organs of the wormwood (Artemisia annua L.). The enzyme activity was found to change during the growth and development of the plant. The maximal activity was revealed in reproductive organs at flowering and fruiting stages. Using ion-exchange chromatography, isoelectric focusing and disc electrophoresis in PAAG, two molecular isoforms of beta-galactosidase were detected. Some physicochemical properties of the enzyme were investigated.


Efficacy of continuous catheter analgesia of the sciatic nerve after total knee arthroplasty.
This study investigated and compared the outcomes after continuous femoral nerve block alone, continuous femoral nerve analgesia combined with single-shot sciatic nerve analgesia, and continuous femoral and sciatic nerve analgesia in patients with total knee replacement. The retrospective study evaluated three groups: continuous femoral nerve analgesia alone, continuous femoral nerve analgesia combined with single-shot sciatic nerve analgesia and continuous femoral nerve analgesia combined with continuous sciatic nerve analgesia. All patients had a hemi- or total knee arthroplasty (TKA), which were performed by a single surgeon. The postoperative analgesia was managed by the same team. A total of 362 patient charts were evaluated from the years 2005-2012. Pain scored with a visual analogue scale (VAS) was recorded 8 hours and 24 hours postoperatively on a standardised form. The amount of opioids required with and without additional sciatic nerve analgesia was documented by monitoring the VAS. Overall, 364 patient files could be assessed. The VAS scores after 8 and 24 hours of patients with an additional continuous sciatic nerve catheter were lower (mean values 1.8 and 4.0, respectively) than those of patients with a continuous femoral catheter alone (mean values 2.7 and 4.9). After 8 and 24 hours, patients with a continuous sciatic nerve catheter had lower VAS scores than those with additional single-shot sciatic nerve anaesthesia (mean values 1.9 and 4.5). Pethidine consumption in the continuous sciatic nerve catheter group was lower (32% of patients) as compared with the two other groups (65%). The side effects of opioids per group consequently were also lower: 24% patients with side effects in the continuous sciatic nerve block group, 52% in the additional single shot sciatic nerve group, 44% in the femoral nerve block group. On the basis of these results, which correspond well to other studies of a topic that is under discussion in the literature, we adapted our postoperative pain regimen to continuous sciatic and femoral nerve analgesia for at least 24 hours after hemi- and total knee replacement.


Biliary extracorporeal shock wave lithotripsy: the efficacy and safety of concomitant catheter cholecystostomy during biliary lithotripsy.
The major limitations of biliary extracorporeal shock wave lithotripsy (ESWL) relate to adequate stone fragmentation and clearance of the stone fragments. We hypothesized the removal of small fragments with concomitant catheter cholecystostomy during ESWL would improve its efficacy. ESWL with aspiration or flushing through three different cholecystostomy catheters was performed on pigs with surgically implanted gallstones. Twenty-two percent and 46% of the pre-ESWL stone weight were aspirated through the 10 and 12 French catheters respectively. The clearance, size, and visualization of fragments was not significantly different between any of the groups. No significant post-mortem tissue or catheter damage was found. Catheter aspiration is a safe and effective method of removing gallstone fragments during biliary ESWL, but it does not improve stone fragmentation, stone clearance, or visualization of other fragments.


First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound.
Magnetic resonance-guided focused ultrasound surgery (MRgFUS) allows for precise thermal ablation of target tissues. While this emerging modality is increasingly used for the treatment of various types of extracranial soft tissue tumors, it has only recently been acknowledged as a modality for noninvasive neurosurgery. MRgFUS has been particularly successful for functional neurosurgery, whereas its clinical application for tumor neurosurgery has been delayed for various technical and procedural reasons. Here, we report the case of a 63-year-old patient presenting with a centrally located recurrent glioblastoma who was included in our ongoing clinical phase I study aimed at evaluating the feasibility and safety of transcranial MRgFUS for brain tumor ablation. Applying 25 high-power sonications under MR imaging guidance, partial tumor ablation could be achieved without provoking neurological deficits or other adverse effects in the patient. This proves, for the first time, the feasibility of using transcranial MR-guided focused ultrasound to safely ablate substantial volumes of brain tumor tissue.


BEHAVIORAL AND NEUROBIOLOGICAL MECHANISMS OF PAVLOVIAN AND INSTRUMENTAL EXTINCTION LEARNING.
This article reviews the behavioral neuroscience of extinction, the phenomenon in which a behavior that has been acquired through Pavlovian or instrumental (operant) learning decreases in strength when the outcome that reinforced it is removed. Behavioral research indicates that neither Pavlovian nor operant extinction depends substantially on erasure of the original learning but instead depends on new inhibitory learning that is primarily expressed in the context in which it is learned, as exemplified by the renewal effect. Although the nature of the inhibition may differ in Pavlovian and operant extinction, in either case the decline in responding may depend on both generalization decrement and the correction of prediction error. At the neural level, Pavlovian extinction requires a tripartite neural circuit involving the amygdala, prefrontal cortex, and hippocampus. Synaptic plasticity in the amygdala is essential for extinction learning, and prefrontal cortical inhibition of amygdala neurons encoding fear memories is involved in extinction retrieval. Hippocampal-prefrontal circuits mediate fear relapse phenomena, including renewal. Instrumental extinction involves distinct ensembles in corticostriatal, striatopallidal, and striatohypothalamic circuits as well as their thalamic returns for inhibitory (extinction) and excitatory (renewal and other relapse phenomena) control over operant responding. The field has made significant progress in recent decades, although a fully integrated biobehavioral understanding still awaits.


What Environmental Factors Influence the Concentration of Fecal Indicator Bacteria in Groundwater? Insights from Explanatory Modeling in Uganda and Bangladesh.
Information about microbial water quality is critical for managing water safety and protecting public health. In low-income countries, monitoring all drinking water supplies is impractical because financial resources and capacity are insufficient. Data sets derived from satellite imagery, census, and hydrological models provide an opportunity to examine relationships between a suite of environmental risk factors and microbial water quality over large geographical scales. We investigated the relationships between groundwater fecal contamination and different environmental parameters in Uganda and Bangladesh. In Uganda, groundwater contamination was associated with high population density (p < 0.001; OR = 1.27), high cropland coverage (p < 0.001; OR = 1.47), high average monthly precipitation (p < 0.001; OR = 1.14), and high surface runoff (p < 0.001; OR = 1.37), while low groundwater contamination was more likely in areas further from cities (p < 0.001; OR = 0.66) and with higher forest coverage (p < 0.001; OR = 0.70). In Bangladesh, contamination was associated with higher weekly precipitation (p < 0.001; OR = 1.44) and higher livestock density (p = 0.05; OR = 1.11), while low contamination was associated with low forest coverage (p < 0.001; OR = 1.23) and high cropland coverage (p < 0.001; OR = 0.80). We developed a groundwater contamination index for each country to help decision-makers identify areas where groundwater is most prone to fecal contamination and prioritize monitoring activities. Our approach demonstrates how to harness satellite-derived data to guide water safety management.


[The N-stearoylethanolamine effect on the NO-synthase way of nitrogen oxide formation and phospholipid composition of erythrocyte membranes in rats with streptozotocine diabetes].
The influence of N-stearoylethanolamine (NSE) on the NO-synthase way of NO generation and phospholipids composition of erythrocyte membranes of rats with streptozotocine-induced diabetes has been studied. It has been shown that the activation of iNOS activity, cNOS activity inhibition and increase of the stable NO metabolites content takes place in the red blood cells (RBC) of diabetic rats. The alterations were also found in the RBC membrane phospholipid content: a decrease of phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, sphingomieline content and increase of phosphatidylethanolamine, phosphatidylcholine lysoforms level. The NSE suspension administration (50 mg/kg of body weight) to diabetic rats (3 months after the diabetes induction) resulted in iNOS activity inhibition, recovering of cNOS activity and normalization of NO stable metabolites level in RBC. The decrease of phospholipids lysoform levels, normalization of phosphatidylethanolamine, phosphatidylcholine content and increase of phosphatidylinositol level were found after NSE action.


Temporomandibular joint involvement in rheumatoid arthritis: a radiological and clinical study.
Temporomandibular joint (TMJ) involvement in rheumatoid arthritis (RA) is not uncommon. In this study a questionnaire, clinical assessment, and high resolution computerized tomography (HRCT) were used in 15 patients with rheumatoid arthritis to evaluate the diagnostic criteria of TMJ involvement. Symptoms due to TMJ involvement were present in 33.3% of the patients. Frequency of involvement was 40.0% on clinical assessment but 86.6% with HRCT assessment. The most common HRCT findings were decreases in the joint space (33.3%), mandibular subchondral cysts (23.3%), temporal subchondral cysts (23.3%), degeneration (23.3%), shape (13.3%) and height (13.3%) anomalies of the mandibular condyle, condylar head resorption (13.3%), erosion of the mandibular condyle (13.3%), and demineralization (13.3%). All patients with positive clinical findings also had positive HRCT findings. In seven (46.7%) of the patients, there were no symptoms or clinical findings implying TMJ involvement; however, they had positive results on HRCT evaluation. The HRCT findings may be the initial sign of TMJ involvement in patients with rheumatoid arthritis. In conclusion, it is suggested that RA patients with the suspicion of TMJ involvement should undergo HRCT evaluation, because HRCT findings may precede the clinical findings.


Five-year review (2014-2019) of paediatric accidental deaths in Cook County, Illinois (USA).
In the USA, intentional and accidental injuries are the most frequent causes of death in children. Many of these deaths could be avoided through preventive measures, and aetiological studies are needed to reduce fatalities. The leading causes of accidental death vary by age. We analysed all paediatric accidental deaths recorded by a busy urban Medical Examiner"s Office in Chicago, Illinois (USA). We searched the electronic database for accidental deaths in children aged under 10 between 1 August 2014 and 31 July 2019. 131 deaths were identified with a preponderance of males and African Americans. This is consistent with ratios of other deaths recorded for this age group (during the same period and area). The leading causes of death were asphyxia due to an unsafe sleeping environment (in subjects <1-year-old), and road traffic accidents/drowning (in subjects >1-year-old). Behaviours, risk factors and environments most likely to contribute to fatal injuries are discussed. Our study highlights the role of forensic pathologists and medico-legal death investigators who identify the causes and circumstances surrounding these deaths. The research results may help from an epidemiological perspective to implement age-specific preventive strategies.


The repertoire and features of human platelet microRNAs.
Playing a central role in the maintenance of hemostasis as well as in thrombotic disorders, platelets contain a relatively diverse messenger RNA (mRNA) transcriptome as well as functional mRNA-regulatory microRNAs, suggesting that platelet mRNAs may be regulated by microRNAs. Here, we elucidated the complete repertoire and features of human platelet microRNAs by high-throughput sequencing. More than 492 different mature microRNAs were detected in human platelets, whereas the list of known human microRNAs was expanded further by the discovery of 40 novel microRNA sequences. As in nucleated cells, platelet microRNAs bear signs of post-transcriptional modifications, mainly terminal adenylation and uridylation. In vitro enzymatic assays demonstrated the ability of human platelets to uridylate microRNAs, which correlated with the presence of the uridyltransferase enzyme TUT4. We also detected numerous microRNA isoforms (isomiRs) resulting from imprecise Drosha and/or Dicer processing, in some cases more frequently than the reference microRNA sequence, including 5' shifted isomiRs with redirected mRNA targeting abilities. This study unveils the existence of a relatively diverse and complex microRNA repertoire in human platelets, and represents a mandatory step towards elucidating the intraplatelet and extraplatelet role, function and importance of platelet microRNAs.


Super-Resolution Imaging of Self-Assembled Nanocarriers Using Quantitative Spectroscopic Analysis for Cluster Extraction.
Self-assembled nanocarriers have inspired a range of applications for bioimaging, diagnostics, and drug delivery. The noninvasive visualization and characterization of these nanocarriers are important to understand their structure to function relationship. However, the quantitative visualization of nanocarriers in the sample's native environment remains challenging with the use of existing technologies. Single-molecule localization microscopy (SMLM) has the potential to provide both high-resolution visualization and quantitative analysis of nanocarriers in their native environment. However, nonspecific binding of fluorescent probes used in SMLM can introduce artifacts, which imposes challenges in the quantitative analysis of SMLM images. We showed the feasibility of using spectroscopic point accumulation for imaging in nanoscale topography (sPAINT) to visualize self-assembled polymersomes (PS) with molecular specificity. Furthermore, we analyzed the unique spectral signatures of Nile Red (NR) molecules bound to the PS to reject artifacts from nonspecific NR bindings. We further developed quantitative spectroscopic analysis for cluster extraction (qSPACE) to increase the localization density by 4-fold compared to sPAINT; thus, reducing variations in PS size measurements to less than 5%. Finally, using qSPACE, we quantitatively imaged PS at various concentrations in aqueous solutions with ∼20 nm localization precision and 97% reduction in sample misidentification relative to conventional SMLM.


Healthy brain aging: role of cognitive reserve, cognitive stimulation, and cognitive exercises.
Current knowledge about the roles of cognitively stimulating lifestyles and cognitive training interventions in preserving cognitive function in later life is reviewed. Potential mechanisms for beneficial effects of cognitive stimulation and training are discussed, and key gaps in research identified. Suggestions are provided for advising patients about brain-healthy lifestyles, acknowledging that much remains to be learned in this area of research. More randomized controlled trials, using challenging regimes of training and stimulation and long-term follow-up, are needed, measuring cognitive trajectories in normal aging and relative risk of Alzheimer disease as outcomes.


Medical Malpractice in Nerve Injury of the Upper Extremity.
Background: Medical malpractice accounts for more than $55 billion of annual health care costs. Updated malpractice risk to surgeons and physicians related to upper extremity peripheral nerve injury has not been published. Methods: A comprehensive database analysis of upper extremity nerve injury claims between 1995 and 2014 in the United States was conducted using the Medical Professional Liability Association Data Sharing Project, representing 24 major insurance companies. Results: Nerve injury in the upper extremity accounted for 614 (0.3%) malpractice claims (total of 188 323). Common presenting diagnoses included carpal tunnel syndrome (41%), upper extremity fractures (19%), and traumatic nerve injuries to the shoulder or upper limb (8%). Improper performance (49% of total claims) and claims without evidence of medical error (19%) were the most common malpractice suits. Orthopedic surgeons were the most frequently targeted specialists (42%). In all, 65% of nerve injury claims originated from operative procedures in a hospital, 59% of claims were dismissed or withdrawn prior to trial, and 30% resulted in settlements. Thirty-three percent of claims resulted in an indemnity payment to an injured party, with an average payout of $203 592 per successful suit. Only 8% of claims resulted in a completed trial and verdict, and verdicts were overwhelmingly in favor of the defendant (83%). Conclusions: Most malpractice claims from peripheral nerve injuries in the United States arise from the management of common diagnoses, occur in the operating room, and allege improper performance. Strategies to reduce malpractice risk should emphasize the management of common conditions and patient-physician communication.


Single-sample landscape entropy reveals the imminent phase transition during disease progression.
The time evolution or dynamic change of many biological systems during disease progression is not always smooth but occasionally abrupt, that is, there is a tipping point during such a process at which the system state shifts from the normal state to a disease state. It is challenging to predict such disease state with the measured omics data, in particular when only a single sample is available. In this study, we developed a novel approach, i.e. single-sample landscape entropy (SLE) method, to identify the tipping point during disease progression with only one sample data. Specifically, by evaluating the disorder of a network projected from a single-sample data, SLE effectively characterizes the criticality of this single sample network in terms of network entropy, thereby capturing not only the signals of the impending transition but also its leading network, i.e. dynamic network biomarkers. Using this method, we can characterize sample-specific state during disease progression and thus achieve the disease prediction of each individual by only one sample. Our method was validated by successfully identifying the tipping points just before the serious disease symptoms from four real datasets of individuals or subjects, including influenza virus infection, lung cancer metastasis, prostate cancer and acute lung injury. https://github.com/rabbitpei/SLE. Supplementary data are available at Bioinformatics online.


Blood concentrations of acetaldehyde and ethanol in chronic alcoholics.
Fifteen adult male alcoholic volunteers were studied before, during, and after a 10- to 15-day period of experimentally induced intoxication. Blood acetaldehyde concentrations ranged from 0.11 to 0.15 and from 0.04 to 0.08 milligrams per 100 milliliters when blood ethanol concentrations ranged from 1 to 400 milligrams per 100 milliliters after consumption of bourbon or grain ethanol, respectively. No dose or dose-time relationships were found between blood ethanol concentrations and blood acetaldehyde concentrations during any phase of this study.


Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02.
Radiation Therapy Oncology Group (RTOG) Protocol 92-02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P =.044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037), the cause of which is not clear. The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.


Bifid mandibular canal.
To determine the incidence and characteristics of bifid mandibular canals. A retrospective study was performed using panoramic radiographs of 2012 patients subjected to dental treatment in the Dental Clinic of the Valencia University Dental School (Valencia, Spain) between 1996 and 1999. The goal was to investigate the presence of double mandibular canals. The extraoral panoramic radiographs revealed a total of 7 images suggestive of bifid canals. Mandibular computed tomography revealed the existence of this anatomic variant in 2 of 3 patients. An analysis was performed on the incidence of this type of image in extraoral panoramic radiography, its possible interpretations, and the clinical implications of bifid mandibular canals. In this study, 0.35% of canals were bifid. All cases were in women.


The Effect of Mechanical Massage and Mental Training on Heart Rate Variability and Cortisol in Swedish Employees-A Randomized Explorative Pilot Study.
Work-related stress is relatively common in modern society and is a major cause of sick-leave. Thus, effective stress reducing interventions are needed. This study examined the effects of mental training and mechanical massage, on employee's heart rate variability (HRV) and plasma cortisol at their workplaces. Moreover, it was investigated whether baseline systolic blood pressure (SBP) can explain differences in effectiveness of the intervention. Ninety-three participants from four workplaces were randomly assigned to one of the five programs: (I) Mechanical massage and mental training combined, II) Mechanical massage, III) Mental training, IV) Pause, or V) Control. HRV and plasma cortisol were measured at baseline and after 4 and 8 weeks. SBP was measured at baseline. On the reduction of cortisol levels, a small effect of the mechanical massage program was found, whereas no effect was found for the other programs. None of the programs showed any effect on HRV. Nonetheless, when the level of systolic blood pressure was taken into account, some small beneficial effects on HRV and cortisol of mental training and the mechanical massage were found. This exploratory pilot-study provides useful information for future studies that aim to reduce stress among employees.


Protein metabolism and fibrosis in experimental canine obstructive lymphedema.
Obstructive lymphedema is a pathologic condition resulting in the accumulation and stagnation of serum proteins in the lymphatics and interstitial spaces. In a canine model of obstructive lymphedema, one limb was rendered lymphedematous, and various biochemical parameters were determined in this and an unaffected control limb. Both lymph and interstitial fluid had significantly decreased acid proteinase activity (comprising mostly cathepsin D-like enzymes) and neutral proteinase activity (comprising metallo, sulfhydryl, and serine proteinases, and collagenase). Possible reasons for these decreases could be: (1) saturation of macrophages and their surrounding environment with whole or partially digested proteins, or (2) elevation in the levels of circulating inhibitors like alpha 2-macroglobulin. The lymphedematous skin was significantly thicker than control skin and had elevated levels of collagen. However, unlike some fibrotic conditions, the relative proportions of types I, III, and V collagen, as determined by pepsin solubilization and neutral salt fractionation of the collagen fibrils, were similar to those found in normal skin. It is speculated that a decrease in the breakdown of collagen by collagenase and a continuing synthesis of collagen by fibroblasts led to an imbalance in favor of collagen deposition in the skin.


Ultrafast near-field spectroscopy of single semiconductor quantum dots.
Excitonic and spin excitations of single semiconductor quantum dots (QDs) currently attract attention as possible candidates for solid-state-based implementations of quantum logic devices. Due to their rather short decoherence times in the picosecond to nanosecond range, such implementations rely on using ultrafast optical pulses to probe and control coherent polarizations. We combine ultrafast spectroscopy and near-field microscopy to probe the nonlinear optical response of a single QD on a femtosecond time-scale. Transient reflectivity spectra show pronounced oscillations around the QD exciton line. These oscillations reflect phase-disturbing Coulomb interactions between the excitonic QD polarization and continuum excitations. The results show that although semiconductor QDs resemble in many respects atomic systems, Coulomb many-body interactions can contribute significantly to their optical nonlinearities on ultrashort time-scales.


COVID-19 Isolation in Healthy Population in Israel: Challenges in Daily Life, Mental Health, Resilience, and Quality of Life.
Pandemics produce long-lasting secondary impacts on health, with a significant burden on people and society. Until now, the secondary impact of COVID-19 has been little estimated. Our aim was to investigate factors underlying quality of life (QOL) during COVID-19 lockdown among a healthy population, while QOL reduction expands vulnerability to the pandemic secondary impact. During the spring lockdown in Israel, 571 healthy adults completed a survey that included standard measurements for psychological distress, participation in daily life activities, a sense of social connectedness, resilience, and QOL. We found a high level of psychological distress, significant reduction in participation dimensions, and in QOL (psychical, psychological, and social). These indices were even lower among women, younger adults, and the unemployed. Path analysis demonstrated that psychological distress, participation dimensions, social connectedness, and self-efficacy explained QOL, while participation dimensions were found to be the mediators. The COVID-19 has had a wide impact on the general population, with the potential for negative secondary impacts. Women, young adults, and the unemployed are at high risk for secondary effects. Public health strategies should address the reported factors and populations in order to improve QOL in a healthy population and limit the impact of the pandemic.


Folding mechanism of all-beta globular proteins.
Elucidating the mechanism for the fast folding of proteins is a challenging task. In our earlier work, we introduced the concept of "long-range order" and related it successfully to protein folding rates. In this article, we propose a new hypothesis for the folding of two-state all-beta proteins. The mechanism is based on the formation of a hydrophobic core, propagation of beta-strands, and the establishment of hydrogen bonds. Our hypothesis has been strengthened by the observation of a folding nucleus in beta-strands and the hydrogen-bonding network between residues in beta-strands. Our insights on protein folding show an excellent agreement with experimental observations.


Nigral GABAergic inhibition upon cholinergic neurons in the rat pedunculopontine tegmental nucleus.
We investigated, in a midbrain parasagittal slice preparation of Wistar rats (postnatal day 9-17), the synaptic inhibition of neurons in the pedunculopontine tegmental nucleus (PPN), which was mediated by gamma (gamma)-amino-butyric acid (GABA). Whole-cell patch-clamp recording was used, in combination with a single-cell reverse transcription-polymerase chain reaction amplification technique, to record synaptic potentials and to identify the phenotype of the recorded PPN neuron. In the presence of the ionotropic glutamate receptor antagonists, 6-cyano-2, 3-dihydroxy-7-nitro-quinoxaline-2, 3, dione, and dl-2-amino-5-phosphonovaleric acid, single electrical stimuli were applied to the substantia nigra pars reticulata (SNr), one of the basal ganglia output nuclei. Stimulation of the SNr evoked inhibitory postsynaptic potentials (IPSPs) in 73 of the 104 neurons in the PPN. The IPSPs were abolished with a GABAA receptor antagonist, bicuculline. Inhibitory postsynaptic currents of the neurons were reversed in polarity at approximately -93.5 mV, which was close to the value of the equilibrium potential for chloride ions of -88.4 mV. Single-cell reverse transcription-polymerase chain reactions revealed that approximately 30% (9/32) of the PPN neurons that received inhibition from the SNr expressed detectable levels of choline acetyltransferase mRNA. These findings show that output from the SNr regulates the activity of cholinergic PPN neurons through GABAA receptors.


Central and peripheral cardiovascular changes immediately after waterpipe smoking.
Tobacco cigarette smoking is a global health problem that kills millions each year. Recently, tobacco smoking using a waterpipe (WP) has become popular worldwide. However, unlike cigarettes, the cardiovascular (CV) risks associated with WP smoking are uncertain. In this study, the immediate effects of WP smoking on central and peripheral CV indices were evaluated in 53 young healthy smokers. Strain-gauge plethysmography was used to measure forearm blood flow (Bf), vascular resistance (Vr), and venous capacitance (Vc) and outflow (Vf) at rest (R) and after occlusion (Oc), whereas heart rate (HR) and blood pressure (BP) were measured using standard automated auscultatory methods immediately before and after a 30-min WP smoking session. Smoking resulted in HR, diastolic BP, mean arterial BP, rate pressure product and OcVr increases (p < 0.05) 6.6, 3.6, 2.5, 8.0 and 16%, respectively, whereas OcBf and OcVf decreased (p < 0.05) 8.8 and 14.3%, respectively. Additionally, smoking-induced changes in the central CV components correlated (p < 0.05) with changes in the periphery. These results demonstrated changes in the CV central and peripheral components immediately after WP smoking. The correlations between the changes in these components suggest that the periphery is controlled, at least partially, by the same mechanism(s) affecting the central CV components during WP smoking.


Classifying Autism Spectrum Disorder Using the Temporal Statistics of Resting-State Functional MRI Data With 3D Convolutional Neural Networks.
Resting-state functional magnetic resonance imaging (rs-fMRI) data are 4-dimensional volumes (3-space + 1-time) that have been posited to reflect the underlying mechanisms of information exchange between brain regions, thus making it an attractive modality to develop diagnostic biomarkers of brain dysfunction. The enormous success of deep learning in computer vision has sparked recent interest in applying deep learning in neuroimaging. But the dimensionality of rs-fMRI data is too high (~20 M), making it difficult to meaningfully process the data in its raw form for deep learning experiments. It is currently not clear how the data should be engineered to optimally extract the time information, and whether combining different representations of time could provide better results. In this paper, we explored various transformations that retain the full spatial resolution by summarizing the temporal dimension of the rs-fMRI data, therefore making it possible to train a full three-dimensional convolutional neural network (3D-CNN) even on a moderately sized [~2,000 from Autism Brain Imaging Data Exchange (ABIDE)-I and II] data set. These transformations summarize the activity in each voxel of the rs-fMRI or that of the voxel and its neighbors to a single number. For each brain volume, we calculated regional homogeneity, the amplitude of low-frequency fluctuations, the fractional amplitude of low-frequency fluctuations, degree centrality, eigenvector centrality, local functional connectivity density, entropy, voxel-mirrored homotopic connectivity, and auto-correlation lag. We trained the 3D-CNN on a publically available autism dataset to classify the rs-fMRI images as being from individuals with autism spectrum disorder (ASD) or from healthy controls (CON) at an individual level. We attained results competitive on this task for a combined ABIDE-I and II datasets of ~66%. When all summary measures were combined the result was still only as good as that of the best single measure which was regional homogeneity (ReHo). In addition, we also applied the support vector machine (SVM) algorithm on the same dataset and achieved comparable results, suggesting that 3D-CNNs could not learn additional information from these temporal transformations that were more useful to differentiate ASD from CON.


How does the functional diversity of frugivorous birds shape the spatial pattern of seed dispersal? A case study in a relict plant species.
Genetic markers used in combination with network analysis can characterize the fine spatial pattern of seed dispersal and assess the differential contribution of dispersers. As a case study, we focus on the seed dispersal service provided by a small guild of frugivorous birds to the common yew, Taxus baccata L., in southern Spain. We build the spatial networks of seed dispersal events between trees and seed-plots within the studied population-local network-and the spatial network that includes all dispersal events-regional network. Such networks are structured in well-defined modules, i.e. groups of tightly connected mother trees and seed-plots. Neither geographical distance, nor microhabitat type explained this modular structure, but when long-distance dispersal events are incorporated in the network it shows a relative increase in overall modularity. Independent field observations suggested the co-occurrence of two complementary groups, short- and long-distance dispersers, mostly contributing to the local and regional seed rain, respectively. The main long-distance disperser at our site, Turdus viscivorus, preferentially visits the most productive trees, thus shaping the seed rain at the landscape scale and affecting the local modular organization. We end by discussing how DNA barcoding could serve to better quantify the role of functional diversity.


The dinoflagellate Akashiwo sanguinea will benefit from future climate change: The interactive effects of ocean acidification, warming and high irradiance on photophysiology and hemolytic activity.
Due to global climate change, marine phytoplankton will likely experience low pH (ocean acidification), high temperatures and high irradiance in the future. Here, this work report the results of a batch culture experiment conducted to study the interactive effects of elevated CO2, increased temperature and high irradiance on the harmful dinoflagellate Akashiwo sanguinea, isolated at Dongtou Island, Eastern China Sea. The A. sanguinea cells were acclimated in high CO2 condition for about three months before testing the responses of cells to a full factorial matrix experimentation during a 7-day period. This study measured the variation in physiological parameters and hemolytic activity in 8 treatments, representing full factorial combinations of 2 levels each of exposure to CO2 (400 and 1000μatm), temperature (20 and 28°C) and irradiance (50 and 200μmol photons m-2s-1). Sustained growth of A. sanguinea occurred in all treatments, but high CO2 (HC) stimulated faster growth than low CO2 (LC). The pigments (chlorophyll a and carotenoid) decreased in all HC treatments. The quantum yield (Fv/Fm) declined slightly in all high-temperature (HT) treatments. High irradiance (HL) induced the accumulation of ultraviolet-absorbing compounds (UVabc) irrespective of temperature and CO2. The hemolytic activity in the LC treatments, however, declined when exposed to HT and HL, but HC alleviated the adverse effects of HT and HL on hemolytic activity. All HC and HL conditions and the combinations of high temperature*high light (HTHL) and high CO2*high temperature*high light (HCHTHL) positively affected the growth in comparison to the low CO2*low temperature*low light (LCLTLL) treatment. High temperature (HT), high light (HL) and a combination of HT*HL, however, negatively impacted hemolytic activity. CO2 was the main factor that affected the growth and hemolytic activity. There were no significant interactive effects of CO2*temperature*irradiance on growth, pigment, Fv/Fm or hemolytic activity, but there were effects on Pm, α, and Ek. If these results are extrapolated to the natural environment, it can be hypothesized that A. sanguinea cells will benefit from the combination of ocean acidification, warming, and high irradiance that are likely to occur under future climate change. It is assumed that faster growth and higher hemolytic activity and UVabc of this species will occur under future conditions compared with those the current CO2 (400μatm) and temperature (20°C) conditions.


Are pregnant and postpartum women: at increased risk for violent death? Suicide and homicide findings from North Carolina.
The purpose of this study is to estimate rates of suicide and homicide death among pregnant, postpartum and non-pregnant/non-postpartum women ages 14-44, and to determine comparative rates of violent death for pregnant and/or postpartum women compared to non-pregnant/non-postpartum women. North Carolina surveillance and vital statistics data from 2004 to 2006 were used to examine whether pregnant or postpartum women have higher (or lower) rates of suicide and homicide compared to other reproductive-aged women. The suicide rate for pregnant women was 27% of the rate for non-pregnant/non-postpartum women (rate ratio= 0.27, 95% CI = 0.11-0.66), and the suicide rate for postpartum women was 54% of the rate for non-pregnant/non-postpartum women (rate ratio = 0.54, 95% CI = 0.31-0.95). Homicide rates also were lower for pregnant and postpartum women, with the homicide rate for pregnant women being 73% of the rate for non-pregnant/non-postpartum women (rate ratio = 0.73, 95% CI = 0.39-1.37), and the homicide rate for postpartum women being half the rate for non-pregnant/non-postpartum women (rate ratio = 0.50, 95% CI = 0.26-0.98). Although pregnant and postpartum women are at risk for homicide and suicide death, the highest risk group is non-pregnant/non-postpartum women. Violence prevention efforts should target all women of reproductive age, and pay particular attention to non-pregnant/non-postpartum women, who may have less access to health care services than pregnant and postpartum women.


The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans.
Wnts control a wide range of essential developmental processes, including cell fate specification, axon guidance and anteroposterior neuronal polarization. We identified a conserved transmembrane RING finger protein, PLR-1, that governs the response to Wnts by lowering cell-surface levels of the Frizzled family of Wnt receptors in Caenorhabditis elegans. Loss of PLR-1 activity in the neuron AVG causes its anteroposterior polarity to be symmetric or reversed because signaling by the Wnts CWN-1 and CWN-2 are inappropriately activated, whereas ectopic PLR-1 expression blocks Wnt signaling and target gene expression. Frizzleds are enriched at the cell surface; however, when PLR-1 and Frizzled are co-expressed, Frizzled is not detected at the surface but instead is colocalized with PLR-1 in endosomes. The Frizzled cysteine-rich domain (CRD) and invariant second intracellular loop lysine are crucial for PLR-1 downregulation. The PLR-1 RING finger and protease-associated (PA) domain are essential for activity. In a Frizzled-dependent manner, PLR-1 reduces surface levels of the Wnt receptors CAM-1/Ror and LIN-18/Ryk. PLR-1 is a homolog of the mammalian transmembrane E3 ubiquitin ligases RNF43 and ZNRF3, which control Frizzled surface levels in an R-spondin-sensitive manner. We propose that PLR-1 downregulates Wnt receptor surface levels via lysine ubiquitylation of Frizzled to coordinate spatial and temporal responses to Wnts during neuronal development.


Evaluation of MINOCA syndrome and HEART score in patients presenting to the emergency department with panic attack and chest pain complaints.
Patients presenting with chest pain may or may not be experiencing a panic attack. Is chest pain caused by a panic attack or myocardial infarction with non-obstructive coronary arteries (MINOCA) syndrome? In this study, we evaluated both MINOCA syndrome and HEART score in patients who presented to the emergency department with panic attacks and chest pain. Patients who applied to the emergency department with panic disorder and chest pain complaints were included. Patients who met the MINOCA diagnostic criteria were identified. The study was completed with 143 eligible patients out of a total of 217 patients evaluated. The patients were divided into two groups. The first group was those whose symptoms and test results were consistent with MINOCA. The second group was composed of those whose chest pain was considered non-specific. The HEART score of all patients was calculated. The demographic characteristics, symptoms, and HEART scores were compared between the groups. Of the 143 patients evaluated in the study, 62 (43.3%) were male and 81 (56.7%) were female. While the mean HEART score was 4.7 ± 1.5 in the MINOCA group, it was 2.0 ± 1.0 in the non-cardiac group, a statistically significant difference. Clinicians should pay attention to the patient's age, gender, number of attacks per week, HEART score, and which symptoms (palpitations, shortness of breath, and fear of death) are present in patients who meet the panic attack diagnostic criteria. Clinicians should be alert to the MINOCA syndrome in panic attack patients.


[Regulation of the metabolism of ethyl alcohol in the body with oligomeric proanthocyanides as a preventive measure against its toxic effect].
The study evaluated the effects of a complex of oligomer proanthocyanidines derived from the crowns of the grapes Vitis vinifera on the oxidation of ethanol and on the activity of alcohol dehydrogenase and aldehyde dehydrogenase in the plasma of male volunteers given ethanol once, as well as in the rat liver during long-term alcohol use. Oligomer proanthocyanides were shown to be actively involved in the human and animal metabolism of ethyl alcohol in vivo. Under their action, the reductase activity was preserved, which prevented acetaldehyde from accumulating in the body since it reduces to less toxic ethanol. Oligomer proanthocyanidines from the crowns of the grape may be used to prevent a significant toxic effect of excess doses of ethyl alcohol on the body.


Interventions to promote an integrated approach to public health problems: an application to childhood obesity.
Experts stress the need to bring the childhood obesity epidemic under control by means of an integrated approach. The implementation of such an approach requires the development of integrated enabling policies on public health by local governments. A prerequisite for developing such integrated public health policies is intersectoral collaboration. Since the development of integrated policies is still in its early stages, this study aimed to answer the following research question: "What interventions can promote intersectoral collaboration and the development of integrated health policies for the prevention of childhood obesity?" Data were collected through a literature search and observations of and interviews with stakeholders. Based on a theoretical framework, we categorized potential interventions that could optimize an integrated approach regarding children's physical activity and diet. The intervention categories included education, persuasion, incentivization, coercion, training, restriction, environmental restructuring, modeling, and enablement.


Effects of exercise training in heart failure with preserved ejection fraction: an updated systematic literature review.
Physical activity is associated with a lower risk of adverse cardiovascular outcomes, including heart failure (HF). Exercise training is a class IA level recommendation in patients with stable HF, but its impact is less clear in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to analyze the effects of the exercise training on cardiovascular outcomes in patients with HFpEF. A systematic literature search was conducted on the main electronic databases, proceedings of major meetings, and reference lists of the identified studies, using specific terms for only English language studies published between 2000 and 2018. We followed the PRISMA to perform our review. Quality of studies was also assessed. The systematic review identified 9 studies on 348 patients, of moderate (n = 2) to good (n = 7) quality. The training consisted of a combination of supervised in-hospital and home-based outpatient programs, including aerobic exercise, endurance and resistance training, walking, and treadmill and bicycle ergometer. Most of the protocols ranged 12-16 weeks, with a frequency of 2-3 sessions weekly, lasting 20-60 min per session. There were significant improvements in peak oxygen uptake, 6-min walking test distance, and ventilatory threshold, whereas quality of life and echocardiographic parameters improved only in some studies. Endothelial function/arterial stiffness remained unchanged. No adverse events were reported. Appropriate exercise programs are able to get a favorable cardiovascular outcome in patients with HFpEF. This could also benefit in terms of quality of life, even if more controversial. Further researches are necessary.


PAM-DenseNet: A Deep Convolutional Neural Network for Computer-Aided COVID-19 Diagnosis.
Currently, several convolutional neural network (CNN)-based methods have been proposed for computer-aided COVID-19 diagnosis based on lung computed tomography (CT) scans. However, the lesions of pneumonia in CT scans have wide variations in appearances, sizes, and locations in the lung regions, and the manifestations of COVID-19 in CT scans are also similar to other types of viral pneumonia, which hinders the further improvement of CNN-based methods. Delineating infection regions manually is a solution to this issue, while excessive workload of physicians during the epidemic makes it difficult for manual delineation. In this article, we propose a CNN called dense connectivity network with parallel attention module (PAM-DenseNet), which can perform well on coarse labels without manually delineated infection regions. The parallel attention module automatically learns to strengthen informative features from both channelwise and spatialwise simultaneously, which can make the network pay more attention to the infection regions without any manual delineation. The dense connectivity structure performs feature maps reuse by introducing direct connections from previous layers to all subsequent layers, which can extract representative features from fewer CT slices. The proposed network is first trained on 3530 lung CT slices selected from 382 COVID-19 lung CT scans, 372 lung CT scans infected by other pneumonia, and 200 normal lung CT scans to obtain a pretrained model for slicewise prediction. We then apply this pretrained model to a CT scans dataset containing 94 COVID-19 CT scans, 93 other pneumonia CT scans, and 93 normal lung scans, and achieve patientwise prediction through a voting mechanism. The experimental results show that the proposed network achieves promising results with an accuracy of 94.29%, a precision of 93.75%, a sensitivity of 95.74%, and a specificity of 96.77%, which is comparable to the methods that are based on manually delineated infection regions.


Cellular toxicity induced by the photorelease of a caged bioactive molecule: design of a potential dual-action Ru(II) complex.
The series [Ru(tpy)(CH3CN)3](2+) (1), cis-[Ru(tpy)(CH3CN)2Cl](+) (2), and [Ru(tpy)(5CNU)3](2+) (3), where tpy = 2,2':6',2″-terpyridine and 5CNU = 5-cyanouracil, was synthesized, and their photochemical properties were investigated for use as potential photodynamic therapy (PDT) agents. When irradiated with visible light, 1-3 exhibit efficient exchange of the axial CH3CN or 5CNU ligand with H2O solvent molecules. Complexes 1-3 also exhibit photoinitiated binding to DNA when irradiated with λirr ≥ 395 nm light, and DNA binding can be accessed for 2 with λirr > 645 nm, well within the PDT window. Since 3 binds DNA and simultaneously releases biologically active 5CNU, it has the potential to be a dual-action therapeutic agent. Indeed, 3 is cytotoxic upon irradiation with visible light, whereas 1 is not under similar experimental conditions. The lack of toxicity imparted by 1 is explained by the exchange of only one CH3CN ligand in the complex under the irradiation conditions used for the cellular studies. Strategies are being sought to increase the quantum yields of ligand exchange and the cellular penetration of these compounds.


Effects of income and dental insurance coverage on need for dental care in Canada.
To estimate the strength of the associations among income, dental insurance coverage and need for dental care (both urgent and nonurgent) in Canada. Multinomial logistic models were fit to data from the 2009 Canadian Health Measures Survey to test unadjusted associations among household income, dental insurance coverage and the need for urgent and nonurgent dental care. Adjusted associations, controlling for socio-demographic variables (age, sex, immigration status, education and province of residence) and oral health habits (brushing, flossing and visits to the dentist) were also evaluated. In the unadjusted model, need for treatment was lower among people with dental insurance than among those without insurance coverage (for urgent treatment: odds ratio [OR] 0.76, 95% confidence interval [CI] 0.66-0.89; for nonurgent treatment: OR 0.59, 95% CI 0.50-0.70). In addition, there was an income gradient, whereby people with higher income had less need for dental treatment (for urgent treatment: OR 0.99, 95% CI 0.99-1.00; for nonurgent treatment: OR 0.99, 95% CI 0.98-0.99). Controlling for socio-demographic and oral health variables decreased the magnitude of the association between dental insurance coverage and need for treatment (for urgent treatment: OR 0.80, 95% CI 0.68-0.95; for nonurgent treatment: OR 0.76, 95% CI 0.63-0.92). An interaction term between dental coverage and income was significant in relation to the need for nonurgent treatment: among lower-income individuals, having insurance slightly decreased the odds of needing nonurgent treatment, with this decrease in odds becoming greater for middle-income earners and even greater for high-income earners. Income-related inequality in need for dental care exists even in the presence of dental insurance coverage and good dental hygiene habits. These findings highlight the need for increased access to dental care for low-income populations and families living in poverty.


Diffuse coronary artery dilatation in a neonate: a case report.
In this case, we describe a newborn that presented on the first day of life with diffuse, bilateral coronary artery dilatation, in the absence of intrauterine hypoxia or other identifiable causes of coronary artery ectasia. The infant's symptoms followed an acute course before spontaneously recovering. Kawasaki disease, though relatively rare in neonates, may present in this population in the absence of classical criteria. If untreated, the cardiac sequelae of this disease can be serious. Through this case, where spontaneously remitting coronary dilatation is the paramount finding, we entertain the possibility that this may represent the earliest known presentation of Kawasaki disease.


Functional interactions between the fusion protein and hemagglutinin-neuraminidase of human parainfluenza viruses.
The fusion glycoprotein (F) and hemagglutinin-neuraminidase (HN) genes of human parainfluenza virus type 2 (PI2) were molecularly cloned and expressed in HeLa-T4 cells by using the vaccinia virus-T7 transient expression system. Expression of the F and HN proteins was detected by using immunoprecipitation and surface immunofluorescence staining. Although the F protein was found to be cleaved into F1 and F2 and expressed on cell surfaces, no cell fusion was observed. However, cotransfection of the F-protein gene together with the P12 HN gene resulted in significant levels of cell fusion. Cell fusion was also observed when separate cell cultures were transfected with the HN and F genes and the F-expressing cells were mixed with the HN-expressing cells. Surprisingly, when the PI2 F protein was expressed together with the parainfluenza virus type 3 (PI3) HN protein, no fusion was detectable in the transfected cells. Similarly, no fusion was found upon coexpression of the PI2 HN and PI3 F proteins. However, coexpression of the PI3 F and HN proteins resulted in extensive cell fusion, which resembled the PI2 coexpression result. These results indicate that under the conditions used, the F protein is unable to cause fusion by itself and the HN protein provides a specific function in cell fusion which cannot be provided by another paramyxovirus attachment protein. Further, the results suggest that a type-specific functional interaction between the F and HN proteins is involved in mediating cell fusion.


An alternative ICU staffing model: implementation of the non-physician provider.
Literature in Europe regarding implementation of nurse practitioners or physician assistants in the intensive care unit (ICU) is lacking, while some available studies indicate that this concept can improve the quality of care and overcome physician shortages on ICUs. The aim of this study is to provide insight on how a Dutch ICU implemented non-physician providers (NPP), besides residents, and what this staffing model adds to the care on the ICU. This paper defines the training course and job description of NPPs on a Dutch ICU. It describes the number and quality of invasive interventions performed by NPPs, residents, and intensivists during the years 2015 and 2016. Salary scales of NPPs and residents are provided to describe potential cost-effectiveness. The tasks of NPPs on the ICU are equal to those of the residents. Analysis of the invasive interventions performed by NPPs showed an incidence of central venous catheter insertion for NPPs of 20 per fulltime equivalent (FTE) and for residents 4.3 per FTE in one year. For arterial catheters the NPP inserted 61.7 per FTE and the residents inserted 11.8 per FTE. The complication rate of both groups was in line with recent literature. Regarding their salary: after five years in service an NPP earns more than a starting resident. This is the first European study which describes the role of NPPs on the ICU and shows that practical interventions normally performed by physicians can be performed with equal safety and quality by NPPs.


Stigma and coping experiences in Latinx individuals at clinical high-risk for psychosis.
The experiences of culturally diverse individuals at clinical high-risk for psychosis (CHR) is not well studied. Exploratory research needs to examine whether differences exist between racial/ethnic groups within the CHR population. Understanding experiences of Latinx patients is of importance, as the Latinx population represents the most rapidly growing paediatric population in the United States and they face significant barriers to mental health treatment. Because Latinx persons experience high rates of mental illness-based stigma and discrimination in their communities, they may face additional stigma-based barriers to CHR treatment. Twenty-six participants (15 Latinx, 11 non-Latinx white/NLW) who met CHR criteria based on the Structured Interview for Psychosis-Risk Syndromes (SIPS) were interviewed regarding stigma associated with CHR identification and symptoms. Using a consensus-based open-coding thematic analysis approach, data were analysed for stigma, discrimination, and coping responses. Instances of internalization of stereotypes appeared to be more salient to NLW participants than Latinx participants, and Latinx participants reported seemingly more anticipated rejection from stereotypes than NLW participants. Experiences of discrimination also appeared to be more salient to Latinx participants than NLW participants. Moreover, Latinx participants reported evidently greater instances of discrimination across anticipated, individual, and structural discrimination. Finally, while covering strategies appeared to be more salient to NLW's, Latinx clients more often described using secrecy as well as a greater range of coping responses, including empowerment. While the experience of anticipated rejection appeared to be more salient to Latinx CHR participants and they seemingly report more secrecy than NLW, they also engaged in empowerment-related coping strategies. Future research should continue to explore the roles of cultural values in influencing coping strategies among CHR individuals.


Successful expansion of community-based drug-resistant TB care in rural Eswatini - a retrospective cohort study.
Provision of drug-resistant tuberculosis (DR-TB) treatment is scarce in resource-limited settings. We assessed the feasibility of ambulatory DR-TB care for treatment expansion in rural Eswatini. Retrospective patient-level data were used to evaluate ambulatory DR-TB treatment provision in rural Shiselweni (Eswatini), from 2008 to 2016. DR-TB care was either clinic-based led by nurses or community-based at the patient's home with involvement of community treatment supporters for provision of treatment to patients with difficulties in accessing facilities. We describe programmatic outcomes and used multivariate flexible parametric survival models to assess time to adverse outcomes. Both care models were costed in supplementary analyses. Of 698 patients initiated on DR-TB treatment, 57% were women and 84% were HIV-positive. Treatment initiations increased from 27 in 2008 to 127 in 2011 and decreased thereafter to 51 in 2016. Proportionally, community-based care increased from 19% in 2009 to 77% in 2016. Treatment success was higher for community-based care (79%) than clinic-based care (68%, P = 0.002). After adjustment for covariate factors among adults (n = 552), the risk of adverse outcomes (death, loss to follow-up, treatment failure) in community-based care was reduced by 41% (adjusted hazard ratio 0.59, 95% CI: 0.39-0.91). Findings were supported by sensitivity analyses. The care provider's per-patient costs for community-based (USD13 345) and clinic-based (USD12 990) care were similar. Ambulatory treatment outcomes were good, and community-based care achieved better treatment outcomes than clinic-based care at comparable costs. Contextualised DR-TB care programmes are feasible and can support treatment expansion in rural settings.