Hospital volume-outcome relationships among medical admissions to ICUs.
Positive relationships between hospital volume and outcomes have been demonstrated for several surgeries and medical conditions. However, little is known about the volume-outcome relationship in patients admitted to medical ICUs. To determine the relationship between hospital volume and risk-adjusted in-hospital mortality for patients admitted to ICUs with respiratory, neurologic, and GI disorders. Retrospective cohort study. Twenty-nine hospitals in a single metropolitan area. Adult ICU admissions from 1991 through 1997. Using Cox proportional hazards models, we compared in-hospital mortality between tertiles of hospital volume (high, medium, and low) for respiratory (n = 16,949), neurologic (n = 13,805), and GI (n = 12,881) diseases after adjusting for age, gender, admission severity of illness, admitting diagnosis, and source. Severity of illness was measured using the APACHE (acute physiology and chronic health evaluation) III methodology. Among respiratory and neurologic ICU admissions, hazard ratios were similar (p > or = 0.05) in patients in low-, medium-, and high-volume hospitals. However, among GI diagnoses, risk of mortality was lower in high-volume hospitals, relative to low-volume hospitals (hazard ratio, 0.68; 95% confidence interval [CI], 0.54 to 0.85; p < 0.001), and was somewhat lower in medium-volume hospitals (hazard ratio, 0.83; 95% CI, 0.68 to 1.01; p = 0.06). Among subgroups based on severity of illness, high-volume hospitals had lower mortality, relative to low-volume hospitals, among sicker patients (APACHE III score > 57) in the respiratory cohort (hazard ratio, 0.77; 95% CI, 0.59 to 0.99) and the GI cohort (hazard ratio, 0.67; 95% CI, 0.53 to 0.85). Associations between ICU volume and risk-adjusted mortality were significant for patients with GI diagnoses and for sicker patients with respiratory diagnoses. However, associations were not significant for patients with neurologic diagnoses. The lack of a consistent volume-outcome relationship may reflect unmeasured patient complexity in higher-volume hospitals, relative standardization of care across ICUs, or lack of efficacy of some accepted ICU processes of care.


Causes of elevated D-dimer in patients admitted to a large urban emergency department.
Although the request for D-dimer is widespread in emergency departments (EDs), the causes of elevation and their relationship with D-dimer levels in patients with diagnostic values are uncertain. In this retrospective investigation, the study population consisted of all patients who visited our large urban ED in the year 2012, for whom a D-dimer test was requested for excluding or diagnosing venous thromboembolism (VTE). Only patients with D-dimer values >243ng/mL were included, regardless of their pre-test clinical probability for VTE. The final study population consisted of 1647 patients. A significant positive correlation was found between age and D-dimer. Infection was the most frequent diagnosis (15.6%), followed by VTE (12.1%), syncope (9.4%), heart failure (8.9%), trauma (8.2%) and cancer (5.8%). D-dimer was higher in patients with VTE than in those with other diagnoses (2541ng/mL vs 1030ng/mL; p<0.001). The frequency of VTE gradually increased from patients with values <1000ng/mL to those with D-dimer >3000ng/mL (4.1 vs 26.7%; p<0.001). As compared with D-dimer values <1000ng/mL, the Odds Ratio for VTE was 8.5 for values >3000ng/mL. These results show that D-dimer lacks specificity for diagnosing VTE, especially in elderly patients admitted to the ED with significant co-morbidities. In older patients, elevated values (>1000ng/mL) are more frequently associated with VTE, so the use of higher cut-offs may be advantageous.


Sub-inhibitory concentrations of penicillin G induce biofilm formation by field isolates of Actinobacillus pleuropneumoniae.
Actinobacillus pleuropneumoniae is a Gram-negative bacterium and causative agent of porcine pleuropneumonia. This is a highly contagious disease that causes important economic losses to the swine industry worldwide. Penicillins are extensively used in swine production and these antibiotics are associated with high systemic clearance and low oral bioavailability. This may expose A. pleuropneumoniae to sub-inhibitory concentrations of penicillin G when the antibiotic is administered orally. Our goal was to evaluate the effect of sub-minimum inhibitory concentration (MIC) of penicillin G on the biofilm formation of A. pleuropneumoniae. Biofilm production of 13 field isolates from serotypes 1, 5a, 7 and 15 was tested in the presence of sub-MIC of penicillin G using a polystyrene microtiter plate assay. Using microscopy techniques and enzymatic digestion, biofilm architecture and composition were also characterized after exposure to sub-MIC of penicillin G. Sub-MIC of penicillin G significantly induced biofilm formation of nine isolates. The penicillin G-induced biofilms contained more poly-N-acetyl-D-glucosamine (PGA), extracellular DNA and proteins when compared to control biofilms grown without penicillin G. Additionally, penicillin G-induced biofilms were sensitive to DNase which was not observed with the untreated controls. Furthermore, sub-MIC of penicillin G up-regulated the expression of pgaA, which encodes a protein involved in PGA synthesis, and the genes encoding the envelope-stress sensing two-component regulatory system CpxRA. In conclusion, sub-MICs of penicillin G significantly induce biofilm formation and this is likely the result of a cell envelope stress sensed by the CpxRA system resulting in an increased production of PGA and other matrix components.


A major surface antigen of procyclic stage Trypanosoma congolense.
Five monoclonal antibodies (mAb) were raised that bound to the surface of procyclic stage Trypanosoma congolense with high intensity in immunofluorescence. Immunoblot analysis of trypanosome lysates using 3 of these mAb revealed a diffuse SDS-PAGE band of 36-40 kDa. The purified antigen did not react with Coomassie Blue or silver stains, but did stain blue with Stains-all, indicating acidity. For the one mAb tested, the epitope was periodate-sensitive and therefore probably glycan. Although this antigen shares properties with procyclin/PARP, which forms a surface coat on procyclic Trypanosoma brucei, a search in T. congolense for homologues of a procyclin/PARP gene revealed only non-coding sequence of partial similarity. Using a differential screen, a procyclic stage T. congolense cDNA clone was isolated that encoded a putative 256-amino acid protein containing 2 peptides chemically sequenced independently by Beecroft et al. [36]. The protein, termed glutamate and alanine-rich protein (GARP), has potential hydrophobic leader and tail sequences (the latter with potential for replacement by a glycosyl phosphoinositol anchor) and no potential N-linked glycosylation sites. It has no significant sequence homology with known proteins. Antibodies against a translational fusion of GARP bound specifically in Western blots to a band very similar to that detected by the mAb and also to the purified antigen. Immunogold electron microscopy revealed a dense packing of the antigen on the cell surface. It appears that procyclic T. brucei and T. congolense have major surface proteins with structural analogy, but with no sequence homology.


UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug.
Protein-protein interactions play critical regulatory roles in mediating signal transduction. Previous studies have identified an unconventional, small-molecule, Src signal transduction inhibitor, UCS15A. UCS15A differed from conventional Src-inhibitors in that it did not alter the levels or the tyrosine kinase activity of Src. Our studies suggested that UCS15A exerted its Src-inhibitory effects by a novel mechanism that involved the disruption of protein-protein interactions mediated by Src. In the present study we have examined the ability of UCS15A to disrupt the interaction of Src-SH3 with Sam68, both in vivo and in vitro. This ability of UCS15A was not restricted to Src-SH3 mediated protein-protein interactions, since the drug was capable of disrupting the in vivo interactions of Sam68 with other SH3 domain containing proteins such as Grb2 and PLCgamma. In addition, UCS15A was capable of disrupting other typical SH3-mediated protein-protein interactions such as Grb2-Sos1, cortactin-ZO1, as well as atypical SH3-mediated protein-protein interactions such as Grb2-Gab1. However, UCS15A was unable to disrupt the non-SH3-mediated protein-protein interactions of beta-catenin, with E-cadherin and alpha-catenin. In addition, UCS15A had no effect on the SH2-mediated interaction between Grb2 and activated Epidermal Growth Factor receptor. Thus, the ability of UCS15A, to disrupt protein-protein interactions appeared to be restricted to SH3-mediated protein-protein interactions. In this regard, UCS15A represents the first example of a non-peptide, small molecule agent capable of disrupting SH3-mediated protein-protein interactions. In vitro analyses suggested that UCS15A did not bind to the SH3 domain itself but rather may interact directly with the target proline-rich domains.


[Efficacy of purine nucleotides on purinergic P2 platelet receptors by small angle light scattering].
The effect of purines on the activation and aggregation of thrombocytes in rats and rabbits was studied by the method of small-angle light scattering. The EC50 values of ADP, inducing the activation and aggregation of thrombocytes, reflect the sequence of the agonist action on various receptors: P2X1, 20-40 nM; P2Y1, 90-110 nM; P2YADP, 120-240 nM. It was demonstrated that ADP behaves as partial agonist not only with respect to P2X1 receptors, but with respect to P2Y1 receptors as well. Thrombocytes activated by 20 nM ADP or 100-nM ATP pass into a refracter state in the absence of further stimulation. The reaction halftime is tau 1/2 = 6.0 +/- 0.2 min for the cells activated with ADP and tau 1/2 = 16.5 +/- 0.2 min for ADP.


Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia.
Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clinicians in the twenty first century. Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus. Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fibrates), but these have low potency and limited selectivity for PPARα. Modulating the unique receptor-cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, offers a new therapeutic approach and provides the rationale for development of pemafibrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα). In clinical trials, pemafibrate either as monotherapy or as add-on to statin therapy was effective in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII. Pemafibrate also increased serum fibroblast growth factor 21, implicated in metabolic homeostasis. There were no clinically meaningful adverse effects on hepatic or renal function, including no relevant serum creatinine elevation. A major outcomes study, PROMINENT, will provide definitive evaluation of the role of pemafibrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy.


Effect of three anorectic drugs on central catecholamine levels and synthesis in the Zucker rat.
1. Genetically obese Zucker rats and their lean littermates were treated during 5 days with fenfluramine, mazindol or amphetamine. Norepinephrine and dopamine levels were assayed in the hypothalamus, striatum, medulla-oblongata pons and remainder of the brain, and the amine synthesis was estimated, when possible. 2. Fenfluramine acted especially on norepinephrine in the obese rat hypothalamus. 3. Mazindol was active on norepinephrine and dopamine levels only in obese animals. 4. Amphetamine acted on norepinephrine levels only in obese rats and on dopamine levels in both obese and lean rats.


[Resistance to Streptococcus pneumoniae to penicillin and its association with clinical and epidemiological factors].
Penicillin and third generation cephalosporin resistant pneumococcal isolates have emerged in Chile, mainly in the pediatric population. These isolates complicate therapeutic alternatives, specially among patients with central nervous system infections. To assess the frequency of penicillin and third generation cephalosporin resistance among isolates obtained from pediatric patients with invasive pneumococcal infections, and to study serotypes and clinical risk factors associated with resistance. Microbiological isolates obtained from children between April 1994 and May 1999 with pneumococcal invasive infections, were serotyped and analyzed according to their susceptibility to penicillin and cefotaxime by E-test and broth microdilution testing. Potential risk factors studied included patient's age, previous antibiotic use or admissions, comorbidity, and serotypes. Seventy eight patients were studied. Penicillin-resistant pneumococcal isolates were detected in 35.9% of cases (21.8% with intermediate and 14.1% with high level resistance) without significant variation among different clinical conditions. Most of the high level penicillin-resistant pneumoccocal isolates had MIC > or = 4 micrograms/mL (8 out of 11 strains). One third of penicillin-resistant isolates also expressed cefotaxime resistance. Multivariate analysis indicated an age < or = 36 months (OR = 6.8; IC 95%: 1.4 to 33.5) and serotype 14 (OR = 6.3; IC 95%: 1.7 to 23.3) as factors associated with penicillin resistance. One third of the invasive pneumococcal isolates obtained from pediatric patients were resistant to penicillin. Risk factors involved a younger age and pneumococcal isolates belonging to serotype 14.


National vaccination policies for health workers - A cross-sectional global overview.
Immunization is essential for safeguarding health workers from vaccine-preventable diseases (VPDs) that they may encounter at work; however, information about the prevalence and scope of national policies that protect health workers through vaccination is limited. Understanding the global landscape of health worker immunization programmes can help direct resources, assist decision-making and foster partnerships as nations consider strategies for increasing vaccination uptake among health workers. A one-time supplementary survey was distributed to World Health Organization (WHO) Member States using the WHO/United Nations Children's Fund (UNICEF) Joint Reporting Form on Immunization (JRF). Respondents described their 2020 national vaccination policies for health workers - detailing VPD policies and characterising technical and funding support, monitoring and evaluation activities and provisions for vaccinating health workers in emergencies. A total of 53 % (103/194) Member States responded and described health worker policies: 51 had a national policy for vaccinating health workers; 10 reported plans to introduce a national policy within 5 years; 20 had subnational/institutional policies; 22 had no policy for vaccinating health workers. Most national policies were integrated with occupational health and safety policies (67 %) and included public and private providers (82 %). Hepatitis B, seasonal influenza and measles were most frequently included in policies. Countries both with and without national vaccination policies reported monitoring and reporting vaccine uptake (43 countries), promoting vaccination (53 countries) and assessing vaccine demand, uptake or reasons for undervaccination (25 countries) among health workers. Mechanisms for introducing a vaccine for health workers in an emergency existed in 62 countries. National policies for vaccinating health workers were complex and context specific with regional and income-level variations. Opportunities exist for developing and strengthening national health worker immunization programmes. Existing health worker immunization programmes might provide a foothold on which broader health worker vaccination policies can be built and strengthened.


Magnitude of Antibody Cross-Reactivity in Medically Important Mosquito-Borne Flaviviruses: A Systematic Review.
Flaviviruses are a genus of enveloped single-stranded RNA viruses that include dengue virus (DENV), yellow fever virus, West Nile virus (WNV), Japanese encephalitis virus, and Zika virus. Nowadays, diverse serological assays are available to diagnose flaviviruses. However, infection with flaviviruses induces cross-reactive antibodies, which are a challenge for serological diagnosis. This systematic review aimed to assess the magnitude of medically important mosquito-borne flavivirus-induced antibody cross-reactivity and its influence on serological test outcomes. This study was designed based on the PRISMA guidelines. It includes original research articles published between 1994 and 2019 that reported serological cross-reactions between medically important mosquito-borne flaviviruses. Articles were searched on PubMed using controlled vocabulary. Eligibility was assessed by title, abstract, and finally by reading the full paper. The articles included are compared, evaluated, and summarized narratively. A total of 2,911 articles were identified, and finally 14 were included. About 15.4%-84% of antibodies produced against non-DENV flaviviruses were cross-reactive with DENV on different assays. Up to 30% IgM and up to 60% IgG antibodies produced against non-WNV flaviviruses were cross-reactive with WNV on EIA assays. The magnitude of antibodies produced against flaviviruses that are cross-reactive with chikungunya virus (Alphavirus) was minimal (only about 7%). The highest antibody cross-reactivity of flaviviruses was reported in IgG-based assays compared to IgM-based assays and assays based on E-specific immunoglobulin compared to NS1-specific immunoglobulin. It was found that preexisting immunity due to vaccination or prior flavivirus exposure to antigenetically related species enhanced the cross-reactive antibody titer. This review found the highest cross-reaction between DENV and non-DENV flaviviruses, especially yellow fever virus, and the least between chikungunya virus and DENV. Moreover, cross-reaction was higher on IgG assays than IgM ones and assays based on Eprotein compared to NS1protein. This implies that the reliability of serological test results in areas where more than one flavivirus exists is questionable. Therefore, interpretation of the existing serological assays should be undertaken with a great caution. Furthermore, research on novel diagnostic signatures for differential diagnosis of flaviviruses is needed.


Comparison of Oral and Intravenous Tranexamic Acid for Prevention of Perioperative Blood Loss in Total Knee and Total Hip Arthroplasty.
Tranexamic acid (TA) is an antifibrinolytic agent that prevents perioperative blood loss in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). This benefit has been established with the intravenous (IV) dosage form, but there is limited evidence evaluating oral TA in this setting. To compare the effect of oral versus IV TA on perioperative blood loss in those undergoing TKA or THA. In this single-centered retrospective chart review, participants at least 18 years of age who received IV or oral TA from a single surgeon who performed their THA or TKA were included. The primary outcome evaluated hemoglobin (Hgb) reduction. Power analysis determined that 165 participants were required in each group to achieve 80% power, with a noninferiority margin of 0.3 mg/dL. Both study groups included 165 participants. Oral TA was noninferior to IV TA (Hgb difference = -0.12 g/dL [95% CI = -0.28 to 0.05; P = 0.0250]). A subgroup analysis of THA and TKA revealed that oral TA was noninferior to IV TA in THA (Hgb difference = 0.24 g/dL [95% CI = -0.17 to 0.5]), but oral TA failed to meet the noninferiority margin in the TKA subgroup (Hgb difference = -0.20 [95% CI = -0.38 to -0.02]). This study provides evidence that oral TA is a clinically effective and cost-efficient alternative to IV TA in the setting of THA and TKA.


Construction of sandwich-structured CoAl-layered double hydroxide@zeolitic imidazolate framework-67 (CoAl-LDH@ZIF-67) hybrids: towards enhancing the fire safety of epoxy resins.
In this work, sandwich-like structured CoAl-LDH@ZIF-67 hybrids were constructed by in situ growth of nanosized ZIF-67 crystallites on CoAl-LDH nanoplates. The structure and morphology of CoAl-LDH@ZIF-67 hybrids were represented by X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and Transmission Electron Microscopy (TEM). Accordingly, the hybrids were introduced into epoxy resins to explore their effect on the thermal and fire safety properties of epoxy composites. With the introduction of 2% CoAl-LDH@ZIF-67 hybrids, the T 10%, T 50% and T max values were decreased to some extent and the char residue yield was higher than that of pristine epoxy. The peak heat release rate (PHRR) of epoxy composites declined by 26.4%, in comparison with those of pure epoxy. Moreover, the quantity of smoke produced, toxic CO released and CO2 produced were suppressed markedly and decreased by 16.7%, 59.8% and 32.2%, respectively. A possible mechanism for improving fire safety was put forward based on the analysis of the carbon residues.


Efficacy of Tamsulosin, Oxybutynin, and their combination in the control of double-j stent-related lower urinary tract symptoms.
Indwelling double J ureteral stents are used routinely in the resolution of ureteral obstruction caused by different etiologies. Evaluation of urinary symptoms related to double-J stent, indicate that these affect 73-90% of patients. We conducted a prospective, randomized study, to evaluate the efficacy of tamsulosin, oxybutinin and combination therapy in improving the urinary symptoms. Patients who underwent ureteral stent placement after ureterolithotripsy (total 51), were randomized into three groups: Group I: Tamsulosin 0.4 mg. Once per day(17 patients), Group II: Oxybutinin 5 mg. once per day (17 patients), Group III: Tamsulosin+ oxybutynin once per day (17 patients). All the groups received the drugs for three weeks and completed a Spanish validated Ureteral Stent Symptom Questionnaire (USSQ) at day 7 and 21. Repeated measures ANOVA showed mean urinary symptom index score was 22.3 vs. 15.5 in group three (p<0.001) at day 7 and 21 respectively. The mean work performance index was 6.6 vs 8.1 (p=0.049) favoring tamsulosin group, the mean sexual score was 0.5 vs 1.5 (p=0.03). Among additional problems the mean was 7.2 vs 6.2 (p=0.03). No significant difference was noted among pain and general health index. No side effects were reported. Combination therapy with tamsulosin and oxybutynin improved irritative symptoms and work performance as well as sexual matters. Combination therapy should be considered for patients who complained of stent related symptoms.


Mutational screening of ARX gene in Brazilian males with mental retardation of unknown etiology.
ARX gene mutations have been known as important causes of developmental and neurological disorders and are responsible for a large spectrum of abnormal phenotypes, includeing syndromic as well as nonsyndromic forms of mental retardation. We have screened the entire coding and flanking intronic sequences of ARX gene in 143 mentally impaired males in order to investigate the contribution of ARX mutations to mental retardation in the population of Rio de Janeiro, Brazil. Three sequence variants were identified: one patient had the most recurrent mutation already observed in ARX gene, the c.428_451dup(24 bp), two patients presented the c.1347C>T (p.G449G) in exon 4, and one patient had the intronic variant c.1074-3T>C. Although two of these alterations were considered polymorphisms, the known pathogenic variant c.428_451dup(24 bp) was found at a high rate (4.8%) among X-linked mental retardation (XLMR) families. Our results, the first in Latin America, reinforce the idea that ARX mutations are relevant to mental retardation and are indicative that molecular screening of exon 2 should be considered in males with mental retardation of unknown etiology, associated or not with neurological manifestations, especially in familial cases.


Procedural Benzodiazepine and Post-Vasectomy Opioid and Nonopioid Prescribing Variation in a Large Health Care System.
Our goal was to describe variation in procedural benzodiazepine and post-vasectomy nonopioid pain and opioid prescription dispense events, and multilevel factors associated with the probability of an opioid refill. Patients (40,584) undergoing vasectomies in the U.S. Military Health System between January 2016-January 2020 were included in this observational retrospective study. The main outcome was the probability of being dispensed an opioid prescription refill within 30 days post-vasectomy. Bivariate analyses examined the relationships between patient- and care-level characteristics, prescription dispense and 30-day opioid prescription refill. A generalized additive mixed-effects model and sensitivity analyses examined factors associated with opioid refill. There was wide variation in procedural benzodiazepine (32%) and post-vasectomy nonopioid (71%) and opioid (73%) prescription dispense patterns across facilities. Only 5% of the patients dispensed opioids received a refill. Probability of an opioid refill was associated with race (White), younger age, opioid dispense history, documented mental health or pain condition, lack of post-vasectomy nonopioid pain medication dispense events and higher dispensed post-vasectomy opioid prescription dose; albeit the effect of dose did not replicate in sensitivity analyses. Despite the wide variation in vasectomy-related pharmacological pathways across a large health care system, most patients do not require an opioid refill. Significant variation in prescribing practices indicated racial inequities. Given the low rates of opioid prescription refill, combined with the wide variation in opioid prescription dispense events and American Urological Association recommendations for conservative opioid prescribing after vasectomy, intervention to address excessive opioid prescribing is warranted.


Custom optical imaging system for ex-vivo breast cancer detection based on spectral signature.
Breast cancer is a popular well-known tumor in women globally and the subsequent driving reason for malignancy death. The purpose of the present study is to develop Low cost, commercial, and affordable system that discriminates malignant from normal breast tissues by exploiting the unique properties of Hyperspectral (HS) Imaging. The difference in the optical properties of the investigated breast tissues gives various reactions to light transmission, absorption, and especially the reflection over the spectral range. A custom optical imaging system (COIS) was designed to assess variable responses to monochromatic LEDs (415, 565, 660 nm) to highlight the differences in the reflectance properties of malignant/normal tissue. Statistical analysis was computed for determining the ideal wavelength to differentiate between normal and malignant regions. The experiment was repeated using the same LEDs, and low-cost CCD camera to examine the capability of such a system to discriminate between normal and malignant tissue. Spectral images obtained by Hyperspectral camera, have been analyzed to reveal the difference of reflectance malignant and normal breast tissue. Superficial spectral reflection image with blue LED (415 nm) showed high variance (10.11). However, a more-depth reflection image with red LED (660 nm) showed low variance (4.44). So the optimum contrast image was produced by combining the three spectral information images from blue, green, and red LED. The COIS using a commercial CCD camera was in agreement with the HS camera. The novel COIS of the commercial Low-cost CCD Camera is reliable and can be used with endoscopy technique as an assistant tool for surgical doctor to make decision and assess the resection edges in real time during surgery.


Immunologgical self-tolerance in allophenic and embryo-aggregated mice.
Allophenic mice, supposedly containing almost equal numbers of cells derived from embryos of mouse strains C57Bl and FVB, were shown in a recent paper to grow the B16 melanoma, a long transplanted tumor of C57Bl origin, much better than did mice of either the parental C57Bl strain or the C57Bl x FVB F1 hybrid. Mice containing smaller proportions of C57Bl cells rejected the tumor. A reconsideration of these suprising data, in light of the current literature, suggests that the better growth of the tumor in the 50-50% allophenics than in the C57Bl parental strain was almost certainly caused by the tumor stimulation engendered by a weak anti-C57Bl immune reaction in the overtly healthy allophenic mice.


Effects of food-cue exposure on dieting-related goals: a limitation to counteractive-control theory.
The present study investigated the effects of exposure to a food cue on the self-reported importance of dieting in those with low, medium, and high levels of dietary restraint. The results indicated that exposure to a food cue bolstered dieting-related goals in those who were low in dietary restraint but had no effect on the importance of dieting-related goals for those with medium or high levels of dietary restraint. The results demonstrate that exposure to temptations may differentially affect self-control processes depending on an individuals' level of dietary restraint.


Natural hybrid silica/protein superstructure at atomic resolution.
Formation of highly symmetric skeletal elements in demosponges, called spicules, follows a unique biomineralization mechanism in which polycondensation of an inherently disordered amorphous silica is guided by a highly ordered proteinaceous scaffold, the axial filament. The enzymatically active proteins, silicateins, are assembled into a slender hybrid silica/protein crystalline superstructure that directs the morphogenesis of the spicules. Furthermore, silicateins are known to catalyze the formation of a large variety of other technologically relevant organic and inorganic materials. However, despite the biological and biotechnological importance of this macromolecule, its tertiary structure was never determined. Here we report the atomic structure of silicatein and the entire mineral/organic hybrid assembly with a resolution of 2.4 Å. In this work, the serial X-ray crystallography method was successfully adopted to probe the 2-µm-thick filaments in situ, being embedded inside the skeletal elements. In combination with imaging and chemical analysis using high-resolution transmission electron microscopy, we provide detailed information on the enzymatic activity of silicatein, its crystallization, and the emergence of a functional three-dimensional silica/protein superstructure in vivo. Ultimately, we describe a naturally occurring mineral/protein crystalline assembly at atomic resolution.


Tackling of Immunorefractory Tumors by Targeting Alternative Immune Checkpoints.
Physiologically, well known or traditional immune checkpoints (ICs), such as CTLA-4 and PD-1, are in place to promote tolerance to self-antigens and prevent generation of autoimmunity. In cancer, the ICs are effectively engaged by the tumor cells or stromal ells from the tumor microenvironment through expression of cognate ligands for the ICs present on the cell surface of CD8+ T lymphocytes. The ligation of ICs on CD8+ T lymphocytes triggers inhibitory signaling pathways, leading to quiescence or an exhaustion of CD8+ T lymphocytes. This results in failure of immunotherapy. To overcome this, several FDA-approved therapeutic antibodies are available, but the clinical outcome is quite variable due to the resistance encountered through upregulated expression of alternate ICs such as VISTA, LAG-3, TIGIT and TIM-3. This review focuses on the roles played by the traditional as well as alternate ICs and the contribution of associated signaling pathways in generating such resistance to immunotherapy. Combinatorial targeting of traditional and alternate ICs might be beneficial for immune-refractory tumors.


Intelligent fault diagnosis of planetary gearbox based on refined composite hierarchical fuzzy entropy and random forest.
This paper presents a novel signal processing scheme by combining refined composite hierarchical fuzzy entropy (RCHFE) and random forest (RF) for fault diagnosis of planetary gearboxes. In this scheme, we propose a refined composite hierarchical analysis based method to improve the feature extraction performance of existing MFE and HFE methods. First, RCHFE is applied to extract the fault-induced information from the vibration signals. Because a refined composite analysis is used in HFF, the feature extraction capability of HFF can be effectively enhanced. Then, the extracted features are fed into the RF for effective fault pattern identification. The superiority of the proposed RCHFE-RF method is validated using both simulated and experimental signals. Results show that the proposed method outperforms MFE-RF and HFE-RF in identifying fault types of planetary gearboxes.


Sinking skin flap syndrome visualized by upright computed tomography.
Sinking skin flap syndrome is a craniectomy complication characterized by new neurological dysfunction that typically worsens in the upright position and improves after cranioplasty. We present a 33-year-old man who experienced hemiparesis in the upright position after craniectomy. Upright computed tomography (CT) before cranioplasty showed a remarkable shift of the brain compared to supine CT. After cranioplasty, both symptoms and brain shift on CT resolved. Upright CT enables detection and objective evaluation of paradoxical herniation and midline shift that is not obvious on supine imaging modalities. Clinicians need to be aware of positional brain shift in postcraniectomy patients.


Assessment of the Microbiological Potential for the Natural Attenuation of Petroleum Hydrocarbons in a Shallow Aquifer System.
Abstract A multidisciplinary field study investigating the fate and transport of petroleum hydrocarbons commonly associated with jet-fuel contamination is currently underway at Columbus Air Force Base (AFB), Mississippi. Sixty sediment cores from 12 boreholes were recovered from the study aquifer. The goal of this initial sampling was to characterize the potential microbial activity using 14C-labeled substrates, as well as the presence, abundance, and distribution of specific hydrocarbon degrading genotypes using DNA:DNA hybridization. Enumeration of total microbial abundance using a 16S rDNA universal oligonucleotide probe was compared to traditional enumeration methods. Total culturable populations determined by spread plate analysis ranged from a low of 10(4) to more than 10(6) organisms per gram sediment. Microbial abundance estimated by DNA hybridization studies with 16S rDNA genes ranged from 10(7) to 10(8) organisms per gram sediment. Molecular analysis of aquifer samples using DNA probes targeting genes encoding the degradative enzymes alkane hydroxylase (alkB), catechol 2,3-dioxygenase (nahH), naphthalene dioxygenase (nahA), toluene dioxygenase (todC1C2), toluene monooxygenase (tomA), and xylene monooxygenase (xylA), as well as two probes measuring methanogenic microorganisms, codh (carbon monoxide dehydrogenase) and mcr (methyl coenzyme reductase), revealed that each target gene sequence was present in nearly all 60 samples. The presence of organisms demonstrating the phenotype to degrade BTEX and naphthalene was further supported using mineralization assays with 14C-labeled benzene, toluene, naphthalene, and phenanthrene. Minimal activity occurred during the first 24 hours. After a period of 5-7 days, greater than 40% of the target compounds were mineralized in aquifer sediments.


Expression analysis of cadherins in the songbird brain: relationship to vocal system development.
Songbirds learn their songs as juveniles. The brains of songbirds have a series of nuclei and neural circuits called the song system, which is indispensable for vocal learning and production. In the present study we analyzed the expression patterns of cell adhesion molecules, cadherins, in the Bengalese finch (Lonchura striata var. domestica) to investigate their potential involvement in song nuclei and neural circuit formation. We found that cadherin-6B was expressed in many song nuclei of the juvenile and adult brain, while R-cadherin was complementarily expressed in surrounding areas. On the other hand, cadherin-7 was expressed in the robust nucleus of the arcopallium (RA) in the sensory learning stage, and its expression was downregulated during the sensorimotor learning stage. This downregulation of cadherin-7 was sexually dimorphic, suggesting its involvement in song development. Other cadherins, including cadherin-9, -10, and -12, showed different song-nuclei-related expression profiles. These patterns of song nuclei related expression suggest the possibility that cadherins are involved in the formation and maintenance of the song nuclei or neural pathways of the song system.


Dosimetric comparison of three different treatment techniques in extensive scalp lesion irradiation.
This study compared lateral photon/electron plan (3DCRT), intensity modulated radiation therapy (IMRT) plan, and high dose rate (HDR) brachytherapy plan for total scalp irradiation. The techniques were planned on a patient with squamous cell carcinoma of the scalp for a prescribed dose of 60 Gy. Conformity indexes and dose volume histograms were used for the comparison. Clinical target volume coverage factors for 3DCRT, IMRT, and HDR were 0.976, 0.998, and 0.967, and Conformation Numbers were 0.532, 0.713, and 0.761, respectively. The dose gradient across the target was 59-136%, 91-129%, and 58-242% for 3DCRT, IMRT, and HDR techniques, respectively. The 3DCRT and IMRT techniques produced low optical structure doses. 3DCRT produced hotspots in the brain, while IMRT produced brain sparing. HDR produced the highest integral doses to the brain and optical structures. IMRT provided the best target dose homogeneity and coverage, and delivered clinically acceptable doses to normal structures. HDR produced the most conformal plan, but the total dose delivered is limited by doses to the brain and eyes. HDR is a clinically feasible alternative for less extensive lesions, lower prescription doses, and for patients who cannot lie on the treatment table.


Bioinformatics Analyses of Spatial Peripheral Circadian Clock-Mediated Gene Expression of Glucocorticoid Receptor-Related Genes.
Glucocorticoids are ubiquitous, pleotropic steroid hormones secreted from the cortices of the adrenal glands in a circadian fashion under the strong influence of the central Clock center located in the suprachiasmatic nuclei (SCN) of the hypothalamus. In previous work, we reported that the circadian transcription factor CLOCK and its heterodimer partner BMAL1 suppress the transcriptional activity of the glucocorticoid receptor (GR) by acetylating a lysine cluster located in its hinge region between the DNA- and ligand-binding domains. This regulation of GR transcriptional activity by CLOCK/BMAL1 functions as a counter-regulatory loop against the diurnally fluctuating circulating glucocorticoids. Here, we have performed further analyses of our data using bioinformatics and computational methods. Gene expression data were analyzed using unsupervised machine learning methods, such as hierarchical clustering, k-means, Naïve Bayes classification, and polynomial regression analyses. We determined expression patterns of Clock-related genes, unraveled the dynamics of spatial data, and defined the temporal function of Clock-mediated GR-regulated genes. Gene expressions manifested nonlinear dynamics, possibly because we obtained dynamic results from stationary measurements. The mechanics of the circadian rhythms are still obscure, and more studies are required to understand how such rhythms influence mammalian physiology.


Correlation between plasma levels of radical scavengers and hearing threshold among elderly subjects with age-related hearing loss.
Low plasma melatonin is significant in the development of high frequency hearing loss (HL) among the elderly. To determine the correlation between hearing threshold and the plasma melatonin and ascorbic acid (vitamin C). This was a cross-sectional study involving 126 apparently healthy elderly subjects, 59 males and 67 females, aged >60 years. Subjects underwent pure tone audiometry and plasma melatonin and vitamin C were assayed using high-performance liquid chromatography. The mean ± SD of plasma melatonin among the subjects with normal hearing (NH) (0-30 dB) and those with HL in the speech frequencies was 18.3 ± 3.6 μg/L and 16.4 ± 4.7 μg/L, respectively. In the high frequencies the values were 17.7 ± 6.2 μg/L and 13.1 ± 6.4 μg/L for NH and HL, respectively. For vitamin C, the mean ± SD among subjects with NH and those with HL in the speech frequencies were 1.2 ± 0.2 μg/L and 1.0 ± 0.1 μg/L, respectively. In the high frequencies, the values were 1.0 ± 0.2 μg/L and 0.9 ± 0.3 μg/L for NH and HL, respectively. Among subjects with high frequency HL, Spearman's correlation revealed significant correlation between increasing hearing threshold and melatonin (correlation coefficient = -0.30, p = 0.01), but not for vitamin C (correlation coefficient = -0.12, p = 0.22). Linear regression, adjusting for age, still revealed significant correlation between the melatonin (correlation coefficient = -0.03, p = 0.00) and hearing threshold in the high frequencies.


Immune-related genes in tumor-specific CD4+ and CD8+ T cells in colon cancer.
Immune escape is an immunological mechanism underlying tumorigenesis, and T cells play an important role in this process. In this study, immune-related genes were evaluated in tumor-infiltrating CD4+ and CD8+ T cells in colon cancer. ESTIMATE was used to calculate stromal and immune scores for tumor datasets downloaded from The Cancer Genome Atlas-Colon Cancer (COAD). Differentially expressed genes (DEGs) between samples with high and low stromal and immune scores were screened, followed by a functional enrichment analysis of the overlapping DEGs. The DEGs related to CD4+ and the CD8+ T cells were then screened. Predicted miRNA-mRNA and lncRNA-miRNA pairs were used to construct a competing endogenous RNA (ceRNA) network. Furthermore, chemical-gene interactions were predicted for genes in the ceRNA network. Kaplan-Meier survival curves were also plotted. In total, 83 stromal-related DEGs (5 up-regulated and 78 down-regulated) and 1270 immune-related DEGs (807 up-regulated and 293 down-regulated genes) were detected. The 79 overlapping DEGs were enriched for 39 biological process terms. Furthermore, 79 CD4+ T cell-related genes and 8 CD8+ T cell-related genes, such as ELK3, were screened. Additionally, ADAD1 and DLG3, related to CD4+ T cells, were significantly associated with the prognosis of patients with colon cancer. The chr22-38_28785274-29,006,793.1-miR-106a-5p-DDHD1 and chr22-38_28785274-29,006,793.1-miR-4319-GRHL1 axes obtained from CD4+ and CD8+ T cell-related ceRNAs were identified as candidates for further studies. ELK3 is a candidate immune-related gene in colon cancer. The chr22-38_28785274-29,006,793.1-miR-106a-5p-DDHD1 and chr22-38_28785274-29,006,793.1-miR-4319-GRHL1 axes may be related to CD4+ and CD8+ T cell infiltration in colon cancer.


Ankle Strength Deficits in a Cohort of College Athletes With Chronic Ankle Instability.
Lateral ankle sprains commonly occur in an athletic population and can lead to chronic ankle instability. To compare ankle strength measurements in athletes who have mechanical laxity and report functional instability after a history of unilateral ankle sprains. Retrospective cohort. Athletic Training Research Lab. A total of 165 National Collegiate Athletic Association Division I athletes, 97 males and 68 females, with history of unilateral ankle sprains participated. Functional ankle instability was determined by Cumberland Ankle Instability Tool scores and mechanical ankle instability by the participant having both anterior and inversion/eversion laxity. Peak torque strength measures, concentric and eccentric, in 2 velocities were measured. Of the 165 participants, 24 subjects had both anterior and inversion/eversion laxity and 74 self-reported functional ankle instability on their injured ankle. The mechanical ankle instability group presented with significantly lower plantar flexion concentric strength at 30°/s (139.7 [43.7] N·m) (P = .01) and eversion concentric strength at 120°/s (14.8 [5.3] N·m) (P = .03) than the contralateral, uninjured ankle (166.3 [56.8] N·m, 17.4 [6.2] N·m, respectively). College athletes who present with mechanical laxity on a previously injured ankle exhibit plantar flexion and eversion strength deficits between ankles.


Survival of patients with primary pedal melanoma.
Malignant melanoma is increasing at a rate faster than any other cancer in the United States. Location of the primary tumor on the foot is associated with poorer prognosis. This study evaluates a cohort of 148 patients with melanoma of the lower extremity (37 foot or ankle and 111 leg, knee, or thigh) diagnosed at a university medical center during a 32-year period. The mean follow-up for the foot/ankle patients was 44 months. The overall 5-year survival rate was 52% for patients with a primary melanoma of the foot/ankle compared with 84% for patients with a primary melanoma elsewhere on the lower extremity. Although the study period extended over 32 years, nearly 65% of the foot/ankle patients were diagnosed in the last decade. This increase is most likely because of the documented increase in incidence of melanoma in the United States and an increasing referral pattern at our institution.


A nanoparticle composed of totally hospital-available drugs and isotope for fluorescence/SPECT dual-modal imaging-guided photothermal therapy to inhibit tumor metastasis.
As primary sites of tumor metastasis, sentinel lymph nodes (SLNs) require a highly biocompatible theranostic platform for precise localization and treatment to inhibit tumor metastasis. Herein, indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were fabricated by ICG-induced self-assembly and radiolabeled with technetuim-99 m (99mTc). The fabricated NPs were composed of hospital-available drugs and isotopes, making them highly biocompatible for in vivo applications. In a mouse model of SLN metastasis, the prepared NPs exhibited excellent capacity for preoperative planning by single-photon emission computed tomography (SPECT) imaging-enabled SLN localization, near-infrared fluorescence (NIRF) imaging-enabled intraoperative real-time monitoring, and SLN photothermal treatment. Photothermal treatment with SLN enhanced the inhibition of lung metastasis and significantly increased the survival time of mice. The prepared NPs were highly biocompatible and exhibited efficient theranostic properties for inhibiting cancer metastasis, making them promising candidates for clinical translation.


In Vivo Antioxidant Assays.
Oxidative stress and antioxidant deficiency have been implicated in the pathophysiology of a wide range of diseases and conditions. Consequently, over recent years many different supplementation trials have been implemented, aimed at improving clinical outcomes by boosting antioxidant levels. These trials included supplementation with individual antioxidants, antioxidant combinations, and antioxidant-rich foods such as fruit and vegetable juices and other plant extracts. To ensure that data from these trials are interpreted correctly, it is essential that suitable biomarkers are used to assess changes in in vivo antioxidant activity resulting from supplementation. Therefore, the measurement of antioxidant systems, such as superoxide dismutase, catalase, glutathione reductase, and status of other molecules in biological fluids with their quantification methods are simplified in this chapter.


A brief form of interpersonal psychotherapy for adult patients with bulimic disorders: a pilot study.
The aim of the study was to pilot a brief form of interpersonal psychotherapy (IPT) for the treatment of patients with bulimic disorders. Ten patients with bulimic disorder treated with a new brief version of IPT (IPT-BN10) completed measurements of eating disorders psychopathology (Eating Disorders Examination Questionnaire, Bulimic Investigatory Test Edinburgh) and depression (Beck Depression Inventory). The results were matched with a group of patients treated with conventional IPT and with waiting list control. Statistical differences were found between starting and ending of therapy for those patients treated with IPT-BN10. Statistical difference was also found when comparing with waiting list control. The pilot study suggests that IPT-BN10 may be an effective treatment for patients having bulimic disorders; however, this hypothesis needs to be tested in an experimental way.


[Leiomyosarcoma of the small intestine].
The authors present a case of leiomyosarcoma, a particular type of small intestine tumor. A review of the literature is also made.


Cranial CT revisited: do we really need contrast enhancement?
The aim of this study was to define guidelines for intravenous contrast administration in cranial CT, as currently there are no recent guidelines based on a large series of patients. In 1900 consecutive patients (1480 adults and 420 children) pre- and post-contrast scan was analysed in order to assess the contribution of contrast enhancement to the diagnosis. The findings were grouped according to whether abnormalities were seen on the pre- and/or post-contrast scan, or whether no abnormalities were seen at all. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of a pre-contrast scan were used to determine validity. Intravenous contrast enhancement only contributes to the diagnosis if a suspicious abnormality is seen on the unenhanced scan or in the appropriate clinical setting (33.6%). In the remaining patients (65.6%) there is no diagnostic contribution, except for a small number of abnormalities (0.8%). These are often anatomical variants and have no therapeutic impact. The number of contrast-enhanced cranial CT examinations can significantly be reduced by using four general guidelines for contrast administration resulting in considerable cost savings without affecting the quality of service to the patient. These guidelines are defined by the clinical findings/presentation or by the findings on the unenhanced scan. The number of contrast-related complications will be reduced, which may have medicolegal implications. These guidelines can be applied in any radiology department.


Patient adherence in renal replacement therapy: whose problem is it? The physician's perspective.
Patient compliance is an issue sadly neglected in the literature. Out of 470 scientific papers concerning dialysis published in 1996 only 4 (< 1%) addressed the subject. Doctors have an important role in the process leading to patient adherence, as they often see the patient on an outpatient basis for years before the start of dialysis and have an opportunity to prepare the patients for the forthcoming demands. Studies have shown that patients not seeing a Nephrologist before start of dialysis have a higher mortality and morbidity rate. The doctor has also an important role when informing the patient about the consequences of non-compliance. The aim should be to make the patient feel that he or she is a valuable member of the caring team.


Temporal pattern of alcohol dehydrogenase gene transcription reproduced by Drosophila stage-specific embryonic extracts.
Regulation of transcription during development has been analysed in vitro using extracts derived from Drosophila embryos. Transcription of mutant templates reveals cis-control regions of the alcohol dehydrogenase promoter responsible for temporal regulation. The activity of a trans-acting protein correlates with the profile of alcohol dehydrogenase expression during embryogenesis.


Nitrogen dynamics and carbon sequestration in soil following application of digestates from one- and two-step anaerobic digestion.
Anaerobic digestion (AD) is an important tool for reducing greenhouse gas emissions from agricultural production. A prolonged retention time by adding an extra anaerobic digestion step can be utilized to further degrade the digestates, contributing to increased nitrogen mineralisation and reducing decomposable organic matter. These modifications could influence the potential N fertiliser value of the digestate and soil carbon sequestration after field application. This study investigated the effects of prolonging retention time by implementing an additional anaerobic digestion step on carbon and nitrogen dynamics in the soil and soil carbon sequestration. Two digestates obtained from two biogas plants operating at contrasting hydraulic retention times, with and without an additional digestion step, were applied to a loamy sand soil. N mineralisation dynamics were measured during 80 days and C mineralisation during 212 days. After 80 days of incubation, the net inorganic N release from digestates obtained from a secondary AD step increased by 9-17 % (% of the N input) compared to corresponding digestates obtained from a primary AD step. A kinetic four-pool carbon model was used to fit C mineralisation data to estimate carbon sequestration in the soil. After 212 days of incubation, the net C mineralisation was highest in undigested solid biomass (68 %) and digestates obtained from the primary AD step (59-65 %). The model predicted that 26-54 % of C applied is sequestered in the soil in the long-term. The long-term soil C retention related to the C present before digestion was similar for one- and two-step AD at 12-16 %. We conclude that optimizing the anaerobic digestion configurations by including a secondary AD step could potentially replace more mineral N fertiliser due to an improved N fertiliser value of the resultant digestate without affecting carbon sequestration negatively.


Development of gait performance and dynamic hip and knee joint loading after containment improving surgery in patients with Legg-Calvé-Perthes disease.
Current surgery outcome evaluations in patients with Legg-Calvé-Perthes disease (LCPD) are usually based on static radiological changes. The aim of the present study was to assess the development of characteristic gait parameters and passive hip range of motion (ROM) measurements during the postoperative period up to healed stage of the femoral head represented by Stulberg classification. Twelve children (10 male, 2 female) with unilateral diagnosis of LCPD and 19 healthy control subjects at the same age participated in this prospective longitudinal study. Instrumented gait analysis was performed preoperatively, 13.4 (±1.7), and 28.0 (±4.4) months postoperatively. At final follow-up, the mean leg length of the involved side was reduced by 1.10 (±0.53)cm compared to the non-involved side. In addition, a significant reduction in maximum knee flexion (-26%, p=0.037) and knee flexion/extension ROM (-26%, p=0.017) in stance was still present in the patient group compared to controls indicating a "stiff knee gait pattern". In contrast, the sagittal plane hip parameters, the ipsilateral trunk lean toward the involved stance limb, and the knee and hip joint loading during gait normalized during the postoperative period. The results of the present study should motivate further exploration if patients with LCPD stiffen their knees to compensate for leg length discrepancy. Besides the standard radiological evaluation of the surgery outcome, instrumented gait analysis is a valuable method of recording functional deficits and early recognition of the need for physiotherapeutic treatment or insole supply in patients with LCPD.


Neuropeptide action on the guinea-pig bladder; a comparison with the effects of field stimulation and ATP.
A comparison was made between the effects of several neuropeptides and ATP as possible mediators of the non-adrenergic, non-cholinergic excitatory response in detrusor strips from the guinea-pig urinary bladder. Both substance P and vasoactive intestinal polypeptide produced contractions of the guinea-pig bladder, but the form of the atropine-resistant neurogenic excitation was mimicked more precisely by ATP. Neither methionine enkephalin nor leucine enkephalin had a prominent direct action on the smooth muscle (up to 100 microM) and did not significantly modify the cholinergic or non-cholinergic components of the response elicited by field stimulation. A proteolytic enzyme, chymotrypsin (10 U/ml), antagonised the excitatory effect of substance P, but not that of the non-adrenergic, non-cholinergic excitatory response or ATP. The slow excitation elicited by a high concentration of vasoactive intestinal polypeptide (10 microM), in contrast to responses elicited by ATP or field stimulation, was attenuated by preincubation with the structurally related polypeptide PHI, which was itself inactive (up to 10 microM). The present observations argue against a role for the peptides studied as neuromuscular transmitters in the detrusor but do not preclude such a role for ATP.


Implementation of a clinical pathway may improve alcohol treatment outcome.
This article describes the design, implementation, and evaluation of a clinical pathway system in a two-cohort quasi-experimental study before and after implementation, controlling for confounders. The main outcome measures were retention in care and sensible alcohol use (defined as abstinent or drinking no more than 21 standard drinks per week). Patients with harmful alcohol use or dependence as their primary problem who were seeking psychosocial treatment at one of four alcohol clinics in Denmark participated in the study. After implementation of the clinical pathway system, which incorporated a structured intake, a referral and independent follow-up system, checklists, audit, and feedback, there was no change in length of stay, but significantly more patients had a good clinical outcome (stopped or moderated their consumption) at the end of treatment (OR = 1.9; 1.2-3.1). The study documents the feasibility of using a clinical pathway framework, incorporating a local monitoring system, checklists, audit, and feedback to enhance treatment quality and improve outcomes for alcohol use disorders.


The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients.
To compare the effect of two saline nasal sprays on nasal patency and mucociliary clearance in patients with rhinosinusitis. Randomized double-blind trial. Eighty patients with rhinosinusitis at a tertiary care academic center had nasal patency and mucociliary clearance measured. Each patient was then treated with either physiological or hypertonic saline. Nasal patency and mucociliary clearance measurements were repeated after treatment. Subjective evaluation was also performed. Both solutions improved saccharine clearance times (P < 0.0001). Buffered physiological saline significantly affected nasal airway patency (P = 0.006). Both solutions improved symptoms of nasal stuffiness (P < 0.0001) and nasal obstruction (P < 0.0001). Buffered hypertonic saline caused increased nasal burning/irritation compared with buffered physiological saline (P < 0.0001). Buffered physiological and buffered hypertonic saline nasal sprays both improve mucociliary clearance, which is beneficial for treatment of rhinosinusitis. Additionally, buffered physiological saline improves nasal airway patency, whereas buffered hypertonic saline has no effect. Both solutions provide symptomatic relief, but buffered hypertonic saline is more irritating.


Cortical depth-dependent gradient-echo and spin-echo BOLD fMRI at 9.4T.
To examine cortical depth-related spatial specificity and signal changes in gradient-echo (GE) and spin-echo (SE) blood oxygenation level-dependent (BOLD) fMRI signals, a well-established cat visual stimulation model was used at 9.4T. The GE BOLD signal percent change is the highest at the surface of the cortex containing pial vessels, and decreases as cortical depth increases. In contrast, the SE BOLD signal is more specific to parenchyma, showing the highest signal change in the middle cortical areas. The stimulation-induced DeltaR2* to DeltaR2 ratio is dependent on the vessel size, which is related to basal susceptibility effects. The averaged ratio of DeltaR2* to DeltaR2 in all active regions, including large vessels, is 3.3 +/- 0.5 (N = 6). The averaged ratio of DeltaR2* to DeltaR2 is 8.8 +/- 1.7 (N = 4) on the surface of the cortex with large pial draining vessels, and decreases to 1.9 +/- 0.1 on the middle cortical areas with parenchymal microvessels. DeltaR2*/DeltaR2 is closely related to basal susceptibility effects and can be used to differentiate tissue from vessel regions.


Seroprevalence of anti-SARS-CoV-2 antibodies among children and their parents in Greece.
School closures were enforced as measures to restrain the COVID-19 pandemic, based on the assumption that young children may play a key role in SARS-CoV-2 spread. This study aims to determine the prevalence of SARS-CoV-2 IgG antibodies in children and corresponding parents, in order to improve surveillance and estimate the prevalence of asymptomatic or subclinical COVID-19 cases. A prospective multicenter study was conducted between March and June 2021 in Greece. Children admitted to the hospital or examined in outpatient clinics for reasons other than COVID-19 and their parents were tested for anti-Spike SARS-CoV-2 IgG in serum. A questionnaire about clinical and demographic data was completed. The study included 823 participants: 427 children and 396 corresponding parents. The overall seroprevalence was 16.4% in parents and 13.8% in children. Among families with ≥ 1 seropositive child or parent, the combination of a seropositive parent and a corresponding seronegative child was 29.6%, a seronegative parent and a corresponding seropositive child was 24.7%, and a seropositive child with a corresponding seropositive parent was 45.7%. Age, level of education, and school or work attendance were not significantly associated with increased seropositivity. On the contrary, ethnic minority of Roma, close contact with known COVID-19 case, previous symptoms consistent with COVID-19, and mass gatherings were risk factors for seropositivity. The spread of SARS-CoV-2 during a period of lockdown in Greece was low in children and comparable to adults most likely due to intrafamilial transmission. Accordingly, it is unlikely that children have boosted virus transmission. • In the earliest months of the pandemic, it was demonstrated that children had significantly lower seroprevalence rates than the older age groups, due to the fact that children had decreased exposure to the virus, because of early public health interventions, such as school and day care closure. • Later, further studies reported that children have similar incidence rate of SARS-CoV-2 infection compared to adults in households and community settings. • In this seroprevalence study, the spread of SARS-CoV-2 infection during a period of lockdown in Greece with the predominance of the Alpha-variant was particularly low in children and comparable to adults, most likely due to intrafamilial transmission. • These study findings will be useful for decisions regarding non-pharmaceutical interventions during the pandemic, and especially, to guide in designing and implementing appropriate containment measures for schools and social gatherings.


Exposure to polystyrene nanoplastics impairs lipid metabolism in human and murine macrophages in vitro.
The use of polystyrene micro and nanoplastics in cosmetics and personal care products continues to grow every day. The harmful effects of their biological accumulation in organisms of all trophic levels including humans have been reported by several studies. While we have accumulating evidence on the impact of nanoplastics on different organ systems in humans, only a handful of reports on the impact of polystyrene nanoplastics upon direct contact with the immune system at the cellular level are avialable. The present study offers significant evidence on the cell-specific harmful impact of sulfate-modified nanoplastics (S-NPs) on human macrophages. Here we report that exposure of human macrophages to S-NPs (100 µg/mL) stimulated the accumulation of lipids droplets (LDs) in the cytoplasm resulting in the differentiation of macrophages into foam cells. The observed effect was specific for human and murine macrophages but not for other cell types, especially human keratinocytes, liver, and lung cell models. Furthermore, we found that S-NPs mediated LDs accumulation in human macrophages was accompanied by acute mitochondrial oxidative stress. The accumulated LDs were further delivered and accumulated into lysosomes leading to impaired lysosomal clearance. In conclusion, our study reveals that exposure to polystyrene nanoplastics stabilized with anionic surfactants can be a potent stimulus for dysregulation of lipid metabolism and macrophage foam cell formation, a characteristic feature observed during atherosclerosis posing a serious threat to human health.


Career development among residents completing primary care and traditional residencies in medicine at the Boston City Hospital, 1974-1983.
A primary care (PC) pathway was initiated within the medical residency program at Boston City Hospital (BCH) in 1974. The authors studied the PC and traditional (TD) track graduates of the program to compare career development, goals, and practice patterns. The 185 graduates of the nine resident cohorts from 1974 through 1983 were surveyed; the overall response rate was 74%. Primary care careers have been chosen by 81% of PC graduates, compared with 38% of TD graduates (p less than 0.001); career satisfaction is equally high in the two groups. Among the PC graduates, 68% are practicing in high-need areas, compared with only 37% of TD graduates (p less than 0.001). PC graduates are more likely to make house calls, provide extended office hours, round in nursing homes or chronic care facilities, and co-practice with nurse practitioners or physician's assistants, and they are more active in women's health care, care of the terminally ill, and treating patients with sexual dysfunction (all p less than 0.05). PC graduates utilize various community agencies more frequently and supplement patient education with outside resources more intensively (p less than 0.001). The career choices and practice locations of PC graduates reflect the training goals of the PC curriculum and differ from the career choices and practices of the TD graduates from the same program.


A classification of lesions around interventricular foramen and its clinical value.
Lesions around interventricular foramen are difficult to remove for their important adjacent structures. We classify these tumors according their location on Magnetic Resonance Image (MRI) to help us resect these lesions. Thirty-two tumors around the interventricular foramen were studied according their location and anatomic relations in MRI. Tumors around interventricular foramen were classified into three types. The first one mainly locates in lateral ventricle and the second one growth both in lateral ventricle, interventricular foramen and third ventricle, while the third one mainly in third ventricle. Different surgical approaches were adopted according their classification and the patients recovered well. This classification can help us to chose the surgical approach for these tumors.


A "malignant" variant of status epilepticus.
Status epilepticus (SE) frequently does not respond to common first-line anticonvulsants. In a substantial portion of patients, administration of anticonvulsant anesthetics is inevitable. Even this aggressive approach fails to terminate SE in an undefined number of cases. We have coined the term malignant SE for this most severe variant of SE. To assess frequency, risk factors, and in-hospital outcome of malignant SE. Retrospective cohort study. Neurologic intensive care unit of a large university hospital. Patients Sample of 35 episodes of SE not responding to first-line anticonvulsants in 34 patients. Predictive and prognostic features of episodes of malignant SE with persistent epileptic activity after high-dose anesthetics compared with features of the remainder of cases with refractory SE and persistent epileptic activity after failure of first-line anticonvulsants. Status epilepticus that could not be controlled by first-line anticonvulsants resulted in malignant SE in 20% of cases. Patients with malignant SE were significantly younger than patients with refractory SE (P = .03). Encephalitis was identified as an independent risk factor for malignant SE (P = .008). Outcome in malignant SE was poor, with significantly longer duration of seizure activity (P<.001), longer stay in the neurologic intensive care unit (P<.001) and in the hospital (P = .007), and more patients with functional dependency at discharge from the hospital (P = .04). Malignant SE is not rare after failure of first-line anticonvulsants. The patient at risk is typically young and suffers from encephalitis. Such patients should be treated aggressively early in the course of SE to prevent malignant SE.


Social Support and Depressive Symptoms Among Men and Women With Same-Sex Experiences in Later Life.
Social support is a vital psychological health resource for well-being in later life. However, research on the associations of social support has largely excluded sexual minorities. This study compares the association between sources of social support and depressive symptoms across groups of older heterosexual and sexual minority men and women. Sexual minority status herein is based on self-reported sexual histories of having same-sex and opposite-sex only experiences (SSE and OSO). Based on a pooled cross-sectional data set drawn from 3 waves of the National Social Life, Health, and Aging Project, we used ordinary least squares regression and moderation tests to evaluate how 3 sources of social support-partner, family, friend-are related to depressive symptoms for SSE and OSO men and women. Results show OSO men and women both had significant negative associations between depressive symptoms and social support regardless of the source. SSE women, in contrast, only have a significant association between high levels of friend support, and SSE men only show significant effects in relation to high levels of partner support. These results suggest the effects of social support on psychological health are significantly constrained/circumscribed for sexual minority men and women. Interventions designed to decrease symptoms of depression in older sexual minorities through social support are discussed.


Colony size selection determines adult survival and dispersal preferences: allee effects in a colonial bird.
Avian coloniality traditionally has been investigated by examining how breeding success varies with colony size, but other crucial fitness components rarely have been examined. This may lead to wrong conclusions because unmeasured parameters may change the final fitness balance. We used multistate capture-recapture models to investigate adult survival and dispersal in relation to colony size within a long-term monitored population of lesser kestrels (Falco naumanni). Nest predation probability decreases with colony size, and adult survival is predicted to show the same trend because adults are exposed to the same suite of predators. As expected, survival probability was higher in large colonies (0.72+/-0.015; mean+/-SE) than in medium or small colonies (0.65+/-0.02). Additionally, dispersal probabilities were higher going from small to large colonies (0.20+/-0.01) than from large to small (0.08+/-0.01), as predicted by theory of habitat selection shaped by fitness maximization. These asymmetries are likely to generate size-specific colony population dynamics, so they should be taken into account in studies of colonial birds and other metapopulation-like systems. Allee effects, that is, positive density dependence, appear to be the cause of the evolution of dispersal behavior and may explain the maintenance of coloniality in this species.


Protein Kinase A activity is increased in mouse lumbar spinal cord but not brain following morphine antinociceptive tolerance for 15 days.
The present study investigated the effect of morphine antinociceptive tolerance on Protein Kinase A (PKA) activity in mouse brain (periaqueductal gray (PAG), thalamus, medulla) and lumbar spinal cord (LSC). A model was developed in which mice expressed a 21-fold level of morphine antinociceptive tolerance following implantation of a 75-mg morphine pellet for 15 days. Cytosolic and particulate PKA activity was measured directly in homogenates from the PAG, thalamus, medulla and LSC which studies have shown play a role in morphine-induced analgesia. In addition, a kinetic analysis of cytosolic and particulate PKA activity in homogenates from these regions was conducted and PKA V(max) and K(m) values were determined. Results demonstrated that chronic morphine treatment did not alter PKA activity or PKA kinetics in mouse brain. Moreover, particulate PKA activity/kinetics were not altered in LSC. However, cytosolic PKA activity was significantly increased in LSC following morphine treatment for 15 days. Furthermore, an increase in cytosolic PKA V(max) was observed in LSC. These results suggest that spinal and supraspinal PKA activity are differentially altered during morphine tolerance in mice. Thus, neurons in mouse brain and LSC that comprise the pain pathway descending from the brainstem and ending in the spinal cord respond differently to chronic morphine treatment.


Isoelectric focusing of human serum high density lipoprotein in the presence of radioactive ampholines.
Preparative isoelectric focusing of a serum high density lipoprotein fraction (rho 1.063-1.125 g/ml) in the presence of radioactive Ampholines showed that there were no significant 14-C-activity peaks in the lipoprotein region of the pH gradient. This suggests that the discrete lipoprotein subspecies obtained by electrofocusing are not artefacts caused by the binding of Ampholines to serum high density lipoprotein.


Pathogenesis of cystic fibrosis: possible importance of alteration in epithelial surface topography.
As the pathogenesis in cystic fibrosis (CF) has been considered to lie in a disturbance in the behavior of secretions, particularly mucins, from exocrine glands, it has been proposed that an alteration in surface topography (form, number or distribution of microvilli or blebs) of epithelial cells lining ducts could impair distribution leading to retention of mucus leading to the clinical phenotype. Scanning electronmicroscopy of human epithelial suspension cultures now offers an opportunity to evaluate the role of plasmalemma topography in CF.


Hemoglobin-oxygen-carbon monoxide equilibria with the MWC model.
Fractional saturation equations for the Monod, Wyman and Changeux model are derived for the case of two distinct ligands bonding to a host molecule with four ligand sites and two conformational states. A variety of useful graphical studies can be derived from these equations when applied to normal human hemoglobin with O2 and CO as ligands. For example, the oxygen transport capability of hemoglobin can be assessed at different environmental CO levels and the concentrations of various liganded species can be displayed as a function of fractional saturation with oxygen. In addition, the CO pressure in the tissue, PCOtissue, can be calculated as a function of the tissue oxygen pressure, PO2tissue, at different environmental levels of CO. In an environment of a given CO concentration, PCOtissue decreases with PO2tissue until a minimum is reached. Further decrease in PO2tissue results in a fairly steep rise in PCOtissue.


Ethics and cloning.
Scientists have cloned animals since the late 19th century, but the crucial step for ethics was the cloning of the first mammal by somatic cell nuclear transfer in 1997. This suggested that scientists could also clone, and possibly enhance, human beings. This survey examines ethical literature on cloning since the 1960s. The one ethical area of agreement in this issue is that we should not try to create new human beings by somatic cell nuclear transfer now. Ethicists disagree, however, on what justifies this norm. Some appeal to preference satisfaction and freedom from external constraints, others question this approach by more profound religious and moral considerations. The discussion is currently not progressing, as the same arguments have been in use since the 1970s. Philosophers should prepare deeper analyses of the presuppositions of the ethical arguments used in the discussion before the issue surfaces again.


How sleep disturbances affect internet gaming disorder: The mediating effect of hippocampal functional connectivity.
Studies have revealed that sleep disturbances lead to an increased risk of Internet gaming disorder (IGD). However, the neural underpinnings of this feature remain unknown. Exploring this issue would be valuable in understanding the relationship between sleep and psychiatric disorders. Given the impact of sleep on reward circuitry, we examined nucleus accumbens (NAcc) and hippocampal resting-state functional connectivity (rsFC) differences between 41 IGD subjects and 59 healthy controls. Significant connections were determined and used to examine correlations with clinical variables. Finally, we explored the relationship between neuroimaging findings, IGD severity and sleep disturbances through a mediation model. We observed the connection deviation between the hippocampus and a wide range of cerebral cortexes in IGD subjects, including the prefrontal, parietal and temporal lobes. More importantly, the right posterior hippocampus (pHIP)-left caudate rsFC was positively correlated with both the Pittsburgh Sleep Quality Index (PSQI) and Internet Addiction Test scores and mediated the relationship between the two. For the NAcc, a difference between groups was only observed in the rsFC between the shell partition of the NAcc and the inferior orbitofrontal cortex, but this connectivity was not related to the PSQI score. IGD subjects showed a wide range of abnormal connections in the hippocampus, involving memory, reward motivation, and cognitive control. Here we emphasized the potential of the hippocampus in studying sleep disturbances in IGD, especially the coupling between the pHIP and caudate nucleus, which could provide novel insight into how sleep interacts with motivational systems in IGD subjects.


Evaluation of VP2 epitopes of infectious bursal disease virus using in vitro expression and radioimmunoprecipitation.
A clone (pV 17-7) spanning a portion of the VP2 gene of infectious bursal disease virus (IBDV) was selected from a cDNA library produced using the variant A virus strain. This clone was expressed in vitro and the protein products were immunoprecipitated with various virus-neutralizing antisera made against 6 different strains of IBDV. The antisera made against 4 variant strains immunoprecipitated the translation products from the pV 17-7 clone, but the antisera to the classic STC virus and the serotype 2 OH virus did not immunoprecipitate the pV 17-7 translation products.


Flexible, high-resolution cortical arrays with large coverage capture microscale high-frequency oscillations in patients with epilepsy.
Effective surgical treatment of drug-resistant epilepsy depends on accurate localization of the epileptogenic zone (EZ). High-frequency oscillations (HFOs) are potential biomarkers of the EZ. Previous research has shown that HFOs often occur within submillimeter areas of brain tissue and that the coarse spatial sampling of clinical intracranial electrode arrays may limit the accurate capture of HFO activity. In this study, we sought to characterize microscale HFO activity captured on thin, flexible microelectrocorticographic (μECoG) arrays, which provide high spatial resolution over large cortical surface areas. We used novel liquid crystal polymer thin-film μECoG arrays (.76-1.72-mm intercontact spacing) to capture HFOs in eight intraoperative recordings from seven patients with epilepsy. We identified ripple (80-250 Hz) and fast ripple (250-600 Hz) HFOs using a common energy thresholding detection algorithm along with two stages of artifact rejection. We visualized microscale subregions of HFO activity using spatial maps of HFO rate, signal-to-noise ratio, and mean peak frequency. We quantified the spatial extent of HFO events by measuring covariance between detected HFOs and surrounding activity. We also compared HFO detection rates on microcontacts to simulated macrocontacts by spatially averaging data. We found visually delineable subregions of elevated HFO activity within each μECoG recording. Forty-seven percent of HFOs occurred on single 200-μm-diameter recording contacts, with minimal high-frequency activity on surrounding contacts. Other HFO events occurred across multiple contacts simultaneously, with covarying activity most often limited to a .95-mm radius. Through spatial averaging, we estimated that macrocontacts with 2-3-mm diameter would only capture 44% of the HFOs detected in our μECoG recordings. These results demonstrate that thin-film microcontact surface arrays with both highresolution and large coverage accurately capture microscale HFO activity and may improve the utility of HFOs to localize the EZ for treatment of drug-resistant epilepsy.


What is required to evaluate the impact of pharmaceutical reference pricing?
To describe empirical studies evaluating the impact of reference pricing (RP) interventions in pharmaceutical markets in order to discuss the requirements for these evaluations. Ten studies were included in this review. For each study, the nature of the intervention, the nature of the data available, the nature of the question to be answered and the requirements of the evaluation method were examined through a questionnaire. The most frequently used evaluation method was the conventional before-after estimator, and only three studies used the difference-in-differences method. Nine studies evaluated a therapeutic RP system and one evaluated a generic RP system. All of the papers reported how the reference price level was established, but only one study directly reported the updating frequency and criteria of the RP system. In four studies, details of simultaneous interventions were not reported. There is no paper providing evidence on overall social welfare impact. Four papers estimated the impact of intervention on the consumer price of drugs covered by the RP system. Only one provided information about the impact on the price of related drugs not covered by the system. Three studies included an outcome variable for the use of health services. The impact of RP intervention on the level of competition in the market for those medicines covered by the system was reported in only three of ten papers. Despite the rigorous effort made to evaluate the impact of RP policies in some countries, several limitations may affect both their internal validity (the nature of the data available, statistical problems common to non-experimental data, etc.) and their external validity (heterogeneity in the nature of the intervention).


Getting paid less for more: shoulder arthroplasty incidence and reimbursement within Medicare from 2000 to 2019.
Shoulder arthroplasty has grown in popularity in the past 2 decades, especially following US Food and Drug Administration approval of reverse total shoulder arthroplasty (TSA) in 2003. Studies have shown that Medicare reimbursement for a variety of orthopedic procedures has decreased significantly over the past 2 decades. No study has evaluated this trend in the setting of shoulder arthroplasty, however. The purpose of this study was to assess true reimbursement trends in primary and revision shoulder arthroplasty since 2000. Information was collected from the publicly available Medicare Part B National Summary Data Files for the period of 2000 to 2019. Data from Current Procedural Terminology codes 23470 (shoulder hemiarthroplasty), 23472 (TSA), 23473 (single-component revision shoulder arthroplasty), and 23474 (both-component revision shoulder arthroplasty) were analyzed. Reimbursement amounts were adjusted for inflation to May 2021 dollars. From 2000 to 2019, the number of shoulder hemiarthroplasty procedures billed to Medicare decreased 70% (from 5847 to 1750) whereas the number of TSA procedures increased 1527% (from 4044 to 65,477). During the same period, per-procedure Medicare reimbursement for hemiarthroplasty decreased 35% (from $1545.71 to $1003.43) after adjustment for inflation to 2021 dollars. Similarly, TSA reimbursement decreased 22% (from $1600.98 to $1248.76) after adjustment for inflation. For revision procedures, the number of single- and both-component revisions billed to Medicare increased 381% (from 344 to 1655) and 1331% (from 220 to 3147), respectively. Adjusted reimbursement per procedure decreased 36% (from $1931.62 to $1244.49) and 37% (from $2293.08 to $1449.43), respectively. This study shows an increase in the annual volume of primary and revision shoulder arthroplasty procedures from 2000 to 2019. During the same period (2000-2019), true Medicare reimbursement to physicians for TSA decreased when adjusted for inflation. This study provides data that may be useful for surgeons, hospitals, and policy makers to maintain access to quality shoulder arthroplasty care moving forward.


Exogenous leukaemia inhibitory factor enhances nerve regeneration after late secondary repair using a bioartificial nerve conduit.
The clinical outcome of peripheral nerve injuries remains disappointing, even in the ideal situation of a primary repair performed with optimal microsurgical techniques. Primary repair is appropriate for only about 85% of injuries, and outcome is worse following secondary nerve repair, partly owing to the reduced regenerative potential of chronically axotomised neurons. Leukaemia inhibitory factor (LIF) is a gp-130 neurocytokine that is thought to act as an 'injury factor', triggering the early-injury phenotype within neurons and potentially boosting their regenerative potential after secondary nerve repair. At 2-4 months after sciatic nerve axotomy in the rat, 1 cm gaps were repaired using either nerve isografts or poly-3-hydroxybutyrate conduits containing a calcium alginate and fibronectin hydrogel. Regeneration was determined by quantitative immunohistochemistry 6 weeks after repair, and the effect of incorporating recombinant LIF (100 ng/ml) into the conduits was assessed. LIF increased the regeneration distance in repairs performed after both 2 months (69%, P=0.019) and 4 months (123%, P=0.021), and was statistically comparable to nerve graft. The total area of axonal immunostaining increased by 21% (P>0.05) and 63% (P>0.05), respectively. Percentage immunostaining area was not increased in the 2 months group, but increased by 93% in the repairs performed 4 months after axotomy. Exogenous LIF, therefore, has a potential role in promoting peripheral nerve regeneration after secondary repair, and can be effectively delivered within poly-3-hydroxybutyrate bioartificial conduits used for nerve repair.


Aortic rupture in a child diagnosed by cross-sectional echocardiography.
We report the first case of a child with an aortic rupture into the pericardial cavity secondary to a dissecting aneurysm developing in the context of aortic coarctation. The combination was diagnosed by cross-sectional echocardiography.


Case Series Describing the Use of Low-Temperature Vacuum-Dehydrated Amnion (Omnigen) for the Treatment of Corneal Ulcers in Cats and Dogs: 46 Cases (2016-2017).
Amniotic membrane is widely used in the treatment of ocular surface disorders in human and veterinary patients. Preservation and storage of amnion has proven challenging, prompting the development of new preservation techniques. Omnigen, a novel low-temperature vacuum-dehydrated amnion, is reported to possess enhanced structural properties and biochemical stability in vitro, but its clinical use in veterinary patients is not well described. This study aims to document and describe the varied use of Omnigen for the surgical treatment of corneal ulceration in cats and dogs. A total of 45 patients (46 eyes) were recruited from the clinical record system of the Royal Veterinary College (London) between January 2016 and December 2017. Brachycephalic breeds were over-represented (37/45; 82.2%). Omnigen was used as a standalone graft in 5/46 (10.9%) eyes, as a supplementary graft in 29/46 (63.0%) eyes and as a patch in 12/46 (26.1%) eyes. Graft failure occurred in 10/46 eyes (21.7%). At final examination 43/46 eyes (93.5%) had healed and 31/33 eyes (93.9%) were visual. This study demonstrates the successful use of Omnigen for the surgical treatment of corneal ulceration in cats and dogs. Further studies are needed to clarify its properties and benefits in the clinical field.


Intrafascicular peripheral nerve stimulation produces fine functional hand movements in primates.
Restoring dexterous hand control is critical for people with paralysis. Approaches based on surface or intramuscular stimulation provide limited finger control, generate insufficient force to recover functional movements, and require numerous electrodes. Here, we show that intrafascicular peripheral electrodes could produce functional grasps and sustained forces in three monkeys. We designed an intrafascicular implantable electrode targeting the motor fibers of the median and radial nerves. Our interface selectively and reliably activated extrinsic and intrinsic hand muscles, generating multiple functional grips, hand opening, and sustained contraction forces for up to 2 months. We extended those results to a behaving monkey with transient hand paralysis and used intracortical signals to control simple stimulation protocols that enabled this animal to perform a functional grasping task. Our findings show that just two intrafascicular electrodes can generate a rich portfolio of dexterous and functional hand movements with important implications for clinical applicability.


Point-of-care sural nerve conduction could predict the presence of cardiovascular autonomic neuropathy in type 1 diabetes mellitus.
Assessment for cardiovascular autonomic neuropathy (CAN) in patients with type 1 diabetes mellitus remains time-consuming in the clinical setting. We aimed to examine the diagnostic performance of a portable point-of-care diagnostic tool (POCD) for assessing sural nerve conduction during the screening of CAN. Nerve amplitude (AMPPOCD ) and conduction velocity (CVPOCD ) were measured in a cross-sectional study including 198 asymptomatic patients with type 1 diabetes. CAN was diagnosed by the Ewing score and power spectral heart rate [low-frequency (LF) and high-frequency (HF) activity]. Diagnostic accuracy was determined by ROC curves. CVPOCD and AMPPOCD showed positive correlations with LF and HF, and a negative correlation with age. Overall, AMPPOCD had an 81.7% accuracy in identifying CAN [AUC = 0.817 (95% CI 0.692-0.942)] with an AMPPOCD ≤6 μV showing 90% sensitivity and 73% specificity. In a stepwise binary logistic regression analysis, the model (R2 : 0.297; P < 0.001) retained the duration of type 1 diabetes [β: 1.131 (95% CI: 1.051-1.216); P = 0.001) and A1c [β: 2.131 (95% CI: 1.060-4.283); P = 0.034) as significant predictors of CAN. The combination of AMPPOCD ≤6 μV + a type 1 diabetes duration of ≥8 years maximized the sensitivity, showing a diagnostic performance of 87% [AUC = 0.867 (95% CI 0.769-0.965)] with 90%, 76%, and 99%, sensitivity, specificity, and NPV, respectively. Adding A1c ≥ 7% to this model maintained accuracy [AUC = 0.867 (95% CI: 0.788-0.963) and NPV (99%), while increasing specificity to 84%. The combination of AMPPOCD with A1c and the duration of type 1 diabetes mellitus showed a good performance for the detection of asymptomatic CAN, making POCD an easy and rapid test for its routine screening in the clinical setting.


Using motivational interviewing combined with digital shoe-fitting to improve adherence to wearing orthopedic shoes in people with diabetes at risk of foot ulceration: study protocol for a cluster-randomized controlled trial.
Diabetic foot ulcers have a high impact on mobility and daily functioning and lead to high treatment costs, for example, by hospitalization and amputation. To prevent (re)ulcerations, custom-made orthopedic shoes are considered essential. However, adherence to wearing the orthopedic shoes is low, and improving adherence was not successful in the past. We propose a novel care approach that combines motivational interviewing (MI) with a digital shoe-fitting procedure to improve adherence to orthopedic shoes. The aim of this trial is to assess the (cost-)effectiveness of this novel care approach compared to usual care (no MI and casting-based shoe-fitting) in promoting footwear adherence and ulcer prevention. The trial will include people with diabetes, with IWGDF Risk categories 1-3, who have been prescribed orthopedic shoes. Participants will be randomized at the level of the podiatrist to the novel care approach or usual care. The primary outcome is the proportion of participants who adhere to the use of their orthopedic shoes, that is, who take at least 80% of their total daily steps with orthopedic shoes. A temperature microsensor will be built into the participants' orthopedic shoes to measure wearing time continuously over 12 months. In addition, daily activity will be measured periodically using log data with an activity monitor. Data from the temperature microsensor and activity monitor will be combined to calculate adherence. (Re-)experienced complications after receiving orthopedic shoes will be registered. Questionnaires and interviews will measure the experiences of participants regarding orthopedic shoes, experiences of podiatrists regarding motivational interviewing, care consumption, and quality of life. Differences in costs and quality of life will be determined in a cost-effectiveness analysis. This trial will generate novel insights into the socio-economic and well-being impact and the clinical effectiveness of the novel care approach on adherence to wearing orthopedic shoes. Netherlands Trial Register NL7710 . Registered on 6 May 2019.


Seasonal changes of heavy metals and health risk assessment based on Monte Carlo simulation in alternate water sources of the Xinbian River in Suzhou City, Huaibei Plain, China.
The urban alternate water source (AWS) is of great significance to the sustainable development of the city, the pollution degree, and source of heavy metals (HMs) in AWS, and whether it will adversely affect human health has received widespread attention. In this study, the urban AWS of Xinbian River in Suzhou City, Huaibei Plain, China, was used as the research object to study the seasonal changes of HMs (As, Cr, Cu, Cd, Pb, and Zn), quantitative identification of pollution sources, and human health risks (HHR). Research results show that the contents of those HMs, except As, are less than the drinking standards limit set by the World Health Organization (WHO), and the contents of As, Cr, and Zn are the largest in summer. The multivariate statistical analysis combined with positive matrix factorization (PMF) model analysis revealed that industrial sources accounted for 44.83%, and agricultural sources accounted for 55.17%. HHR assessment based on Monte Carlo simulation shows that the noncarcinogenic risks of adults and children are in the acceptable range (hazardous ingestion (HI) < 1), and the probability of carcinogenic risk values of children and adults are 95.03% and 38.96%, respectively, which are exceed the acceptable range (1 × 10-4) recommended by the United States Environment Protection Agency (USEPA). Approximately 30.75% of the carcinogenic risk value of agricultural source HMs to children exceeds the acceptable range (1 × 10-4). The above research results indicate that the effect of agricultural non-point source pollution on AWS should be prevented.


Prevalence, risk factors and molecular characterization of Enterocytozoon bieneusi in raccoon dogs (Nyctereutes procyonoides) in five provinces of Northern China.
The disease microsporidiosis is found worldwide and is mainly caused by Enterocytozoon bieneusi. E. bieneusi can infect a wide range of hosts; however, information regarding the prevalence and genotyping of E. bieneusi infection in raccoon dogs (Nyctereutes procyonoides) is limited. Therefore, in 2015, we examined 305 faecel samples from 80 farmed raccoon dogs in Jilin Province, from 54 in Hebei Province, from 72 in Liaoning Province, from 29 in Shandong Province, and from 40 in Heilongjiang Province. The overall prevalence of E. bieneusi infection in farmed raccoon dogs was 22.30%. Logistic regression analysis suggests that age, gender and region of raccoon dogs were highly related to the prevalence of E. bieneusi infection. Moreover, six E. bieneusi internal transcribed spacer (ITS) region sequences, including four known genotypes, namely D, CHN-DC1, NCF2, and CHN-F1, and two novel genotypes (NCR1 and NCR2), were identified in the present study. The present study firstly indicated the existence of E. bieneusi genotypes NCF2, NCR1, NCR2and CHN-F1 in infected raccoon dogs in Northern China. Integrated control strategies should be implemented to limit E. bieneusi infection in farmed raccoon dogs, and to prevent transmission of this disease to other animals and humans.