Complete Genome Sequence of the Arcobacter skirrowii Type Strain LMG 6621.
Arcobacter skirrowii is a species of veterinary importance, originally recovered from the feces, aborted fetuses, and preputial fluids of livestock. We present here the whole-genome sequence of the A. skirrowii type strain LMG 6621 (= 449/80T = CCUG 10374T), isolated in the United Kingdom from a lamb diarrheal fecal sample.


[Cerebrospinal fluid diagnostics for neuroinfectious diseases].
Cerebrospinal fluid analysis is of prime importance to establish an early diagnosis of central nervous system infections. Beside the basic diagnostics containing CSF white cell count, lactate concentration and protein analysis, the targeted search for agents of bacterial, viral or fungal CNS infectious diseases is essential. Decisive methods are bacterial and fungal staining techniques, microbiological culture methods, nucleic acid amplification and antigen detection methods or indirect identification of pathogens by serologic testings including the determination of pathogen-specific intrathecal immunoglobulin synthesis. Besides imparting basic principles of cerebrospinal fluid analysis, this article focuses on special aspects of detection of infectious agents. Well-directed questions and a close communication between clinician and laboratory allow optimal diagnostic analysis for successful confirmation of the diagnosis and for optimal treatment of the patient.


Exploring the construct validity of the Patient Perception Measure - Osteopathy (PPM-O) using classical test theory and Rasch analysis.
Evaluation of patients' experience of their osteopathic treatment has recently been investigated leading to the development of the Patient Perception Measure - Osteopathy (PPM-O). The aim of the study was to investigate the construct validity of the PPM-O. Patients presenting to osteopathy student-led teaching clinics at two Australian universities were asked to complete two questionnaires after their treatment: a demographic questionnaire and the PPM-O. Confirmatory factor analysis (CFA) and Rasch analysis were used to investigate the construct validity of the PPM-O. Data from the present study did not fit the a-priori 6-domain structure in the CFA. Modifications to the 6-domain model were then made based on the CFA results, and this analysis identified two factors: 1) Education & Information (9 items); and 2) Cognition & Fatigue (6 items). These two factors were Rasch analysed individually. Two items were removed from the Cognition & Fatigue factor during the analysis. The two factors independently were unidimensional. The study produced a 2-factor, 13-item questionnaire that assesses the patients' perception of their osteopathic treatment using the items from a previous questionnaire. The results of the current study provide evidence for the construct validity of the PPM-O and the small number of items makes it feasible to implement into both clinical and research settings. Further research is now required to establish the measures' validity in a variety of patient populations.


Community rheumatology practice in Thunder Bay: a Canadian experience from northwestern Ontario.
The practice experience of a rheumatologist in Thunder Bay, within the well-defined, relatively isolated area of Northwestern Ontario, is described. The population base of approximately 200,000 results in a waiting period for elective consultations of 3 months. (The number of other consultants for musculoskeletal problems in the community compares favorably with national and provincial ratios.) The majority of patients had well-defined rheumatic diseases. Nonarticular rheumatism comprised a relatively small proportion of visits. A ratio of 1 rheumatologist: 100,000 population would seem to be a realistic one.


Lateral Lumbar Interbody Fusion within Three-level for Patients with Neurological Symptoms due to Vertebral Fragility Fractures in the Lumbar Spine.
There is a lack of agreement on whether minimally invasive lateral lumbar intervertebral fusion (LLIF) is a suitable treatment option for vertebral fragility fractures (VFFs). Hence, we sought to evaluate the efficacy and safety of LLIF in the management of VFF with neurological deficits in the lumbar spine. Between April 2015 and March 2020, we conducted a retrospective observational study of patients with VFF treated with three-level or less LLIF. The participants had previously received conservative treatment but had not been able to control their neurological symptoms. To assess the outcomes of the LLIF procedures, the patients were followed up for a minimum of 1 year. Clinical and radiological results, which include the timing and location of the bony fusion, were analyzed. The study involved 19 patients with 23 vertebral fracture levels. The residual height of the fractured vertebra was found to be 57.0 ± 12.3% of the height of the adjacent level. The mean Japanese Orthopedic Association score significantly improved postoperatively. Postoperative radiological parameters were significantly maintained at 1 year, and lumbar lordosis was maintained at the last follow-up (45.0 ± 26.7). In total 31 LLIF levels, bone fusion was observed in four levels at 6 months postoperatively, in 16 levels at 1 year, and in 23 levels at the last follow-up. The facet joint had the highest bony fusion location. LLIF within three levels can be safely performed in certain VFF cases with sufficient residual vertebral height.


[Identification of species of Diplogonoporus balaenopterae and D. grandis (Cestoda, Diphyllobothriidae)].
Comparative study of diplogonadal diphillobothriids from different species of whalebone whales and from man (Japan) and analysis of literary data has made it possible to establish their identity. Only the species Diplogonoporus balaenopterae (Lönnberg, 1892 capable of infecting whalebone whales, dogs and man can be regarded as really existing. The species D. grandis (Blanchard, 1894) Lühe, 1899 is its synonym.


An efficient signal-on aptamer-based biosensor for adenosine triphosphate detection using graphene oxide both as an electrochemical and electrochemiluminescence signal indicator.
An efficient aptasensor was developed in which graphene oxide (GO) was employed as an indicator for both electrochemical impedance spectroscopy and electrochemiluminescence (ECL) signal generation. The aptasensor was fabricated by self-assembling the ECL probe of a thiolated adenosine triphosphate binding aptamer (ABA) tagged with a Ru complex (Ru(bpy)3(2+) derivatives) onto the surface of gold nanoparticle (AuNP) modified glassy carbon electrode (GCE). ABA immobilized onto AuNP modified GCE could strongly adsorb GO due to the strong π-π interaction between ABA and graphene oxide; ECL quenching of the Ru complex then takes place because of energy transfer and electron transfer, and a large increase of the electron transfer resistance (Ret) of the electrode. While in the presence of target adenosine triphosphate (ATP), the ABA prefers to form ABA-ATP bioaffinity complexes, which have weak affinity to graphene oxide and keep the graphene oxide away from the electrode surface, thus allowing the ECL signal enhancement, and in conjunction with the decrease of the Ret. Because of the high ECL quenching efficiency, unique structure, and electronic properties of graphene oxide, the Ret and ECL intensity versus the logarithm of ATP concentration was linear in the wide range from 10 pM to 10 nM with an ultra-low detection limit of 6.7 pM to 4.8 pM, respectively. The proposed aptasensor exhibited excellent reproducibility, stability, and outstanding selectivity, and ATP could be effectively distinguished from its analogues. More significantly, this efficient ECL aptasensor strategy based on GO acting both as an electrochemical and ECL signal indicator is general and can be easily extended to other biological binding events.


Cisplatin treatment induces a transient increase in tumorigenic potential associated with high interleukin-6 expression in head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is characterized by the 5-year survival rate of approximately 50%. Despite aggressive surgical, radiation, and chemotherapeutic interventions, 30% to 40% of patients die from the development of recurrent or disseminated disease that is resistant to chemotherapy. As a model of recurrence, we examined the effects of cisplatin on the ability of head and neck cancer cells to initiate tumors in a xenotransplant model. HNSCC cells were treated in vitro with cisplatin at a concentration that elicited >99% cytotoxicity and assessed for tumorigenic potential in nonobese diabetic/severe combined immunodeficient mice. HNSCC cells that survived cisplatin treatment formed tumors in nonobese diabetic/severe combined immunodeficient mice more efficiently than nontreated cells. Cisplatin-resistant cells were characterized using clonal analysis, in vivo imaging, and transcriptomic profiling. Preliminary functional assessment of a gene, interleukin-6 (IL-6), highly upregulated in cisplatin-treated cells was carried out using clonogenicity and tumorigenicity assays. We show that cisplatin-induced IL-6 expression can contribute to the increase in tumorigenic potential of head and neck cancer cells but does not contribute to cisplatin resistance. Finally, through clonal analysis, we show that cisplatin-induced IL-6 expression and cisplatin-induced tumorigenicity are stochastically derived. We report that cisplatin treatment of head and neck cancer cells results in a transient accumulation of cisplatin-resistant, small, and IL-6-positive cells that are highly tumorigenic. These data also suggest that therapies that reduce IL-6 action may reduce recurrence rates and/or increase disease-free survival times in head and neck cancer patients, and thus, IL-6 represents a promising new target in HNSCC treatment.


Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing.
The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.


Knee stabilization in patients with medial compartment knee osteoarthritis.
Individuals with medial knee osteoarthritis (OA) experience knee laxity and instability. Strategies aimed at muscle stabilization may influence the long-term integrity of the joint. This study sought to determine how individuals with medial knee OA respond to a rapid valgus knee movement, to investigate the relationship between muscle-stabilization strategies and knee instability. Twenty-one subjects with medial knee OA and genu varum and 19 control subjects were tested. Subjects stood with the test limb on a movable platform, comprising a plate that translated laterally to rapidly stress the knee's medial periarticular structures and create a potentially destabilizing sensation at the knee joint. Knee motion and muscle responses were recorded. Subjects rated the condition of their knee with a self-report questionnaire about knee instability during daily activities. Prior to plate movement, the OA subjects demonstrated more medial muscle co-contraction than did controls (P = 0.014). Following plate movement, the OA subjects shifted less weight off the test limb (P = 0.013) and had greater medial co-contraction (P = 0.037). OA subjects without knee instability had higher co-contraction of the vastus medialis medial hamstrings than did those who reported having instability that affected their daily activities (P = 0.038). More knee stability correlated positively with higher co-contraction of the vastus medialis medial hamstrings prior to plate movement (r = 0.459, P = 0.042). Individuals with medial knee OA attempt to stabilize the knee with greater co-contraction of the medial muscle in response to laxity that appears on the medial side of the joint only. This strategy presumably contributes to higher joint compression and could exacerbate joint destruction, and therefore needs to be altered to slow or stop the progression of the OA disease process.


Lip Lifting: Unveiling Dental Beauty.
The focus for the achievement of complete success in the esthetic zone has traditionally been on addressing deficiencies of intraoral hard and soft tissue. Often, these deficiencies are accompanied by esthetic concerns regarding the lips that are routinely neglected by the dental team. A predictable plastic surgery technique - the lip lift - has been used for decades to enhance lip esthetics by shortening the senile upper lip to achieve a more youthful appearance. Over the years, this technique has been refined and used in many different ways, allowing its routine incorporation into full facial esthetic planning. Through restoration of the upper lip to its optimal position, the artistry of the dentist and dental technician can truly be appreciated in the rejuvenated smile. By the introduction of this minimally invasive surgical technique to the dental community, patients stand to benefit from a comprehensive orofacial approach to anterior dental esthetic planning.


Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis.
Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.


Improved neurocognitive functions correlate with reduced inflammatory burden in atrial fibrillation patients treated with intensive cholesterol lowering therapy.
Atrial fibrillation (AF) is associated with increased mortality and morbidity, including risk for cerebral macro- and microinfarctions and cognitive decline, even in the presence of adequate oral anticoagulation. AF is strongly related to increased inflammatory activity whereby anti-inflammatory agents can reduce the risk of new or recurrent AF. However, it is not known whether anti-inflammatory therapy can also modify the deterioration of neurocognitive function in older patients with AF. In the present study, older patients with AF were treated with intensive lipid-lowering therapy with atorvastatin 40 mg and ezetimibe 10 mg, or placebo. We examined the relationship between neurocognitive functions and inflammatory burden. Analysis of inflammatory markers revealed significant reductions in high sensitivity C-reactive protein (hs-CRP), fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor antagonist (IL-1RA), interleukin (IL)-9, IL-13 and IL-17, and interferon-γ (IFNγ) in the treatment group compared to placebo. Reduction in plasma concentration of IL-1RA, IL-2, IL-9 and IL-12, and macrophage inflammatory protein-1β (MIP-1β) correlated significantly with improvement in the neurocognitive functions memory and speed. Loss of volume in amygdala and hippocampus, as determined by magnetic resonance imaging (MRI), was reduced in the treatment arm, statistically significant for left amygdala. Anti-inflammatory therapy through intensive lipid-lowering treatment with atorvastatin 40 mg and ezetimibe 10 mg can modify the deterioration of neurocognitive function, and the loss of volume in certain cerebral areas in older patients with AF. TRIAL REGISTRATION ClinicalTrials.gov: NCT00449410.


A solvent-free matrix application method for matrix-assisted laser desorption/ionization imaging of small molecules.
Matrix application continues to be a critical step in sample preparation for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). Imaging of small molecules such as drugs and metabolites is particularly problematic because the commonly used washing steps to remove salts are usually omitted as they may also remove the analyte, and analyte spreading is more likely with conventional wet matrix application methods. We have developed a method which uses the application of matrix as a dry, finely divided powder, here referred to as dry matrix application, for the imaging of drug compounds. This appears to offer a complementary method to wet matrix application for the MALDI-MSI of small molecules, with the alternative matrix application techniques producing different ion profiles, and allows the visualization of compounds not observed using wet matrix application methods. We demonstrate its value in imaging clozapine from rat kidney and 4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylic acid from rat brain. In addition, exposure of the dry matrix coated sample to a saturated moist atmosphere appears to enhance the visualization of a different set of molecules.


Salvagable free wall rupture of the left ventricle.
Free wall rupture of the left ventricle remains a lethal complication of acute myocardial infarction. Nevertheless, where it presents subacutely with tamponade, salvage with a good outcome is still possible with timely pericardiocentesis preceding definitive repair using a sutureless technique.


Foods as a source of enteropathogens causing childhood diarrhea in Thailand.
Foods obtained in markets in Bangkok were cultured for bacterial enteric pathogens and examined for their similarity to strains isolated from children under 5 years of age in Bangkok in 1986. Salmonella was isolated from 17%, Campylobacter from 12%, and enterotoxigenic Escherichia coli (ETEC) from 3% of 510 foods examined. Campylobacter was isolated from 13.5%, ETEC from 13%, and Salmonella from 12% of 1,230 children under 5 years of age with diarrhea. Eighty-eight percent of children infected with Salmonella were infected with serotypes isolated from foods of animal origin. Six percent of children with Salmonella were infected with the same serotype containing plasmids with identical endonuclease restriction patterns as isolates from food. Eighty-seven percent of children with Campylobacter were infected with the same serotypes and biotypes found in food of animal origin. Thirty-one percent of heat-labile enterotoxin (LT) producing ETEC from foods containing genes coding for LT II, but LT II ETEC was not isolated from children. Twenty-one percent of ETEC isolated from foods vs. 53% isolated from children were resistant to 2 or more antibiotics (P less than 0.01). Salmonella and Campylobacter, but not ETEC, isolated from foods were similar to strains isolated from children. Foods of animal origin are an important source of Salmonella and Campylobacter in Thailand.


Colorectal endoscopic submucosal dissection: present status and future perspective, including its differentiation from endoscopic mucosal resection.
Endoscopic submucosal dissection (ESD) allows en bloc resection of a lesion, irrespective of the size of the lesion. ESD has been established as a standard method for the endoscopic ablation of malignant tumors in the upper gastrointestinal (GI) tract in Japan. Although the use of ESD for colorectal lesions has been studied via clinical research, ESD is not yet established as a standard therapeutic method for colorectal lesions because colorectal carcinoma has unique pathological, organ specific characteristics that differ radically from those of the esophagus and stomach, and scope handling and control is more difficult in the colorectum than in the upper GI tract. Depending on the efficacy of endoscopic mucosal resection (EMR) and the clinicopathological characteristics of the colorectal tumor, the proposed indications for colorectal ESD are as follows: (1) lesions difficult to remove en bloc with a snare EMR, such as nongranular laterally spreading tumors (particularly the pseudo depressed type), lesions showing a type VI: pit pattern, and large lesions of the protruded type suspected to be carcinoma; (2) lesions with fibrosis due to biopsy or peristasis; (3) sporadic localized lesions in chronic inflammation such as ulcerative colitis; and (4) local residual carcinoma after EMR. Colorectal ESD is currently in the development stage, and a standard protocol will be available in the near future. We hope that colorectal tumors will be efficiently treated by a treatment method appropriately selected from among EMR, ESD, and surgical resection after precise preoperative diagnosis based on techniques such as magnifying colonoscopy.


A treated case of rhinocerebral zygomycosis with aspergillosis: a case report from India.
Zygomycosis and aspergillosis are two serious fungal infections that are commonly seen in immunocompromised patients. Since both of these infections involve fungi that invade vessels of the arterial system, an early and rapid diagnosis by direct examination of KOH mounts of the relevant clinical sample can clinch the diagnosis. Here, we present a case of a 60-year-old diabetic patient who presented with swelling and pain over the nose and left eye for 7 days with loss of vision in the left eye. After investigation, the patient was diagnosed as having rhinocerebral mucormycosis and aspergillosis, and was initially treated with amphotericin B (1 mg kg-1 day-1 intravenously), followed by endoscopic debridement under general anaesthesia. The patient gradually improved after surgery, and treatment with intravenous amphotericin B was continued along with the addition of 200 mg oral voriconazole twice daily (for the aspergillosis). With prompt diagnosis and treatment, the patient survived these fatal fungal co-infections and finally was discharged.


Transcranial magnetic stimulation reveals attentional feedback to area V1 during serial visual search.
Visual search tasks have been used to understand how, where and when attention influences visual processing. Current theories suggest the involvement of a high-level "saliency map" that selects a candidate location to focus attentional resources. For a parallel (or "pop-out") task, the first chosen location is systematically the target, but for a serial (or "difficult") task, the system may cycle on a few distractors before finally focusing on the target. This implies that attentional effects upon early visual areas, involving feedback from higher areas, should be visible at longer latencies during serial search. A previous study from Juan & Walsh (2003) had used Transcranial Magnetic Stimulation (TMS) to support this conclusion; however, only a few post-stimulus delays were compared, and no control TMS location was used. Here we applied TMS double-pulses (sub-threshold) to induce a transient inhibition of area V1 at every post-stimulus delay between 100 ms and 500 ms (50 ms steps). The search array was presented either at the location affected by the TMS pulses (previously identified by applying several pulses at supra-threshold intensity to induce phosphene perception), or in the opposite hemifield, which served as a retinotopically-defined control location. Two search tasks were used: a parallel (+ among Ls) and a serial one (T among Ls). TMS specifically impaired the serial, but not the parallel search. We highlight an involvement of V1 in serial search 300 ms after the onset; conversely, V1 did not contribute to parallel search at delays beyond 100 ms. This study supports the idea that serial search differs from parallel search by the presence of additional cycles of a select-and-focus iterative loop between V1 and higher-level areas.


Killer cell immunoglobulin-like receptor genes in Latvian patients with type 1 diabetes mellitus and healthy controls.
T1DM is very common in Sweden and is positively associated with HLA class II genes. Approximately 89% of the newly diagnosed patients carry the high-risk HLA DR4-DQ8 and DR3-DQ2. The remaining 11% develop T1DM without them. This can be due to involvement of other genes and environmental factors. Natural killer (NK) cells of the innate immune system are important in antiviral and antitumor immunity. They are implicated in the etiology of autoimmune T1DM. Human NK cells express killer cell immunoglobulin-like receptors (KIR) that belong to the polymorphic multigene family in chromosome 19q3.4. They modulate NK cell response by interacting with HLA class I. In addition, polymorphic MICA in HLA class I interacts with non-polymorphic NKG2D receptor on NK cells. We have studied, in addition to HLA-DR and -DQ, genes of the innate immune system MICA and KIR in Latvian patients (n = 98) with T1DM and controls (n = 100). They were genotyped using standard PCR-based typing methods. MICA allele 5 is positively associated with T1DM. KIR2DL2 and KIR2DS2 were both positively associated. Combined association of MICA4 and KIR2DL2 gave an odds ration (OR) of 26.7. However, the combined risk of KIR2DL2 and HLA class II genes, HLADR3 (OR = 73.4), DR4 (OR = 66.8), and DR3 and DR4 (OR = 88.3), was higher. The maximum risk was when KIR2DL2, MICA5, and DR3/DR4 were in combination. In conclusion, our results suggest that a balance between innate and acquired immunity is important, and an imbalance coud lead to T1DM.


Galactosyl diglycerides: their possible function in Euglena chloroplasts.
Illumination of euglenas grown in the dark induces the formation of chloroplasts characterized by the simultaneous appearance of chlorophyll and galactosyl diglycerides in a relatively fixed ratio. The fatty acyl chains of the galactosyl diglycerides are constructed so that they can provide a stable lock-and-key fit with the phytol chains of chlorophyll in such a way as to localize the porphyrin structures of chlorophyll and space them for efficient photoreception. Light-starved photobiotic euglenas show chloroplast shrinkage with a concurrent partial loss of galactosyl diglycerides.


Physiology and prevention of heel ulcers: The state of science.
The prevalence of heel ulcers across settings is high and is increasing. Prevention of ulcers requires knowledge of their etiology and the scientific basis for preventive care. The interaction between external pressure and the heel vasculature is central to the prevention of heel ulcers. This article focuses on the prevention of heel pressure ulcers. The physiology of heel tissue perfusion, the effect of external pressure on heel perfusion, as well as what is known about strategies to reduce external pressure and approaches to improve heel skin blood flow will be discussed. It is only through understanding of the physiology of heel tissue perfusion and its relation to external pressure that effective preventive measures to reduce heel skin breakdown can be adapted in clinical practice.


Transatrial-transpulmonary repair of tetralogy of Fallot: extensive infundibular septum resection.
Twenty-seven patients with tetralogy of Fallot underwent total correction during the period from February 1988 through October 1989. Their ages ranged from 11 months to 12 years (mean 3.3 +/- 4.9 years). For 11 patients, the repair was made via the conventional transventricular approach and a partial resection of the infundibular septum. On the other 16 patients, a transatrial-transpulmonary approach was used with total resection of the anterior deviated infundibular septum, with or without a miniventriculotomy incision (1-10 mm). The exposure of the ventricular septal defect (VSD) through the right atrium, and the right ventricular outflow tract (RVOT) through the pulmonary artery in patients with tetralogy of Fallot was excellent. There were no significant differences between transatrial-transpulmonary repair and transventricular repair of the tetralogy of Fallot with respect to pulmonary artery (PA) index (273.2 +/- 36.6 versus 249.9 +/- 63.2 mm2/BSA) or the postoperative ratio of right ventricle/left ventricle (RV/LV) systolic pressure (0.55 +/- 0.16 versus 0.61 +/- 0.17). Postoperative intensive care was simple and uncomplicated, with a significantly lower catecholamine demand, less bleeding, fewer blood transfusions, and shorter stays in the cardiac Intensive Care Unit (ICU). There was no mortality in this series. This method of repair can be successfully accomplished in most patients with tetralogy of Fallot, with resultant preservation of right ventricular function (intact right ventricle).


Does bracing affect bone health in women with adolescent idiopathic scoliosis?
Adolescent idiopathic scoliosis (AIS) is often associated with low bone mineral content and density (BMC, BMD). Bracing, used to manage spine curvature, may interfere with the growth-related BMC accrual, resulting in reduced bone strength into adulthood. The purpose of this study was to assess the effects of brace treatment on BMC in adult women, diagnosed with AIS and braced in early adolescence. Participants included women with AIS who: (i) underwent brace treatment (AIS-B, n = 15, 25.6 ± 5.8 yrs), (ii) underwent no treatment (AIS, n = 15, 24.0 ± 4.0 yrs), and (iii) a healthy comparison group (CON, n = 19, 23.5 ± 3.8 yrs). BMC and body composition were assessed using dual-energy X-ray absorptiometry. Differences between groups were examined using a oneway ANOVA or ANCOVA, as appropriate. AIS-B underwent brace treatment 27.9 ± 21.6 months, for 18.0 ± 5.4 h/d. Femoral neck BMC was lower (p = 0.06) in AIS-B (4.54 ± 0.10 g) compared with AIS (4.89 ± 0.61 g) and CON (5.07 ± 0.58 g). Controlling for lean body mass, calcium and vitamin D daily intake, and strenuous physical activity, femoral neck BMC was statistically different (p = 0.02) between groups. A similar pattern was observed at other lower extremity sites (p < 0.05), but not in the spine or upper extremities. BMC and BMD did not correlate with duration of brace treatment, duration of daily brace wear, or overall physical activity. Young women with AIS, especially those who were treated with a brace, have significantly lower BMC in their lower limbs compared to women without AIS. However, the lack of a relationship between brace treatment duration during adolescence and BMC during young adulthood, suggests that the brace treatment is not the likely mechanism of the low BMC.


When does depression become a disorder? Using recurrence rates to evaluate the validity of proposed changes in major depression diagnostic thresholds.
High community prevalence estimates of DSM-defined major depressive disorder (MDD) have led to proposals to raise MDD's diagnostic threshold to more validly distinguish pathology from normal-range distress. However, such proposals lack empirical validation. We used MDD recurrence rates in the longitudinal 2-wave Epidemiologic Catchment Area Study to test the predictive validity of three proposals to narrow MDD diagnosis: a) excluding "uncomplicated" episodes (i.e., episodes that last no longer than 2 months and do not include suicidal ideation, psychotic ideation, psychomotor retardation, or feelings of worthlessness); b) excluding mild episodes (i.e., episodes with only five to six symptoms); and c) excluding nonmelancholic episodes. For each proposal, we used lifetime MDD diagnoses at wave 1 to distinguish the group proposed for exclusion, other MDD, and those with no MDD history. We then compared these groups' 1-year MDD rates at wave 2. A proposal was considered strongly supported if at wave 2 the excluded group's MDD rate was not only significantly lower than the rate for other MDD but also not significantly greater than the no-MDD-history group. Results indicated that all three excluded groups had significantly lower recurrence rates than other MDD (uncomplicated vs. complicated, 3.4% vs. 14.6%; mild vs. severe, 9.6% vs. 20.7%; nonmelancholic vs. melancholic, 10.6% vs. 19.2%, respectively). However, only uncomplicated MDD's recurrence rate was also not significantly greater than the MDD occurrence rate for the no-MDD-history group (3.4% vs. 1.7%, respectively). This low recurrence rate resulted from an interaction between uncomplicated duration and symptom criteria. Multiple-episode uncomplicated MDD did not entail significantly elevated recurrence over single-episode cases (3.7% vs. 3.0%, respectively). Uncomplicated MDD's general-distress symptoms, transient duration, and lack of elevated recurrence suggest it may generally represent nonpathologic intense sadness that should be addressed in treatment guidelines and considered for exclusion from MDD diagnosis to increase the validity of the MDD/normal sadness boundary.


Large multiprotein structures modeling and simulation: the need for mesoscopic models.
Recent observational techniques based upon confocal microscopy make it possible to observe cells at a scale that has never been probed before: the mesoscopic scale. In the eukaryotic cell nucleus, many objects demonstrating phenomena occurring at this scale, such as nuclear bodies, are current subjects of investigations. But from a modeling perspective, this scale has not been widely explored, and hence there is a lack of suitable models for such studies. By reviewing higher and lower scale modeling techniques, we analyze their relevance in the context of mesoscale phenomena. We emphasize important characteristics that should be included in a mesoscopic model: an explicit continuous three-dimensional space with discrete simplified molecules that still have the characteristics of steric volume exclusion and realistic distant interaction forces. Then we present 3DSPI, a model dedicated to studies of nuclear bodies based on a simple formalism inspired from molecular dynamics and coarse-grained models: particles interacting through a potential energy function and driven by an overdamped Langevin equation. Finally, we present the features expected to be included in the model, pointing out the difficulties that might arise.


Nonlinear wavelet transforms for image coding via lifting.
We investigate central issues such as invertibility, stability, synchronization, and frequency characteristics for nonlinear wavelet transforms built using the lifting framework. The nonlinearity comes from adaptively choosing between a class of linear predictors within the lifting framework. We also describe how earlier families of nonlinear filter banks can be extended through the use of prediction functions operating on a causal neighborhood of pixels. Preliminary compression results for model and real-world images demonstrate the promise of our techniques.


Life history traits in selfing versus outcrossing annuals: exploring the 'time-limitation' hypothesis for the fitness benefit of self-pollination.
Most self-pollinating plants are annuals. According to the 'time-limitation' hypothesis, this association between selfing and the annual life cycle has evolved as a consequence of strong r-selection, involving severe time-limitation for completing the life cycle. Under this model, selection from frequent density-independent mortality in ephemeral habitats minimizes time to flower maturation, with selfing as a trade-off, and/or selection minimizes the time between flower maturation and ovule fertilization, in which case selfing has a direct fitness benefit. Predictions arising from this hypothesis were evaluated using phylogenetically-independent contrasts of several life history traits in predominantly selfing versus outcrossing annuals from a data base of 118 species distributed across 14 families. Data for life history traits specifically related to maturation and pollination times were obtained by monitoring the start and completion of different stages of reproductive development in a greenhouse study of selfing and outcrossing annuals from an unbiased sample of 25 species involving five pair-wise family comparisons and four pair-wise genus comparisons. Selfing annuals in general had significantly shorter plant heights, smaller flowers, shorter bud development times, shorter flower longevity and smaller seed sizes compared with their outcrossing annual relatives. Age at first flower did not differ significantly between selfing and outcrossing annuals. This is the first multi-species study to report these general life-history differences between selfers and outcrossers among annuals exclusively. The results are all explained more parsimoniously by selection associated with time-limitation than by selection associated with pollinator/mate limitation. The shorter bud development time reported here for selfing annuals is predicted explicitly by the time-limitation hypothesis for the fitness benefit of selfing (and not by the alternative 'reproductive assurance' hypothesis associated with pollinator/mate limitation). Support for the time-limitation hypothesis is also evident from published surveys: whereas selfers and outcrossers are about equally represented among annual species as a whole, selfers occur in much higher frequencies among the annual species found in two of the most severely time-limited habitats where flowering plants grow--deserts and cultivated habitats.


Time-Frequency Fragment Selection for Disease Detection from Imbalanced Phonocardiogram Data.
Cardiovascular disease (CVD) has become the most concerning disease worldwide. A Phonocardiogram (PCG), the graphical representation of heart sound, is a non-invasive method that helps to detect CVD by analyzing its characteristics. Several machine learning (ML) approaches have been proposed in the last decade to assist practitioners in interpreting this disease accurately. However, the ML-based method requires a considerable amount of PCG data with a balance between data categories for unbiased performance. Moreover, PCG data in the literature is scarce, and the available database has a strong imbalance between the normal and abnormal categories. This data imbalance causes outcomes to be severely biased towards classes with greater samples. This work proposes a variable-hop fragment selection method with a pre-trained CNN model to counter the issues of data scarcity and imbalance. The proposed framework improves 7.12% of unweighted average recall (UAR) value for assessing an imbalanced PCG dataset compared to the state-of-the-art method and reports an overall UAR of 92.46% on the PhysioNet/CinC Challenge 2016 dataset. The improved performance signifies the clinical relevance of the work providing reliable assistance for heart auscultation and has the potential to screen for heart pathologies in data constraint applications.


When teams shift among processes: insights from simulation and optimization.
This article introduces process shifts to study the temporal interplay among transition and action processes espoused in the recurring phase model proposed by Marks, Mathieu, and Zacarro (2001). Process shifts are those points in time when teams complete a focal process and change to another process. By using team communication patterns to measure process shifts, this research explores (a) when teams shift among different transition processes and initiate action processes and (b) the potential of different interventions, such as communication directives, to manipulate process shift timing and order and, ultimately, team performance. Virtual experiments are employed to compare data from observed laboratory teams not receiving interventions, simulated teams receiving interventions, and optimal simulated teams generated using genetic algorithm procedures. Our results offer insights about the potential for different interventions to affect team performance. Moreover, certain interventions may promote discussions about key issues (e.g., tactical strategies) and facilitate shifting among transition processes in a manner that emulates optimal simulated teams' communication patterns. Thus, we contribute to theory regarding team processes in 2 important ways. First, we present process shifts as a way to explore the timing of when teams shift from transition to action processes. Second, we use virtual experimentation to identify those interventions with the greatest potential to affect performance by changing when teams shift among processes. Additionally, we employ computational methods including neural networks, simulation, and optimization, thereby demonstrating their applicability in conducting team research.


Development of Nursing Informatics in Mainland China: A Bibliometric Analysis.
This study aimed to understand the status of nursing informatics in Mainland China. Articles on nursing informatics, published between 2009 and 2018, were retrieved from the CNKI (China National Knowledge Infrastructure) database. A total of 51 papers were identified and analyzed. The journals, annual publications, and co-occurrence of keywords were analyzed with the bibliometric analysis. The result will help us better understand the nursing informatics research in mainland China.


Smoking, drinking, and incident cognitive impairment: a cohort community based study included in the Gospel Oak project.
Recent longitudinal studies have reported that smoking increases risk for cognitive impairment and that moderate alcohol intake could be preventive. The association between both cigarette smoking and alcohol drinking and incident cognitive impairment was studied in a representative population. This is a 1 year prospective population based cohort study of all residents aged 65 or over in the electoral ward of Gospel Oak in London, UK (n=889). Cognitive impairment was assessed at baseline and 1 year later using the organic brain syndrome (OBS) cognitive impairment scale from the short CARE structured assessment. Subjects who were cognitively impaired at baseline were excluded from this analysis. The prevalence of OBS cognitive impairment was 10.4% at index assessment and the 1 year cumulative incidence of cognitive impairment was 5.7%. Cognitive impairment was not associated with use of alcohol, although there was a non-significant association in the direction of a protective effect against onset of cognitive impairment for moderate drinkers compared with non-drinkers and heavy drinkers. Current smoking status predicted cognitive impairment (risk ratio (RR) 3.7; (95% confidence interval (95% CI)=1.1-12.3) independently from sex, age, alcohol, occupational class, education, handicap, depression, and baseline cognitive function. Smoking seems to be a prospective risk factor for incident cognitive impairment; thus encouragement of older people to stop smoking could be considered as part of a strategy to reduce the incidence of cognitive impairment.


A prognostic and immunotherapy effectiveness model for pancreatic adenocarcinoma based on cuproptosis-related lncRNAs signature.
Pancreatic adenocarcinoma (PAAD) results in one of the deadliest solid tumors with discouraging clinical outcomes. Growing evidence suggests that long non-coding RNAs (lncRNAs) play a crucial role in altering the growth, prognosis, migration, and invasion of pancreatic cancer cells. Cuproptosis is a novel type of cell death induced by copper (Cu) and is associated with mitochondrial respiration during the tricarboxylic acid cycle. However, the relationship between lncRNAs related to cuproptosis and PAAD is poorly studied. In this study, we investigated the association between a signature of cuproptosis-related lncRNAs and the diagnosis of PAAD. Genomic data and clinical information were obtained using the TCGA dataset, while cuproptosis-related genes (CRGs) from previous studies. Co-expression analysis was utilized to identify lncRNAs associated with cuproptosis. We developed and verified a prognostic risk model following a classification of patients into high- and low-risk categories. The prediction capacity of the risk model was assessed using a number of methods including Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, nomograms, and principal component analysis (PCA). Furthermore, differentially expressed genes (DEGs) were used to perform functional enrichment analyses, and to examine the behaviors of various risk groups in terms of immune-related activities and medication sensitivity. We identified 7 cuproptosis-related lncRNA signatures, including CASC19, FAM83A-AS1, AC074099.1, AC007292.2, AC026462.3, AL358944.1, and AC009019.1, as overall survival (OS) predictors. OS and progression-free survival (PFS) showed significant differences among patients in different risk groups. Independent prognostic analysis revealed that the cuproptosis-related lncRNA signatures can independently achieve patient prognosis. The risk model demonstrated strong predictive ability for patient outcomes, as evidenced by ROC curves, nomograms, and PCA. Higher tumor mutation burden (TMB) and lower tumor immune dysfunction and exclusion (TIDE) scores were observed in the high-risk group. Additionally, the low-risk group was hypersensitive to 3 anti-cancer medications, whereas the high-risk group was hypersensitive to one. A prognostic risk model with a good predictive ability based on cuproptosis-related lncRNAs was developed, providing a theoretical basis for personalized treatment and immunotherapeutic responses in pancreatic cancer.


Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract.
Congenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal-dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1-haploinsufficient adult mice backcrossed into a Nos3-null background. Here, we described the congenital cardiac abnormalities in Notch1(+/-);Nos3(-/-) embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1(+/-);Nos3(-/-) embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1(+/-);Nos3(-/-) embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial-derived cells in a Nos3-null background and found that Notch1(fl/+);Tie2-Cre(+/-);Nos3(-/-) mice recapitulate the congenital cardiac phenotype of Notch1(+/-);Nos3(-/-) embryos. Our data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.


Hepatic Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Partial stabilization by molybdate.
In structure and general mode of action, the Ah receptor is very similar to the receptors for steroid hormones. Molybdate previously has been shown to be highly effective at preserving ligand-binding function in steroid receptors during their exposure to elevated temperature or high ionic strength and at stabilizing steroid receptors as high molecular weight oligomeric complexes. Since such stabilization by molybdate can be very useful during characterization and purification of receptors, we tested the effects of molybdate on the Ah receptor to determine if the Ah receptor, like the receptors for steroid hormones, might be stabilized. In hepatic cytosols from C57BL/6N mice and Sprague-Dawley rats, molybdate concentrations up to 30 mM in homogenizing and analysis buffers did not alter the concentration of specific Ah receptor sites detected by binding of [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin. However, inclusion of 20 mM molybdate in the homogenizing buffer did significantly protect unliganded Ah receptor from thermal inactivation at 20 degrees C and from KCl-induced loss of ligand-binding ability. In accord with previous reports, 20 mM molybdate in homogenizing and analysis buffers greatly increased the concentration of detectable glucocorticoid receptor in rat hepatic cytosol and estrogen receptor in rat uterine cytosol. Exposure to 0.4 M KC1 caused the glucocorticoid receptor from rat liver to shift sedimentation from approximately equal to 8 S to approximately equal to 4 S and caused a severe loss of specific glucocorticoid binding. Presence of 20 mM molybdate stabilized the glucocorticoid receptor as a single discrete peak sedimenting at approximately equal to 8 S. In contrast, the Ah receptor from rat liver exposed to 0.4 M KC1 in the presence of molybdate sedimented as biphasic peaks; one peak (approximately equal to 9.5 S) corresponded to the form of Ah receptor observed at low ionic strength, while the other peak (approximately equal to 5.5 S) corresponded to the form of Ah receptor seen in cytosol treated with 0.4 M KC1 in the absence of molybdate. Addition of heparin to hepatic cytosols from mice or rats shifted sedimentation of Ah receptor from approximately equal to 9.5 S to approximately equal to 5.5 S. Molybdate, again, provided stabilization in the approximately equal to 9.5 S form, but only for about one-half the total Ah receptor content in both rat and mouse hepatic cytosols. In sum, molybdate is far less effective at stabilizing rodent Ah receptors than it is at stabilizing steroid receptors in the same species.


[New fungal classification and their applications in medicine].
Fungi are gaining importance with the increased incidence of invasive, often fatal mycoses, in immunocompromised patients. In addition, the increased number of emerging opportunistic pathogens has prompted interest in studies pertaining to fungal classification. The traditional methods of identification and classification of these microorganisms are based on the morphology of the sexual and asexual reproductive structures. Recently, this system of classification has been shown incongruent with approaches that better establish phylogenetic relationships among these organisms. Novel aspects of fungal reclassification are described as follows: 1) the position of fungi in the historical classification systems, 2) the recognition of their polyphyly, based on comparative studies of nucleic acid sequences and on analysis of descent lines and, 3) the contribution of molecular phylogeny to medical mycology, including identification of mycotic agents, their molecular epidemiology, prevention of infection and methods of diagnosis.


Global declines in coral reef calcium carbonate production under ocean acidification and warming.
Ocean warming and acidification threaten the future growth of coral reefs. This is because the calcifying coral reef taxa that construct the calcium carbonate frameworks and cement the reef together are highly sensitive to ocean warming and acidification. However, the global-scale effects of ocean warming and acidification on rates of coral reef net carbonate production remain poorly constrained despite a wealth of studies assessing their effects on the calcification of individual organisms. Here, we present global estimates of projected future changes in coral reef net carbonate production under ocean warming and acidification. We apply a meta-analysis of responses of coral reef taxa calcification and bioerosion rates to predicted changes in coral cover driven by climate change to estimate the net carbonate production rates of 183 reefs worldwide by 2050 and 2100. We forecast mean global reef net carbonate production under representative concentration pathways (RCP) 2.6, 4.5, and 8.5 will decline by 76, 149, and 156%, respectively, by 2100. While 63% of reefs are projected to continue to accrete by 2100 under RCP2.6, 94% will be eroding by 2050 under RCP8.5, and no reefs will continue to accrete at rates matching projected sea level rise under RCP4.5 or 8.5 by 2100. Projected reduced coral cover due to bleaching events predominately drives these declines rather than the direct physiological impacts of ocean warming and acidification on calcification or bioerosion. Presently degraded reefs were also more sensitive in our analysis. These findings highlight the low likelihood that the world's coral reefs will maintain their functional roles without near-term stabilization of atmospheric CO2 emissions.


Retrieval of migrated coils with stent retrievers: an animal study.
Coil migration is a potentially serious complication of endovascular aneurysm treatment. The aim of the study was to systematically investigate the effectiveness of coil retrieval with a stent retriever in an animal model. A total of 148 coils of various types and sizes were placed into arteries of varying diameters in a porcine in vivo model. Coil retrieval was performed by placing a Trevo ProVue stent retriever over the coil and trying to trap a part of the platinum coil within the stent mesh by advancing the microcatheter over the stent or simply by retrieving the stent without trying to trap the coil by advancing the microcatheter. Coil retrieval was successful in 101 of 102 cases (99%), in which trapping of the coil within the stent retriever by advancing the microcathter was applied. When we only pulled back the stent without trapping the coil, retrieval was successful in only 5 of 46 cases (11%). Coil type, coil structure (2D versus 3D), actual coil shape in the affected vessel, investigator experience, aspiration, coil localization, and vessel diameter had no significant influence on retrieval outcome. There was no case of vessel perforation. Retrieval of migrated platinum coils with a stent retriever is an effective treatment option for migrated coils when the correct technique is applied.


Evolution of static allometries: adaptive change in allometric slopes of eye span in stalk-eyed flies.
Julian Huxley showed that within-species (static) allometric (power-law) relations can arise from proportional growth regulation with the exponent in the power law equaling the factor of proportionality. Allometric exponents may therefore be hard to change and act as constraints on the independent evolution of traits. In apparent contradiction to this, many empirical studies have concluded that static allometries are evolvable. Many of these studies have been based, however, on a broad definition of allometry that includes any monotonic shape change with size, and do not falsify the hypothesis of constrained narrow-sense allometry. Here, we present the first phylogenetic comparative study of narrow-sense allometric exponents based on a reanalysis of data on eye span and body size in stalk-eyed flies (Diopsidae). Consistent with a role in sexual selection, we found strong evidence that male slopes were tracking "optima" based on sexual dimorphism and relative male trait size. This tracking was slow, however, with estimated times of 2-3 million years for adaptation to exceed ancestral influence on the trait. Our results are therefore consistent with adaptive evolution on million-year time scales, but cannot rule out that static allometry may act as a constraint on eye-span adaptation at shorter time scales.


Does intraspecific competition promote variation? A test via synthesis.
Competitive diversification, that is, when increasing intraspecific competition promotes population niche expansion, is commonly invoked in evolutionary studies and currently plays a central role in how we conceptualize the process of adaptive diversification. Despite the frequency with which this idea is cited, the empirical evidence for the process is somewhat limited, and the findings of these studies have yet to be weighed objectively through synthesis. Here, we sought to fill this gap by reviewing the existing literature and collecting the data necessary to assess the evidence for competition as a diversifying force. Additionally, we sought to test a more recent hypothesis, which suggests that competition can act to both promote and inhibit dietary diversification depending on the degree to which a consumer depletes its resources. The surprising result of this synthesis was that increasing competition did not have a mean positive effect on population-level diet breadth or the degree of individual specialization. Instead, we found that increasing intraspecific competition had a restricting effect on population-level diet breadth in as many cases as it had a diversifying effect. This wide disparity in the effect of competition on consumer diet variation was negatively related to a metric for consumer resource depletion. Altogether, these findings call into question a long-standing assumption of basic evolutionary models and lend some support to recent theoretical predictions. Specifically, these findings support the idea that competition is primarily diversifying for species with a small effect (per unit biomass) on their resources and that resource depletion limits the diversifying effect of competition for consumers with larger ecological effects.


Gait retraining using real-time feedback in patients with medial knee osteoarthritis: Feasibility and effects of a six-week gait training program.
The knee adduction moment (KAM) is often elevated in medial knee osteoarthritis (KOA). The aim of this study was to evaluate effects on KAM and patient-reported outcomes of a six-week gait training program. Twenty-one patients (61 ± 6 years) with KOA participated in a six-week biofeedback training program to encourage increased toe-in (all patients) and increased step-width (five patients). Patients received real-time visual feedback while walking on an instrumented treadmill. We analysed the effect of the gait modification(s) on peak KAM in week six and three and six months post-training. We also evaluated the effect on pain and functional ability. Of 21 patients starting the program, 16 completed it with high attendance (15 and 16 respectively) at the three and six month follow-ups. First peak KAM was significantly reduced by up to 14.0% in week six with non-significant reductions of 8.2% and 5.5% at the follow-ups. Functional ability (assessed using the WOMAC questionnaire) improved significantly after the training (eight point reduction, p = 0.04 in week six and nine point reduction, p = 0.04 at six-month follow-up). There was also a trend towards reduction in WOMAC pain (p = 0.06) at follow-up. Biofeedback training to encourage gait modifications is feasible and leads to short-term benefits. However, at follow-up, reductions in KAM were less pronounced in some participants suggesting that to influence progression of KOA in the longer term, a permanent regime to reinforce the effects of the training program is needed. Trial number: ISRCTN14687588.


Prenatal counseling for myelomeningocele in the era of fetal surgery: a shared decision-making approach.
The Management of Myelomeningocele Study demonstrated that fetal surgery, as compared to postnatal repair, decreases the rate of hydrocephalus and improves expected motor function. However, fetal surgery is associated with significant maternal and neonatal risks including uterine wall dehiscence, prematurity, and fetal or neonatal death. The goal of this study was to provide information about counseling expectant mothers regarding myelomeningocele in the era of fetal surgery. The authors conducted an extensive review of topics pertinent to counseling in the setting of myelomeningocele and introduce a new model for shared decision-making to aid practitioners during counseling. Expectant mothers must decide in a timely manner among several potential options, namely termination of pregnancy, postnatal surgery, or fetal surgery. Multiple factors influence the decision, including maternal health, fetal heath, financial resources, social support, risk aversion, access to care, family planning, and values. In many cases, it is a difficult decision that benefits from the guidance of a pediatric neurosurgeon. The authors review critical issues of prenatal counseling for myelomeningocele and discuss the process of shared decision-making as a framework to aid expectant mothers in choosing the treatment option best for them.


[Primary sclerosing cholangitis: modern concepts].
This review deals with primary sclerosing cholangitis (PSC) as a challenging problem in gastroenterology. Definition of PSC is presented, its putative pathogenetic and etiological factors, clinical symptoms, complications and concomitant disorders, methods of laboratory and instrumental diagnostics are described. Special attention is given to modern approaches to the treatment of the disease, dietoherapy, pharmacotherapy, auxiliary therapeutic modalities, indications for liver transplantation and its outcomes.


Modulation of adrenocorticotrophin hormone (ACTH)-induced expression of stress-related genes by PUFA in inter-renal cells from European sea bass (Dicentrarchus labrax).
Dietary fatty acids have been shown to exert a clear effect on the stress response, modulating the release of cortisol. The role of fatty acids on the expression of steroidogenic genes has been described in mammals, but little is known in fish. The effect of different fatty acids on the release of cortisol and expression of stress-related genes of European sea bass (Dicentrarchus labrax) head kidney, induced by a pulse of adenocorticotrophin hormone (ACTH), was studied. Tissue was maintained in superfusion with 60 min of incubation with EPA, DHA, arachidonic acid (ARA), linoleic acid or α-linolenic acid (ALA) during 490 min. Cortisol was measured by RIA. The quantification of stress-related genes transcripts was conducted by One-Step TaqMan real-time RT-PCR. There was an effect of the type of fatty acid on the ACTH-induced release of cortisol, values from ALA treatment being elevated within all of the experimental period. The expression of some steroidogenic genes, such as the steroidogenic acute regulatory protein (StAR) and c-fos, were affected by fatty acids, ALA increasing the expression of StAR after 1 h of ACTH stimulation whereas DHA, ARA and ALA increased the expression of c-fos after 20 min. ARA increased expression of the 11β-hydroxylase gene. Expression of heat shock protein 70 (HSP70) was increased in all the experimental treatments except for ARA. Results corroborate previous studies of the effect of different fatty acids on the release of cortisol in marine fish and demonstrate that those effects are mediated by alteration of the expression of steroidogenic genes.


Effect of transient stretch on intracellular Ca2+ during triggered propagated contractions in intact trabeculae.
Transient stretch of cardiac muscle during a twitch contraction may dissociate Ca2+ from myofilaments into the cytosol at the moment of quick release of the muscle. We studied the effect of stretch and quick release of trabeculae on changes in intracellular Ca2+ ([Ca2+]i) during triggered propagated contractions (TPCs). Trabeculae were dissected from the right ventricle of 9 rat hearts. [Ca2+]i was measured using electrophoretically injected fura-2. Force was measured using a silicon strain gauge and sarcomere length was measured using laser diffraction techniques. Reproducible TPCs (n = 13) were induced by trains of electrical stimuli (378 +/- 19 ms interval) for 7.5 s at [Ca2+]o of 2.0 mM (27.9 +/- 0.2 degrees C). The latency of the TPC force and the underlying increase in [Ca2+]i was calculated from the time (TimeF) between the last stimulus and the peak of TPC force (PeakF), or the time (TimeCa) between the last stimulus and the peak of the increase in [Ca2+]i during the TPCs (PeakCa). As a result of a 10% increase in muscle length for 150-200 ms during the last stimulated twitches, TimeF and TimeCa decreased and PeakF and PeakCa increased significantly (n = 13). In addition, transient stretch sometimes induced a twitch contraction subsequent to the accelerated TPC and its underlying increase in [Ca2+]i. These results suggest that Ca2+ binding and dissociation from the myofilaments by the stretch and quick release of muscle may modulate the TPC force and the underlying increases in [Ca2+]i and play an important role in the induction of arrhythmias.


Resistance to benzimidazole anthelmintics in equine strongyles. 2. Evidence of side-resistance, and susceptibility of benzimidazole-resistant strongyles to non-benzimidazole compounds.
The susceptibility of a known thiabendazole-resistant population of small strongyles to anthelmintics of both benzimidazole and non-benzimidazole groups, was determined. In the first study, 42 horses infected with thiabendazole-resistant small strongyles were allocated to 6 groups. Treatment groups received one of the following anthelmintics: mebendazole, febantel, febantel plus trichlorphon, morantel tartrate, or a combination of thiabendazole, piperazine and trichlorphon. Morantel tartrate and the thiabendazole/piperazine/trichlorphon combination produced highly significant (p less than 0.001) reductions in faecal strongyle egg counts 20 days post-treatment. Mebendazole, febantel and febantel plus trichlorphon failed to reduce strongyle egg counts significantly. Larval culture and differentiation indicated that in all cases of anthelmintic failure, small strongyles of the sub-family Cyathostominae were involved. Eighteen horses from groups in which treatment had failed were re-allocated to 3 groups. Treatment with either morantel tartrate or haloxon was highly efficient in reducing faecal strongyle egg counts. In the final study, fifty-four horses, infected with benzimidazole-resistant small strongyles were allocated to 10 groups. On day zero, each treatment group received one of the following anthelmintics: thiabendazole, cambendazole, mebendazole, oxibendazole, piperazine, thiabendazole/piperazine, cambendazole/piperazine, mebendazole/piperazine or oxibendazole/piperazine. Oxibendazole, piperazine and the benzimidazole/piperazine combinations produced highly significant reductions in faecal strongyle egg counts 20 days post-treatment (p less than 0.001). When administered alone, benzimidazole anthelmintics failed to reduce strongyle egg counts significantly, with the exception of oxibendazole. Larval culture and differentiation indicated that in all cases of anthelmintic failure, the species involved were small strongyles of subfamily Cyathostominae. There was no significant increase in benzimidazole resistance level (based on in vitro assay) as a result of drug treatment, over one generation.


Milk lymphocyte profile and macrophage functions: new insights into the immunity of the mammary gland in quarters infected with Corynebacterium bovis.
The present study explored the viability of bovine milk macrophages, their intracellular production of reactive oxygen and nitrogen species (RONS), and their phagocytosis of Staphylococcus aureus, as well as the profile of lymphocytes, from healthy udder quarters and udder quarters infected by Corynebacterium bovis. The study included 28 healthy udder quarters from 12 dairy cows and 20 udder quarters infected by C. bovis from 10 dairy cows. The percentages of macrophages and lymphocytes were identified by flow cytometry using monoclonal antibodies. Macrophage viability, RONS production, and S. aureus phagocytosis were evaluated by flow cytometry. Milk samples from quarters infected with C. bovis showed a lower percentage of macrophages but an increased number of milk macrophages per mL and a higher percentage of macrophages that produced intracellular RONS and phagocytosed S. aureus. No effect of C. bovis infection on macrophage viability was found. Udder quarters infected by C. bovis showed a higher percentage of T cells and CD4+ T lymphocytes, but no effect was found on the percentage of CD8+ CD4- T, CD8- CD4- T, or B lymphocytes. Thus, our results corroborate, at least in part, the finding that intramammary infections by C. bovis may offer protection against intramammary infections by major pathogens.


Auricular neural stimulation as a new non-invasive treatment for opioid detoxification.
The recent opioid crisis is one of the rising challenges in the history of modern health care. New and effective treatment modalities with less adverse effects to alleviate and manage this modern epidemic are critically needed. The FDA has recently approved two non-invasive electrical nerve stimulators for the adjunct treatment of symptoms of acute opioid withdrawal. These devices, placed behind the ear, stimulate certain cranial nerves with auricular projections. This neural stimulation reportedly generates a prompt effect in terms of alleviation of withdrawal symptoms resulting from acute discontinuation of opioid use. Current experimental evidence indicates that this type of non-invasive neural stimulation has excellent potential to supplement medication assisted treatment in opioid detoxification with lower side effects and increased adherence to treatment. Here, we review current findings supporting the use of non-invasive neural stimulation in detoxification from opioid use. We briefly outline the neurophysiology underlying this approach of auricular electrical neural stimulation and its role in enhancing medication assisted treatment in treating symptoms of opioid withdrawal. Considering the growing deleterious impact of addictive disorders on our society, further studies on this emerging treatment modality are warranted.


Direct synthesis of an anionic 13-vertex closo-cobaltacarborane cluster.
Reaction of 1,2-bis(diphenylphosphino)-ortho-carborane (L) with [K(thf){(MesBIAN)Co(η4-cod)}] (1, MesBIAN = bis(mesityliminoace-naphthene)diimine, cod = 1,5-cyclooctadiene) affords an anionic 13-vertex closo-cobaltacarborane cluster (2) in one step. The mechanism of this transformation has been studied by experimental and quantum chemical techniques, which suggest that a series of outer-sphere electron transfer and isomerisation processes occurs. This work shows that low-valent metalate anions are promising reagents for the synthesis of anionic metallacarborane clusters.


Coordination of specialty referrals and physician satisfaction with referral care.
To describe how physicians coordinate patient care for specialty referrals and to examine the effects of these activities on referring physicians' satisfaction with the specialty care their patients receive and referral completion. Prospective study of a consecutive sample of referrals (N = 963) made from the offices of 122 pediatricians in 85 practices in a national practice-based research network. Data sources included a physician survey completed when the referral was made (response rate, 99%) and a physician survey and medical record review conducted 3 months later (response rate, 85%). Referral completion was defined as receipt of written communication of referral results from the specialist. Pediatricians scheduled appointments with specialists for 39.3% and sent patient information to specialists for 50.8% of referrals. The adjusted odds of referral completion were increased 3-fold for those referrals for which the pediatrician scheduled the appointment and communicated with the specialist compared with those for which neither activity occurred. Referring physicians' satisfaction ratings were significantly increased by any type of specialist feedback and were highest for referrals involving specialist feedback by both telephone and letter. Elements of specialists' letters that significantly increased physician ratings of letter quality included presence of patient history, suggestions for future care, follow-up arrangements, and plans for comanaging care; only the inclusion of plans for comanaging patient care was significantly related to the referring physicians' overall satisfaction. Better coordination between referring physicians and specialists increases physician satisfaction with specialty care and enhances referral completion. Improvements in the referral process may be achieved through better communication and collaboration between primary care physicians and specialists.


Bone metastases in thyroid cancer.
Whereas preemptive screening for the presence of lymph node and lung metastases is standard-of-care in thyroid cancer patients, bone metastases are less well studied and are often neglected in thyroid cancer patient surveillance. Bone metastases in thyroid cancer are, however, independently associated with poor/worse prognosis with a median overall survival from detection of only 4 years despite an otherwise excellent prognosis for the vast majority of thyroid cancer patients. In this review we summarize the state of current knowledge as pertinent to bony metastatic disease in thyroid cancer, including clinical implications, impacts on patient function and quality of life, pathogenesis, and therapeutic opportunities, proposing approaches to patient care accordingly. In particular, bone metastasis pathogenesis appears to reflect cooperatively between cancer and the bone microenvironment creating a "vicious cycle" of bone destruction rather than due exclusively to tumor invasion into bone. Additionally, bone metastases are more frequent in follicular and medullary thyroid cancers, requiring closer bone surveillance in patients with these histologies. Emerging data also suggest that treatments such as multikinase inhibitors (MKIs) can be less effective in controlling bone, as opposed to other (e.g. lung), metastases in thyroid cancers, making special attention to bone critical even in the setting of active MKI therapy. Although locoregional therapies including surgery, radiotherapy and ablation play important roles in palliation, antiresorptive agents including bisphosphonates and denosumab appear individually to delay and/or lessen skeletal morbidity and complications, with dosing frequency of every 3 months appearing optimal; their early application should therefore be strongly considered.


Effects of age and MAOA genotype on the neural processing of social rejection.
Adolescents are often sensitive to peer rejection, a factor that might contribute to the risk of affective disorder in this age group. Previous studies suggest a significant overlap among socioaffective brain regions involved in the response to social rejection, regions continuing to develop functionally during adolescence and regions influenced by monoamine oxidase A (MAOA) polymorphism. The current study investigated whether the neural response to social rejection is functionally immature in adolescents compared with adults, and whether these responses are modulated by MAOA genotype. Blood-oxygen-level-dependent response was measured with functional magnetic resonance imaging during a rejection-themed emotional Stroop task in 19 adolescents (aged 14-16) and 16 adults (aged 23-28) genotyped for MAOA polymorphism. Similar numbers of MAOA-L and MAOA-H carriers were recruited to maximize power to detect genotype effects. Main effects of rejection stimuli (relative to neutral and acceptance control stimuli) were seen in predicted socioaffective brain regions. Adolescents did not show the adult pattern of modulation by rejection stimuli in the right ventrolateral prefrontal cortex, suggesting continued functional maturation of this regulatory region during adolescence. Age and genotype interacted in the left amygdala, in which the predicted effect of genotype on responses to rejection stimuli was seen in the adults, but not in the adolescents. The data suggest continued functional development of the circuitry underlying the processing of social rejection between adolescence and adulthood, and show that the effects of MAOA genotype on neural responses may vary with age.


VEGF-induced mobilization of caveolae and increase in permeability of endothelial cells.
Glomerular epithelial cells (GEC) are a known site of vascular endothelial growth factor (VEGF) production. We established immortalized rat GEC, which retained the ability to produce VEGF. The isoforms expressed by GEC were defined as VEGF-205, -188, -120, and -164. The electrical resistance of endothelial cells cultured on GEC-conditioned matrix, an indicator of the permeability of monolayers to solutes, was significantly increased by the treatment with the neutralizing polyclonal antibodies to VEGF and decreased by VEGF-165. Transfection of endothelial cells with green fluorescence protein-caveolin construct and intravital confocal microscopy showed that VEGF results in a rapid appearance of transcellular elongated structures decorated with caveolin. Transmission electron microscopy of endothelial cells showed that caveolae undergo rapid internalization and fusion 30 min after application of VEGF-165. Later (36 h), endothelial cells pretreated with VEGF developed fenestrae and showed a decrease in electrical resistance. Immunoelectron microscopy of glomeruli confirmed VEGF localization to podocytes and in the basement membrane. In summary, immortalized GEC retain the ability to synthesize VEGF. Matrix-deposited and soluble VEGF leads to the enhancement of caveolae expression, their fission and fusion, formation of elongated caveolin-decorated structures, and eventual formation of fenestrae, both responsible for the increase in endothelial permeability.


Finite element analysis of tissue deformation with a radiofrequency ablation electrode for strain imaging.
Recent studies have shown that radiofrequency (RF) electrode displacement or deformation-based strain imaging can be used as an alternate imaging modality to monitor and to evaluate ablative therapies for liver tumors. This paper describes a biomechanical model used to study RF electrode deformation-based strain imaging, in conjunction with a simulated medical ultrasound linear array transducer. The computer simulations reported here are important steps toward understanding this biomechanical system in vivo, thus providing a basis for improving system design, including the motion tracking algorithm and image guidance for performing RF electrode displacement-strain imaging in vivo.


Frontal-striatal dysfunction during planning in obsessive-compulsive disorder.
Dysfunction of frontal-striatal, particularly orbitofrontal-striatal, circuitry has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD), characterized by obsessions, ritualistic behavior, anxiety, and specific cognitive impairments. In addition, neuropsychological studies in OCD have reported impairments in visuospatial tasks and executive functions, such as planning. To determine whether dorsal prefrontal-striatal dysfunction mediates planning impairment in patients with OCD. A parametric self-paced pseudorandomized event-related functional magnetic resonance imaging version of the Tower of London task was used in 22 medication-free patients with OCD and 22 healthy control subjects. This paradigm, allowing flexible responding and post hoc classification of correct responses, was developed to compare groups likely to differ in performance. Behavioral results showed significant planning impairments in OCD patients compared with control subjects. During planning, decreased frontal-striatal responsiveness was found in OCD patients, mainly in dorsolateral prefrontal cortex and caudate nucleus. In addition, OCD patients showed increased, presumably compensatory, involvement of brain areas known to play a role in performance monitoring and short-term memory processing, such as anterior cingulate, ventrolateral prefrontal, and parahippocampal cortices. These findings support the hypothesis that decreased dorsal prefrontal-striatal responsiveness is associated with impaired planning capacity in OCD patients. Because the described frontal-striatal dysfunction in OCD is independent of state anxiety and disease symptom severity, we conclude that executive impairment is a core feature in OCD.


Degradation of chloroaromatics: structure and catalytic activities of wild-type chlorocatechol 2,3-dioxygenases and modified ones.
To improve the efficiency and to investigate the molecular determinants that direct substrate specificity of chlorocatechol 2,3-dioxygenase CbzE(GJ31) , several mutant enzymes were constructed. Loci for substitutions of amino acids were selected by sequence comparisons as well as by homology modelling of known chlorocatechol 2,3-dioxygenases (CbzE(BASF) , CbzE(SK1) and CbzE(16-6A)). Activity measurements with various catechols showed that most of the modifications influenced activity only to a minor degree. The amino acid at position 154 seems to be located at a non-important position in the enzyme with minor extension into the substrate tunnel. Similarly, the change of related amino acids such as D95E and Y223F did not influence the catalysis since both residues are far away from the catalytic centre and the substrate tunnel. Even the modification of isoleucine to threonine in position 310, located at the outer substrate tunnel, showed a significant alteration of activities. Position 196 seems to be of higher relevance since the modification of valine to alanine, i.e. the reduction of the side-chain, produced much alteration. The amino acid is located at the interface of inner to outer substrate tunnel. CbzE(V196A) showed high relative k(cat) for 3-chlorocatechol. A pronounced increase in activity for 3-chlorocatechol resulted by the change from alanine to valine and from aspartic acid to glycine laying in the outer substrate tunnel at position 211 and 212 respectively.


Lack of relationship of hypogonadism to muscle wasting in myotonic dystrophy.
Myotonic dystrophy is frequently associated with testicular atrophy. Since androgens may play a role in the maintenance of muscle mass, we have studied the levels of plasma testosterone and gonadotropins and of urinary 17-ketosteroids in 22 men with myotonic dystrophy, 36 normal men, and 16 men (control group) with muscle wasting. Results were correlated with muscle mass as estimated by creatinine excretion and total body potassium. Patients with myotonic dystrophy had significantly lower testosterone and higher gonadotropin levels than normal, and these changes were progressive in longitudinal studies. Testosterone levels were also lower than normal in disease control subjects. There was no correlation between low testosterone levels and diminished muscle mass in either myotonic dystrophy or disease control patients. The low plasma concentration of testosterone in men with myotonic dystrophy and other neuromuscular diseases does not appear to be directly related to their muscle wasting. This study does not exclude the possibility that an alteration in testosterone receptor or tissue effects may contribute to a loss of muscle tissue.


Alcohol consumption and midlife cognitive change in the British 1946 birth cohort study.
Cross-sectional studies suggest that alcohol consumption benefits cognitive function. However, more longitudinal studies are required to confirm that alcohol has an effect on cognitive change and to rule out the possibility that those of higher ability engage in a lifestyle that protects against cognitive decline. We investigated the association between self-reported alcohol consumption and change in memory, speed and concentration in midlife, in 903 men and 861 women enrolled in the MRC National Survey of Health and Development (the British 1946 birth cohort). After controlling for educational attainment, occupational social class and general cognitive ability, it was found that alcohol consumption was associated with a slower memory decline from 43 to 53 years in men, but a more rapid decline in visual search speed for the same interval in women. These effects were not explained by a further control for health status (body water weight, smoking, exercise, cardio-respiratory disease and affective state). Our data suggest that alcohol consumption is associated with a slower memory decline. However, the negative association between alcohol and psychomotor function in women is a potential cause for concern.


Established Models and New Paradigms for Hypoxia-Driven Cancer-Associated Bone Disease.
The five-year survival rate for primary bone cancers is ~ 70% while almost all cases of secondary metastatic bone cancer are terminal. Hypoxia, the deficiency of oxygen which occurs as the rate of tumour growth exceeds the supply of vascularisation, is a key promoter of tumour progression. Hypoxia-driven effects in the primary tumour are wide ranging including changes in gene expression, dysregulation of signalling pathways, resistance to chemotherapy, neovascularisation, increased tumour cell proliferation and migration. Paget's seed and soil theory states that for a metastasising tumour cell 'the seed' it requires the correct microenvironment 'soil' to colonise. Why and how metastasising tumour cells colonise the bone is a complex and intriguing problem. However, once present tumour cells are able to disrupt bone homeostasis through increasing osteoclast activity and downregulating osteoblast function. Osteoclast resorption releases growth factors from the bone matrix that subsequently contribute to the proliferation of invasive tumour cells creating the vicious cycle of bone loss and metastatic cancer progression. Recently, we have shown that hypoxia increases expression and release of lysyl oxidase (LOX) from primary mammary tumours, which in turn disrupts bone homeostasis to favour osteolytic degradation to create pre-metastatic niches in the bone microenvironment. We also demonstrated how treatment with bisphosphonates could block this cancer-induced bone remodelling and reduce secondary bone metastases. This review describes the roles of hypoxia in primary tumour progression to metastasis, with a focus on key signalling pathways and treatment options to reduce patient morbidity and increase survival.


Detection of classic and cryptic Strongyloides genotypes by deep amplicon sequencing: A preliminary survey of dog and human specimens collected from remote Australian communities.
Strongyloidiasis is caused by the human infective nematodes Strongyloides stercoralis, Strongyloides fuelleborni subsp. fuelleborni and Strongyloides fuelleborni subsp. kellyi. The zoonotic potential of S. stercoralis and the potential role of dogs in the maintenance of strongyloidiasis transmission has been a topic of interest and discussion for many years. In Australia, strongyloidiasis is prevalent in remote socioeconomically disadvantaged communities in the north of the continent. Being an isolated continent that has been separated from other regions for a long geological period, description of diversity of Australian Strongyloides genotypes adds to our understanding of the genetic diversity within the genus. Using PCR and amplicon sequencing (Illumina sequencing technology), we sequenced the Strongyloides SSU rDNA hyper-variable I and hyper-variable IV regions using Strongyloides-specific primers, and a fragment of the mtDNA cox1 gene using primers that are broadly specific for Strongyloides sp. and hookworms. These loci were amplified from DNA extracted from Australian human and dog faeces, and one human sputum sample. Using this approach, we confirm for the first time that potentially zoonotic S. stercoralis populations are present in Australia, suggesting that dogs represent a potential reservoir of human strongyloidiasis in remote Australian communities.


Verification of a method to detect glass microspheres via micro-CT.
The ability to determine the microscopic distribution of glass microspheres in 90 Y radioembolization has important applications in post-treatment microdosimetry and cluster analysis. Current methods are time-intensive and labor-intensive and thus are typically only applied to small samples. A high-resolution micro-CT image with a voxel size of 8.74 µm was acquired of phantoms containing ~25 µm-diameter glass microspheres embedded in tissue-equivalent materials that were optically transparent, which allowed true microsphere locations to be determined using transmission light microscopy. A 3-stage algorithm was developed to estimate the number and locations of microspheres in tissue regions. The stages are thresholding the CT image and discarding regions with insufficient voxels, estimating the number of microspheres in each region using the values of the detected and neighboring region voxels and estimating locations for each microsphere using the outputs of the previous two stages. Two different methods for estimating the number of microspheres in each region were derived, as were five methods for localizing microspheres. Metrics for each stage were computed, and the mean absolute error (MAE) between the dose to 72 µm voxels of the true and estimated dose maps created from the microsphere locations was used as the figure of merit for overall algorithm performance. Microsphere locations identified in the optical micrograph were used as the gold standard for the metrics of all stages. The method's utility was then demonstrated using a specimen from a human neuroendocrine tumor (NET) treated with glass 90 Y microspheres. The stage detecting regions containing microspheres found 100% of microspheres inside regions. The number of incorrectly detected regions without microspheres was 1.5% of the total number of regions. In stage 2, with these parameters, nearly 94% of the actual number of spheres in each region was correctly counted, and only 5% of the estimated sphere quantities in each region were false positives. The MAE between the true dose maps and dose maps estimated using the full algorithm with optimal parameter and method choices was 4.2%. A total of 5,713 glass microspheres were identified as being distributed heterogeneously in the NET specimen with a maximum tumor dose of >2500 Gy and 46% of the specimen receiving <20 Gy. This work developed and evaluated a method to detect and estimate the three-dimensional locations of glass microspheres in whole tissue samples that require less manual effort than traditional methods. This method could be used to gain important insights into the heterogeneity of microsphere distributions that would be useful for improving radioembolization treatment planning.


How racial animus forms and spreads: Evidence from the coronavirus pandemic.
This paper studies the formation and the spread of crisis-driven racial animus during the coronavirus pandemic. Exploiting plausibly exogenous variation in the timing of the first COVID-19 diagnosis across US areas, we find that the first local case leads to an immediate increase in local anti-Asian animus, as measured by Google searches and Twitter posts that include a commonly used derogatory racial epithet. This rise in animus specifically targets Asians and mainly comes from users who use the epithet for the first time. These first-time ch-word users are more likely to have expressed animosity against non-Asian minorities in the past, and their interaction with other anti-Asian individuals predicts the timing of their first ch-word tweets. Moreover, online animosity and offline hate incidents against Asians both increase with the salience of the connection between China and COVID-19; while the increase in racial animus is not associated with the local economic impact of the pandemic. Finally, the pandemic-driven racial animus we documented may persist beyond the duration of the pandemic, as most racist tweets do not explicitly mention the virus.


Laser-induced primate glaucoma. II. Histopathology.
A sustained, moderate pressure elevation was produced in 15 nonhuman primate eyes by application of laser energy to the trabecular meshwork. By light and electron microscopy, the trabecular beams were blunted, and scattered synechiae were present. Backward bowing of the lamina cribrosa, partial loss of the myelin sheath surrounding axonal segments just posterior to the lamina, and diffuse axonal loss involving the entire nerve cross section were noted. A quantitative analysis of this axonal loss revealed that eyes with moderate nerve head damage (cup-disc ratio, 0.6 to 0.8) had only 38% to 69% of the expected normal axonal count. The eyes with nearly total cupping (cup-disc ratio, 0.9 to 1.0) maintained between 10% and 36% of the normal axonal count. The disc changes in these experimental eyes are similar to those previously described in human eyes with glaucoma.


Pilonidal sinus of the umbilicus.
Only 15 cases of pilonidal sinus of the umbilicus have so far been reported. A 16th case is described; it supports the theory of acquired origin of the disease. The case fulfilled the criterion for pilonidal sinus--the 36-year-old man had a hair in the infected umbilical cyst. The cyst and umbilicus were excised. The umbilicus was not reconstructed because of the danger of recurrence. It is recommended that a careful search be carried out for hair in all patients with an infected umbilicus.


Creating metasummaries of qualitative findings.
The translation and grounded theory techniques typically cited as the method for producing qualitative metasyntheses do not lend themselves well to qualitative survey findings as they do not contain the integrating concepts or controlling metaphors upon which these techniques depend. The purpose of this article is to describe a process for creating metasummaries of qualitative survey findings. This article is based on completed work in an ongoing methodological study aimed at developing a usable and transparent protocol for combining the findings in reports of health-related qualitative studies. The sample for this work included 45 published and unpublished reports of qualitative studies of HIV-positive women with findings on motherhood, 39 of which contained findings in the form of surveys of data. Almost 800 findings were extracted. These extracted findings were reduced to 93 abstracted findings, and manifest frequency and intensity effect sizes were calculated. Five findings had effect sizes ranging from 25-60%, with both published and unpublished reports contributing about equally to the strength of these findings. Seventy-three findings had effect sizes of <9%, 47 of them with effect sizes of only 2%. In most of these cases, only one work contained the finding and these works had generally fewer space restrictions. Four reports with few space restrictions contained 63% of the findings across all 45 reports. Qualitative metasummaries are useful end products of research integration studies involving reports of findings in the form of qualitative surveys, and may serve as a foundation for qualitative metasyntheses.


Reciprocal amplification of caspase-3 activity by nuclear export of a putative human RNA-modifying protein, PUS10 during TRAIL-induced apoptosis.
Pus10 is a pseudouridine synthase present in Archaea and Eukarya, but not in Bacteria and yeast. It has been suggested that the human PUS10 (DOBI) gene is needed during TRAIL-induced apoptosis. We analyzed the role of PUS10 in TRAIL-induced apoptosis by immunofluorescence, immunoblotting and several indicators of apoptosis. We examined several TRAIL-sensitive cell lines and we also examined some resistant cell lines after treatment with cycloheximide. PUS10 is mainly present in the nucleus. Early during apoptosis, PUS10 translocates to mitochondria via CRM1-mediated export with the concurrent release of cytochrome c and SMAC. Caspase-3 is required for PUS10 translocation, which reciprocally amplifies the activity of caspase-3 through the intrinsic/mitochondrial pathway. This suggests that in addition to cytoplasmic factors, nuclear factors also have a direct role in the major apoptosis pathways. However, p53 is not involved in TRAIL-induced PUS10 movement. The caspase-3-mediated movement of PUS10 and the release of mitochondrial contents enhancing caspase-3 activity creates a feedback amplification loop for caspase-3 action. Therefore, any defect in the movement or interactions of PUS10 would reduce the TRAIL sensitivity of tumor cells.