Postpyloric enteral feeding costs for patients with severe head injury: blind placement, endoscopy, and PEG/J versus TPN.
This study describes the advantages and disadvantages of several forms of enteral nutrition for patients with severe head injury (Glasgow Coma Scale Score [GCS], <12). Included in the study are nasoenteric nutrition delivery using blind, endoscopic, percutaneous endoscopic gastrostomy (PEG) and PEG with jejeunostomy (PEG/J), and open jejeunostomy tube placement methods. These methods are compared with parenteral delivery of nutrition. The study constituted a retrospective analysis of the success rate of early enteral feedings by blind, endoscopic PEG and PEG/J and by open jejeunostomy placement of small-bowel feeding tubes for 57 patients with severe head injury. The delivery cost of enteral nutrition per intensive care unit day was compared to the delivery cost of parenteral nutrition per intensive care unit day in the same group of patients. Fifty-three percent of patients were adequately maintained nutritionally with nasoenteric delivery alone and did not require parenteral feeding. The average number of days for initiation of either enteral or parenteral feedings was 1.8 +/- 0.2 days from injury [standard error of mean (SEM); range, 0-10 days]. An average of 3.3 days (range, 0-23 days) was required for feeding tube placement in all patients. For 70% of patients, tube placement was completed within 48 h after injury. Full-strength, full-rate enteral feedings were achieved by a mean of 4.9 days after injury. A total of 128 feeding tubes were placed while the patients were in the intensive care unit (ICU; 2.2 +/- 0.2 tubes per patient). Blind placement of feeding tubes into the small bowel was rarely achieved without repositioning. Endoscopic tube placement into the duodenum was achieved in 50% of patients, into the jejunum for 33% of patients, and into the stomach for 18% of patients. While in the intensive care unit, patients received an average of 77 +/- 2% of their measured energy expenditure (range, 57-114%). Eleven percent of patients experienced severe gastrointestinal problems. Other problems were associated with the inability to achieve or maintain access: dislodged tubes (30%), clogged or kinked tubes (21%), and mechanical access problems (7 %). Seventy-one percent of patients in barbiturate coma were able to tolerate early nasoenteric feedings. Aspiration pneumonitis occurred equally among patients fed nasogastrically and those fed nasoenterically. The overall aspiration rate was 14%. The cost of acute enteral feeding was $170 per day and that for parenteral feeding, $308 per day. We conclude that blind transpyloric feeding tube placement is difficult to achieve in patients with severe head injury; endoscopically guided placement is a better option. Endoscopic feeding tube placement most consistently allows for early enteral nutritional support in severe head injured patients. Limitations include the inability to establish and/or maintain enteral access, increased intracranial pressure, unstable cervical spinal injuries, facial fractures, and dedication of the physician to tube placement and monitoring.


Detection of human herpes virus 8 DNA and sequence polymorphism in classical, epidemic, and iatrogenic Kaposi's sarcoma in South Africa.
The aetiology and detection of human herpes virus type 8 (HHV-8) DNA sequences in Kaposi's sarcoma (KS) is a matter of intense investigation. We report on the detection of HHV-8 DNA and sequence polymorphism in different clinicopathological subtypes of cutaneous KS samples from South Africa. The diagnosis was confirmed by histological examination in all cases. Six patients had classic KS (CKS), 3 epidemic KS (EKS), and 3 iatrogenic KS (IKS). A nested polymerase chain reaction (PCR) assay was used to detect HHV-8 DNA in cell lysates, prepared from formalin fixed, paraffin embedded sections. We investigated polymorphism in the HHV-8 DNA using single-stranded conformational polymorphism (SSCP) analysis on the PCR products, followed by direct sequencing. HHV-8 DNA was detected in all the patients with KS, irrespective of the clinicopathological subtype. Direct sequencing was performed on 5 selected cases and showed single base pair substitutions in all. The spectrum of mutations was similar to those described previously. No correlation was found between the different types of KS and sequence variation. The results support the hypothesis that HHV-8 is strongly associated with different clinicopathological subtypes of KS and confirm the occurrence of HHV-8 in patients with CKS, EKS, and IKS in South Africa.


Nutrient-Controlled Niche Differentiation of Western Lake Erie Cyanobacterial Populations Revealed via Metatranscriptomic Surveys.
Although toxic cyanobacterial blooms in western Lake Erie threaten drinking water supplies and are promoted by nutrient loading, the precise nutrient regime that selects specific cyanobacteria populations is poorly understood. Here, we assess shifts in cyanobacterial abundances and global gene-expression patterns in response to natural and manipulated gradients in nitrogen and phosphorus to identify gene pathways that facilitate dominance by different cyanobacteria. Gradients in soluble reactive phosphorus shaped cyanobacterial communities and elicited the largest transcriptomic responses. Under high-P conditions (closest to the mouth of the Maumee River), Anabaena and Planktothrix were the dominant cyanobacterial populations, and experimental P and ammonium enrichment promoted nitrogen fixation gene (nifH) expression in Anabaena. For Microcystis, experimental additions of P up-regulated genes involved in phage defense, genomic rearrangement, and nitrogen acquisition but led to lower abundances. Within offshore, low-P regions of the western basin of Lake Erie, Microcystis up-regulated genes associated with P scavenging (pstSCAB, phoX) and dominated cyanobacterial communities. Experimental additions of ammonium and urea did not alter Microcystis abundances but did up-regulate protease inhibitors (aer and mcn gene sets) and microcystin synthetase genes (mcy), with urea enrichment yielding significant increases in microcystin concentrations. Our findings suggest that management plans that reduce P loads alone may not significantly reduce the risk of cyanobacterial blooms in western Lake Erie but rather may promote a shift among cyanobacterial populations (Microcystis, Anabaena, and Planktothrix) toward a greater dominance by toxic strains of Microcystis.


A density functional study of the spin state energetics of polypyrazolylborato complexes of first-row transition metals.
Density Functional Theory (DFT) was used to analyse and explain spin state energetics of first-row transition metals (Mn(II), Fe(II), Co(II); Cr(III), Mn(III), Fe(III), Co(III); Mn(IV)) in polypyrazolylborato complexes. We explored the effects of substitutions at the 3 and 5 positions of the pyrazolyl rings, as well as the influence of Jahn-Teller (JT) distortions on spin-state switching. Although the stabilizations due to JT distortion are sometimes substantial, this does not lead to switching of the spin ground-state. On the other hand, electron withdrawing or donating substituents do lead to significant changes in the spin-crossover (SCO) properties of the investigated complexes.


In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.
Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated the in vitro and in vivo activity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against both C. neoformans and C. gattii APX001A and APX2020 demonstrated in vitro synergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10 CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10 CFU/g lung tissue and from 7.00 and 0.92 log10 CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.


Presynaptic plasticity at cerebellar parallel fiber terminals.
The cerebellum plays a role in the control of sensorimotor functions and possibly also of higher cognitive processing. The granule cells, which are abundant and unique in their characteristic dendritic morphology, allow the cerebellum to combine the advantages of sparse coding with a high sensitivity for individual afferents at the input stage. Plastic changes in the granular layer circuitry may thus control instant transformation of inputs as well as long-term modifications so as to support procedural memory formation. Over recent decades, substantial research has been done to explore the mechanisms of postsynaptic changes that may sustain learning processes in the cerebellum, especially bidirectional plasticity at the parallel fiber to Purkinje cell synapse. In contrast, the presynaptic occurrence of synaptic plasticity has been relatively neglected. Here we review the current models of granular layer processing in the framework of cerebellar functioning with special emphasis on the presynaptic modulations of operations at the parallel fiber to Purkinje cell synapse. We argue that the wide range of possible mechanisms that can strengthen the parallel fiber to Purkinje cell synapse at the presynaptic level endows the cerebellar cortex with optimal computational capacities to potentiate both spatial and temporal cues that are relevant for fine-regulating memory formation.


Developmental basis of homeosis in precociously germinating Brassica napus embryos: phase change at the shoot apex.
Precociously germinating Brassica napus (oilseed rape) embryos produce extra cotyledons or chimeric organs with sectors of cotyledon and leaf tissue, rather than leaves, at the shoot apex. To investigate this phenomenon in more detail, scanning electron microscopy was used to examine the development of organ primordia at the shoot apex. In situ hybridizations with molecular markers of the embryonic phase were used to assess the status of individual cells in the shoot apex with regard to the transition between embryonic and vegetative phases. The results indicate that, under conditions that support precocious germination, primordia develop at the shoot apex in the mode characteristic of postgerminative growth, i.e. they arise sequentially in a spiral phyllotaxy. Cells in the rest of the embryo, however, can continue to express molecular markers of the embryonic phase for several weeks after the start of culture. When patterns of gene expression and the fate of individual primordia were compared, a strong correlation was found between organ identity and the status of cells in the vicinity of the meristem with regard to phase. Primordia that develop in situations where neighboring cells are in the embryonic phase always produce organs with cotyledon morphology. Primordia that develop in situations where neighboring cells have exited the embryonic phase produce leaves. Based on an examination of situations where chimeric organs are produced, I propose that short range interactions or signalling are likely to be involved in communicating information about phase to developing primordia.


Assessment of Graft Maturity After Anterior Cruciate Ligament Reconstruction Using Autografts: A Systematic Review of Biopsy and Magnetic Resonance Imaging studies.
The purpose of this investigation was to evaluate systematically the literature concerning biopsy, MRI signal to noise quotient (SNQ) and clinical outcomes in graft-maturity assessment after autograft anterior cruciate ligament reconstruction (ACLR) and their possible relationships. The systematic review was reported and conducted according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Studies through May 2019 evaluating methods of intra-articular ACL autograft maturity assessment were considered for inclusion. Eligible methods were histologic studies of biopsy specimens and conventional MRI studies reporting serial SNQ and/or correlation with clinical parameters. Ten biopsy studies and 13 imaging studies, with a total of 706 patients, met the inclusion criteria. Biopsy studies show that graft remodeling undergoes an early healing phase, a phase of remodeling or proliferation and a ligamentization phase as an ongoing process even 1 year after surgery. Imaging studies showed an initial increase in SNQ, peaking at approximately 6 months, followed by a gradual decrease over time. There is no evident correlation between graft SNQ and knee stability outcome scores at the short- and long-term follow-up after ACLR. The remodeling of the graft is an ongoing process even 1 year after ACLR, based on human biopsy studies. MRI SNQ peaked at approximately 6 months, followed by a gradual decrease over time. Heterogeneity of the MRI methods and technical restrictions used in the current literature limit prediction of graft maturity and clinical and functional outcome measures by means of MRI graft SNQ after ACLR. Level IV, systematic review, including level III and IV studies.


Right ventricular mechanics in hypertrophic cardiomyopathy using feature tracking.
Right ventricular (RV) mechanics in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigate global and regional deformation of the RV in HCM and its relationship to LV phenotype, using 2D strain vector velocity imaging (VVI). 100 HCM patients (42% females, 41 ± 19 years) and 30 control patients were studied using VVI. Longitudinal peak systolic strain (ϵsys), strain rate (SR), time to peak (ϵ) (TTP), displacement of RV free wall (RVFW) and septal wall were analyzed. Similar parameters were quantified in LV septal, lateral, anterior and inferior segments. Intra-V-delay was defined as SD of TTP. Inter-V-delay was estimated from TTP difference between the most delayed LV segment & RVFW. ϵsys and SR of both RV & LV, showed loss of base to apex gradient and significant decline in HCM (p < 0.001). Deformation variables estimated from RVFW were strongly correlated with each other (r = 0.93, p < 0.0001). Both were directly related to LV ϵsys, SRsys, SRe, ejection fraction (EF)%, RVFW displacement (P < 0.001) and inversely related to age, positive family history (p < 0.004, 0.005), RV wall thickness, maximum wall thickness (MWT), intra-V-delay, LA volume (P < 0.0001), LVOT gradient (p < 0.02, 0.005) respectively. ROC curves were constructed to explore the cut-off point that discriminates RV dysfunction. Global and RVFW ϵsys: - 19.5% shows 77, 70% sensitivity & 97% specificity, SRsys: - 1.3s(- 1) shows 82, 70% sensitivity & 30% specificity. Multivariate analyses revealed that RVFW displacement (β = - 0.9, p < 0.0001) and global LV SRsys (β = 5.9, p < 0.0001) are independent predictors of global RV deformation. Impairment of RV deformation is evident in HCM using feature tracking. It is independently influenced by LV mechanics and correlated to the severity of LV phenotype. RVFW deformation analysis and global RV assessment are comparable.


Effects of unweighting and speed on in-shoe regional loading during running on a lower body positive pressure treadmill.
The purpose of this study was to determine how unweighted running on a lower body positive pressure treadmill (LBPPT) modifies in-shoe regional loading. Ten experienced runners were fit with pressure distribution measurement insoles and ran at 100%, 120%, and 140% of self-reported easy training pace on a LBPPT at 20%, 40%, 60%, 80%, and 100% body weight percentage settings (BWSet). Speeds and BWSet were in random order. A linear mixed effect model (p<0.05 significance level) was used to compare differences in whole foot and regional maximum in-shoe plantar force (FMAX), impulse, and relative load distribution across speeds and BWSet. There were significant main effects (p<0.001) for running speed and BWSet for whole foot Fmax and impulse. The model revealed 1.4% and 0.24% increases in whole foot FMAX (times body weight) and impulse, respectively, for every unit increase in body weight percentage. There was a significant main effect for BWSet on Fmax and relative load (p<0.05) for each of the nine foot regions examined, though four regions were not different between 80% and 100% BWSet. There was a significant (p<0.001) main effect for BWSet on forefoot to rear foot relative load. Linear relationships were found between increases in BWSet and increases in-shoe Fmax and impulse, resulting from regional changes in foot pressure which represent a shift towards forefoot loading, most evident <80% BWSet. Estimating in-shoe regional loading parameters may be useful during rehabilitation and training to appropriately prescribe specific speed and body weight levels, without exceeding certain critical peak force levels while running.


Genome characterization of an extensively drug-resistant Streptococcus pneumoniae serotype 11A strain.
In this study, the whole genome sequences of two Streptococcus pneumoniae clinical isolates from South Korea were determined and compared. They were found to be the same serotype (11 A) and multilocus sequence typing analysis showed that they are single-locus variants (SLVs; ST8279 and ST166) of each other, differing at one allele (aroE). However, the ST8279 strain is extensively drug-resistant (XDR) whereas the ST166 strain is not. The genome of the XDR strain is very similar in structure to that of two previously reported genomes, AP200 (11 A:ST62) and 70585 (5:ST5803); however, some regions were inverted and there were some exogenous regions in the ST8279 strain. It was found that 6,502 single nucleotide polymorphisms are dispersed across the genome between the two serotype 11 A ST8279 and ST166 strains. Many of them are located in genes associated with antibiotic resistance. In addition, many amino acid differences were also identified in genes involved in DNA repair (mutL, uvrA and uvrC) and recombination (recU, recR and recA). On the basis of these results, it was inferred that the XDR strain did not evolve from its SLV via a single recombination event involving a large portion of the genome including the aroE gene. Rather, the strain likely evolved through many point mutations and recombination events involving small portions of the genome.


Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis.
Papillary thyroid cancer (PTC) in young patients may rarely be encountered with pulmonary metastases. Previous studies have suggested that, in the pediatric population, this may not portend a lethal outcome. Our present study, children with pulmonary metastases, was designed to clarify this issue. Fourteen children and young adolescents (mean age, 13.5 years; range, 9.8-17 years) with PTC and pulmonary metastases were treated at our institution between 1937 and 1998. Surgical treatment consisted of total thyroidectomy (n = 10 patients), subtotal thyroidectomy (n = 3 patients), and a biopsy only procedure (n = 1 patient). All patients who underwent thyroidectomy also underwent a variety of cervical lymph node dissections, and all patients proved to have regional nodal disease. After the operation, 12 patients were treated with ablative doses of (131)I, 1 patient was treated with external beam irradiation, and all patients were placed on suppressive thyroid hormone therapy. The mean length of follow-up was 19.3 years (range, 1-45 years). Regional recurrent disease developed in 2 patients (15%). No patient experienced the development of worsening pulmonary disease or extra-pulmonary metastases. All patients with recurrent disease underwent selective nodal resections. No patient died of metastatic PTC. Seven patients (50%) remain completely free of disease and are probably cured; 7 patients (50%) are asymptomatic with residual pulmonary disease. A stepwise treatment approach allows long-term survival and frequent cure for young patients with PTC and concomitant pulmonary metastases.


Ascorbic acid increases healing of excision wounds of mice whole body exposed to different doses of gamma-radiation.
Because of the practical importance of acute radiation exposure associated with combined injuries, it is imperative to investigate the efficacy of cost-effective nutritional factors in the reconstruction of irradiated wounds. Therefore, effect of pretreatment of ascorbic acid was studied on the healing of excised wounds in mice exposed to 2, 4, 6 and 8 Gy whole body gamma-radiation. A full-thickness wound was created on the dorsum of the irradiated mice and the progression of wound contraction was monitored by capturing video images of the wound at various varying days after irradiation. Irradiation caused a dose dependent delay in wound contraction and wound healing time, while ascorbic acid pretreatment resulted in a significant acceleration in the rate of wound contraction and a decrease in the mean wound healing time. To understand the mechanism of healing, collagen, hexosamine, DNA, nitrite and nitrate contents were measured in the granulation tissue of wounded mice treated with ascorbic acid before exposure to 6 Gy gamma-radiation. Ascorbic acid treatment prior to irradiation enhanced the synthesis of collagen, hexosamine, DNA, nitrite and nitrate contents. The histological assessment of wound biopsy revealed an improved collagen deposition, and increase in fibroblast and vascular densities. The present study demonstrates that ascorbic acid pretreatment has a beneficial effect on the irradiated wound and could be a substantial therapeutic strategy to accelerate wound repair in irradiated wounds and in the cases of combined injury situations.


Comparative genomics of BCG vaccines by whole-genome DNA microarray.
Bacille Calmette-Guérin (BCG) vaccines are live attenuated strains of Mycobacterium bovis administered to prevent tuberculosis. To better understand the differences between M. tuberculosis, M. bovis, and the various BCG daughter strains, their genomic compositions were studied by performing comparative hybridization experiments on a DNA microarray. Regions deleted from BCG vaccines relative to the virulent M. tuberculosis H37Rv reference strain were confirmed by sequencing across the missing segment of the H37Rv genome. Eleven regions (encompassing 91 open reading frames) of H37Rv were found that were absent from one or more virulent strains of M. bovis. Five additional regions representing 38 open reading frames were present in M. bovis but absent from some or all BCG strains; this is evidence for the ongoing evolution of BCG strains since their original derivation. A precise understanding of the genetic differences between closely related Mycobacteria suggests rational approaches to the design of improved diagnostics and vaccines.


Extended rodlike polyaromatic receptors with bent tridentate units complexed to lanthanide metal ions.
A synthetic strategy is developed to attach semirigid lipophilic sidearms to the 6-positions of bent aromatic tridentate 2,6-bis(benzimidazol-2-yl)pyridine cores to produce U-shaped ligands, L6,7. Differential scanning calorimetry (DSC) reveals that entropic contributions severely affect the isotropization processes of these flexible receptors, but no mesomorphism is detected. The attachment of oxygen linkers to the 5- or 6-positions of the benzimidazole sidearms lowers the ligand-centered 1 pi pi* and 3 pi pi* excited states, and the semiempirical ZINDO method assigns this effect to a destabilization of the HOMO orbitals resulting from pi-interactions. Reactions of L6 with Ln(NO3)3.xH2O provide the rodlike 1:1 complexes [Ln(L6)(NO3)3] (Ln = La-Lu), which are stable in the solid state but partially dissociate in acetonitrile. The crystal structure of [Lu(L6)(NO3)3].CH3CN (18a, LuC63H84N9O13, monoclinic, P2(1)/n, Z = 4) reveals an I-shaped arrangement of the ligand strand arising from the meridional complexation of the bent tridentate unit to nine-coordinate Lu(III). The replacement of nitrate anions with trifluoroacetate anions gives the centrosymmetric dimer [Lu(L6)(CF3CO2)3]2 (23, Lu2C134H162N10O20F18, triclinic, P1, Z = 1), in which the symmetry-related Lu atoms are connected by two bridging carboxylates, leading to an H-shaped dimetallic edifice. These complexes [Ln(L6)(NO3)3] and [Ln(L6)(CF3CO2)3]2 fulfill the geometrical criteria required by precursors of calamitic metallomesogens, but no mesomorphism can be detected, while photophysical studies indicate that the low energies of ligand-centered 3 pi pi* excited states drastically limit the luminescence of Eu(III) complexes. The relationships between structural and electronic properties resulting from 5- or 6-substitutions of the benzimidazole rings and the effects of these substitutions on photophysical and thermal properties are discussed.


Depressive symptoms associated with scleroderma.
To examine the prevalence and correlates of depressive symptoms among patients with systemic sclerosis (SSc; scleroderma). Fifty-four outpatients with scleroderma were administered the Beck Depression Inventory, the Neuroticism-Extraversion-Openness Personality Inventory, the Health Assessment Questionnaire, and the Psychosocial Adjustment to Illness Scale. In addition, patients underwent a comprehensive clinical assessment, and pulmonary function tests were obtained. Nearly half of the patients had mild depressive symptoms, and an additional 17% had symptoms in the moderate-to-severe range. Younger patients, those with digital ulceration, and those with more self-rate functional impairment had more depressive symptoms, but there were few other relationships between depressive symptoms and either demographic or physician-rated medical variables. In contrast, there were highly significant relationships between depression and aspects of personality, psychosocial adjustment to illness, and social support. Depressive symptoms in patients with SSc are more strongly related to personality, self-rated disability, and adequacy of emotional support than to objective medical indices of illness severity. Depression in scleroderma is a debilitating comorbid condition that should be recognized and treated in its own right.


Effectiveness of passive physical modalities for shoulder pain: systematic review by the Ontario protocol for traffic injury management collaboration.
Shoulder pain is a common musculoskeletal condition in the general population. Passive physical modalities are commonly used to treat shoulder pain. However, previous systematic reviews reported conflicting results. The aim of this study was to evaluate the effectiveness of passive physical modalities for the management of soft tissue injuries of the shoulder. MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched from January 1, 1990, to April 18, 2013. Randomized controlled trials (RCTs) and cohort and case-control studies were eligible. Random pairs of independent reviewers screened 1,470 of 1,760 retrieved articles after removing 290 duplicates. Twenty-two articles were eligible for critical appraisal. Eligible studies were critically appraised using the Scottish Intercollegiate Guidelines Network criteria. Of those, 11 studies had a low risk of bias. The lead author extracted data from low risk of bias studies and built evidence tables. A second reviewer independently checked the extracted data. The findings of studies with a low risk of bias were synthesized according to principles of best evidence synthesis. Pretensioned tape, ultrasound, and interferential current were found to be noneffective for managing shoulder pain. However, diathermy and corticosteroid injections led to similar outcomes. Low-level laser therapy provided short-term pain reduction for subacromial impingement syndrome. Extracorporeal shock-wave therapy was not effective for subacromial impingement syndrome but provided benefits for persistent shoulder calcific tendinitis. Non-English studies were excluded. Most passive physical modalities do not benefit patients with subacromial impingement syndrome. However, low-level laser therapy is more effective than placebo or ultrasound for subacromial impingement syndrome. Similarly, shock-wave therapy is more effective than sham therapy for persistent shoulder calcific tendinitis.


Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells.
Understanding the unique phenotypes and complex signaling pathways of leukemia stem cells (LSCs) will provide insights and druggable targets that can be used to eradicate acute myeloid leukemia (AML). Current work on AML LSCs is limited by the number of parameters that conventional flow cytometry (FCM) can analyze because of cell autofluorescence and fluorescent dye spectral overlap. Single-cell mass cytometry (CyTOF) substitutes rare earth elements for fluorophores to label antibodies, which allows measurements of up to 120 parameters in single cells without correction for spectral overlap. The aim of this study was the evaluation of intracellular signaling in antigen-defined stem/progenitor cell subsets in primary AML. CyTOF and conventional FCM yielded comparable results on LSC phenotypes defined by CD45, CD34, CD38, CD123, and CD99. Intracellular phosphoprotein responses to ex vivo cell signaling inhibitors and cytokine stimulation were assessed in myeloid leukemia cell lines and one primary AML sample. CyTOF and conventional FCM results were confirmed by western blotting. In the primary AML sample, we investigated the cell responses to ex vivo stimulation with stem cell factor and BEZ235-induced inhibition of PI3K and identified activation patterns in multiple PI3K downstream signaling pathways including p-4EBP1, p-AKT, and p-S6, particularly in CD34(+) subsets. We evaluated multiple signaling pathways in antigen-defined subpopulations in primary AML cells with FLT3-ITD mutations. The data demonstrated the heterogeneity of cell phenotype distribution and distinct patterns of signaling activation across AML samples and between AML and normal samples. The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem/progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML. Our data suggest that CyTOF can identify functional signaling pathways in antigen-defined subpopulations in primary AML, which may provide a rationale for designing therapeutics targeting LSC-enriched cell populations.


Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity.
Reduced-intensity conditioning regimens allow application of allogeneic stem cell transplantation to greater numbers of patients with myeloma by reducing transplantation-related mortality. We prospectively evaluated the role of an approach incorporating in vivo T-cell depletion and subsequent adjuvant donor lymphocyte infusions (DLIs) as part of front-line therapy for chemotherapy-sensitive multiple myeloma. Twenty patients with HLA-matched related (n = 12) or unrelated (n = 8) donors entered the study. None had previously undergone autologous transplantation. Acute graft-versus-host disease (GVHD) following transplantation was minimal (3 grade II and no grade III or IV). Nonrelapse mortality rate was relatively low (15%) compared with conventional myeloablative allogeneic transplantation series, although it remained significantly higher than in the autologous setting. Disease responses by 6 months posttransplantation were modest (2 in complete remission, 4 in partial remission, 2 were minimally responsive, 6 had no change, 3 had progressive disease, and 3 were not evaluable). Fourteen patients received escalating-dose DLI for residual/progressive disease. Three developed acute GVHD and 2 developed limited chronic GVHD. Seven demonstrated further disease responses, which appeared to be more common in those developing GVHD (5 of 5 versus 2 of 9; P =.02). All responses were associated with conversion from mixed to full donor T-cell chimerism. Response durations were disappointing (5 <12 months) and progression often occurred despite persisting full donor chimerism. Two-year estimated overall survival and current progression-free survival rates (intention to treat with DLI from 6 months) were 71% and 30%, respectively. The current approach incorporating T-cell depletion appears excessively immunosuppressive despite attempts to restore immune function with DLI. Dose escalation failed to allow convincing dissociation of graft-versus-myeloma from GVHD. Attempts to hasten immune reconstitution and to focus and amplify appropriate components of allogeneic T-cell responses will be required to increase complete remission rates and response durations.


Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients.
About 10% of patients with Merkel cell carcinoma (MCC) suffer from an associated squamous cell carcinoma (SCC). In European patients, Merkel cell polyomavirus (MCPyV) is detectable in 60%-88% of the MCC tumors. In combined lesions, MCPyV was not detectable so far. We investigated 2 combined tumors of MCC and SCC for the presence of MCPyV and human papillomavirus (HPV) by polymerase chain reaction and immunohistochemistry. In both lesions, MCPyV DNA was found, and in 1 case, HPV DNA was also detected. This is the first report of a coinfection with HPV and MCPyV in combined MCC-SCC tumors. The results underline the hypothesis of co-cancerogenesis of 2 oncogenic viruses in nonmelanoma skin cancer. Technical reasons and a low viral copy number of MCPyV hampering immunohistochemical detection may be responsible for the negative results in the literature.


Maintaining Aging Hippocampal Function with Safe and Feasible Shaking Exercise in SAMP10 Mice.
The disabling effects of dementia, an incurable disease with little effect on mortality, affect society far more than many other conditions. The aim of this study was to stop or delay the onset of dementia using low-cost methods such as physical exercise. Senescence-accelerated model-prone (SAMP) 10 mice were made to perform a user-friendly shaking exercise for 25 weeks. The motor function and hippocampal functions (learning, spatial cognition) of the mice were evaluated using behavioral experiments. The degree of hippocampal aging was evaluated based on brain morphology. The association between behavioral performance of the mice and the degree of hippocampal aging was then evaluated. The behavioral test results showed that the shaking group had higher motor coordination (p < 0.01) and motor learning (p < 0.05). Significantly higher performances in the learning ability were observed in the shaking group at a middle-period experiment (p < 0.05); the spatial cognitive functions also improved (p < 0.05). The shaking group showed delayed ageing of cells in the dentate gyrus (DG; area: p < 0.01) and cornu Ammonis (CA; area: p < 0.01) regions of the hippocampus. The shaking exercise enhances the activity of mice and reduces age-associated decreases in learning and spatial cognitive functions. Regarding hippocampal morphology, shaking exercise can prevent non-functional protein accumulation, cell atrophy, and cell loss. Specifically, shaking exercise protects cell growth and regeneration in the DG area and enhances the learning function of the hippocampus. Furthermore, shaking exercise maintained the spatial cognitive function of cells in the CA3 and CA1 regions, and prevented the chronic loss of CA2 transmission that decreased the spatial memory decline in mice.


Chemoselective photooxygenations of furans bearing unprotected amines: their use in alkaloid synthesis.
Very recent investigations are described, which have shown how basic and unprotected nitrogen functionalities can be included, problem-free, in the furan photooxidation step of singlet oxygen-initiated cascade reaction sequences. The amine groups do not react with singlet oxygen, but, instead, participate later on in the sequences that ultimately yield a diverse range of important alkaloid motifs. To illustrate the versatility of this chemistry, six natural products were synthesised very rapidly and efficiently. Furthermore, all the new technologies operated under green conditions and without the use of a single protecting group.


Incidence, risk, and protective factors of bicycle crashes: findings from a prospective cohort study in New Zealand.
To estimate the incidence and risk of medically or police attended bicycle crashes in a prospective cohort study in New Zealand. The Taupo Bicycle Study involved 2590 adult cyclists recruited from the country's largest cycling event in 2006 and followed over a median period of 4.6 years through linkage to four administrative databases. Incidence rates with Poisson distribution confidence intervals were computed and Cox regression modelling for repeated events was performed. The 66 on-road crashes and 10 collisions per 1000 person-years corresponded to 240 crashes and 38 collisions per million hours spent road cycling. The risk increased by 6% and 8% respectively for an extra cycling hour each week. There were 50 off-road crashes per 1000 person-years. Residing in urban areas and in Auckland (region with the lowest level of cycling), riding in a bunch, using a road bike and experiencing a previous crash predicted a higher risk. Habitual use of conspicuity aids appeared to lower the risk. The risk is higher in urban areas and where cycling is less common, and increased by bunch riding and previous crashes. These findings alongside the possible protective effect of conspicuity aids suggest promising approaches to improving cycle safety.


Natural killer cell development is blocked in the context of aberrant T lymphocyte ontogeny.
Over-expression of human or mouse CD3-epsilon transgenes profoundly disturbs T lymphocyte and natural killer (NK) cell development. One of these transgenic strains, termed tgepsilon26, displays a very early block in T lymphocyte and NK cell development. We showed previously that the absence of early thymocyte progenitors results in an abnormal thymic microenvironment. Due to this thymic defect, T cell development could not be restored by bone marrow (BM) transplantation in adult tgepsilon26 mice but could in fetal tgepsilon26 mice. Here we examine the effect of this abnormal thymic environment on NK cell development. We demonstrate that NK cell maturation in tgepsilon26 mice was reconstituted by BM derived from completely T cell-deficient mice, i.e. RAG-2(-/-) and TCRbeta x delta-/-, but not from wild-type mice. Moreover, tgepsilon26 mice transplanted with BM from partially T cell-deficient mice, i.e. TCRalpha-/-, TCRbeta-/- and TCRdelta-/- mice, did not reconstitute their NK cell compartment. We conclude from these studies that the thymic environment is not required for NK cell development, but that aberrantly educated alphabeta or gammadelta T lymphocytes can influence NK cell ontogeny. Furthermore, high serum levels of tumor necrosis factor (TNF) were detected in the vast majority of tgepsilon26 mice transplanted with BM cells derived from partially T cell-deficient mice, but never from tgepsilon26 mice transplanted with BM cells derived from completely T cell-deficient mice. The high levels of TNF may play an important role in the observed inhibition of NK cell development, since in vivo treatment with an anti-TNF antibody restored NK cell development.


Regional ground-water mixing and the origin of saline fluids: midcontinent, United States.
Ground waters in three adjacent regional flow systems in the midcontinent exhibit extreme chemical and isotopic variations that delineate large-scale fluid flow and mixing processes and two distinct mechanisms for the generation of saline fluids. Systematic spatial variations of major ion concentrations, H, O, and Sr isotopic compositions, and ground-water migration pathways indicate that each flow system contains water of markedly different origin. Mixing of the three separate ground waters exerts a fundamental control on ground-water composition. The three ground waters are: (i) dilute meteoric water recharged in southern Missouri; (ii) saline Na-Ca-Cl water in southeastern Kansas of far-traveled meteoric origin that acquired its salinity by halite dissolution; and (iii) Na-Ca-Cl brines in north-central Oklahoma that may have originated as Paleozoic seawater.


Evidence that vasoactive intestinal polypeptide (VIP) mediates neurogenic vasodilation of feline cerebral arteries.
In this study the magnitude of non-sympathetic, non-cholinergic neurogenic vasodilation of feline cerebral arteries in vitro was correlated with the extent of innervation by VIP-immunoreactive nerves. Well-innervated arteries underwent nerve-mediated relaxation whereas those that are not supplied with VIP-containing axons did not relax to transmural nerve stimulation. The relaxation of cerebral arteries that are well endowed with VIP-immunoreactive nerves was selectively and reversibly inhibited by VIP-specific antiserum. Substance P-specific antiserum did not affect the dilator responses. We conclude that VIP is a functional neurodilator transmitter in the cerebral circulation.


Heart rate variability modulation after manipulation in pain-free patients vs patients in pain.
The purpose of this study was to examine heart rate variability (HRV) in the presence or the absence of pain in the lower back, while receiving one chiropractic treatment at L5 from either a manually assisted mechanical force (Activator) or a traditional diversified technique spinal manipulation. A total of 51 participants were randomly assigned to a control (n = 11), 2 treatment, or 2 sham groups (n = 10 per group). Participants underwent an 8-minute acclimatizing period. The HRV tachygram (RR interval) data were recorded directly into a Suunto watch (model T6; FitzWright Company Ltd, Langley, British Columbia, Canada). We analyzed the 5-minute pretreatment and posttreatment intervals. The spectral analysis of the tachygram was performed with Kubios software. All groups decreased in value except the control group that reacted in the opposite direction, when comparing the pretests and posttests for the high-frequency component. The very low frequency increased in all groups except the control group. The low frequency decreased in all groups except the sham pain-free group. The low frequency-high frequency ratio decreased in the treatment pain group by 0.46 and in the sham pain-free group by 0.26. The low frequency-high frequency ratio increase was 0.13 for the sham pain group, 0.04 for the control group, and 0.34 for the treatment pain-free group. The mean RR increased by 11.89 milliseconds in the sham pain-free group, 18.65 milliseconds in the treatment pain group, and 13.14 milliseconds in the control group. The mean RR decreased in the treatment pain-free group by 1.75 milliseconds and by 0.01 milliseconds in the sham pain group. Adjusting the lumbar vertebrae affected the lumbar parasympathetic nervous system output for this group of participants. Adaptation in the parasympathetic output, reflected by changes in high frequency, low frequency, and very low frequency, may be independent of type of adjustment. Therefore, the group differences found in the modulation of the HRV would seem to be related to the presence or absence of pain. The autonomic nervous system response may be specific and sensitive to its effectors organ.


Human white blood cells synthesize morphine: CYP2D6 modulation.
Human plasma contains low, but physiologically significant, concentrations of morphine that can increase following trauma or exercise. We now demonstrate that normal, human white blood cells (WBC), specifically polymorphonuclear cells, contain and have the ability to synthesize morphine. We also show that WBC express CYP2D6, an enzyme capable of synthesizing morphine from tyramine, norlaudanosoline, and codeine. Significantly, we also show that morphine can be synthesized by another pathway via l-3,4-dihydroxyphenylalanine (L-DOPA). Finally, we show that WBC release morphine into their environment. These studies provide evidence that 1) the synthesis of morphine by various animal tissues is more widespread than previously thought and now includes human immune cells. 2) Moreover, another pathway for morphine synthesis exists, via L-DOPA, demonstrating an intersection between dopamine and morphine pathways. 3) WBC can release morphine into the environment to regulate themselves and other cells, suggesting involvement in autocrine signaling since these cells express the mu3 opiate receptor subtype.


Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence.
Current pharmacological treatment of schizophrenia employs drugs that interfere with dopamine neurotransmission, aiming to suppress acute exacerbation of psychosis and maintenance treatment to reduce the risk of psychosis recurrence. According to this treatment scheme, available psychotropic drugs intended to treat negative symptoms, cognitive impairment, or anxiety are administered as add-ons to treatment with antipsychotics. However, an alternative treatment scheme proposes a targeted or intermittent treatment approach, by which antipsychotic drugs are administered upon psychosis exacerbation and discontinued upon remission or stabilization, while negative symptoms, cognitive impairment, or anxiety are treated with specific psychotropics as monotherapy. Along these lines, antipsychotics are renewed only in the event of recurrence of psychotic symptoms. This 50-year-old debate between targeted and continuous treatment schemes arises from disagreements about interpreting scientific evidence and discordant views regarding benefit/risk assessment. Among the debate's questions are: (1) what is the percentage of individuals who can maintain stability without antipsychotic maintenance treatment, and what is the percentage of those who exacerbate despite antipsychotic treatment? (2) how to interpret results of placebo-controlled 9- to 18-month-long maintenance trials in a life-long chronic disorder, and how to interpret results of the targeted trials, some of which are open label or not randomized; (3) how to weigh the decreased risk for psychotic recurrence vs the almost certainty of adverse effects on patient's quality of life. Patients' profiles, preferences, and circumstances of the care provision should be considered as the targeted vs continuous treatment options are considered.


Respiratory tract illnesses during the first year of life: effect of dog and cat contacts.
To investigate the effect of dog and cat contacts on the frequency of respiratory symptoms and infections during the first year of life. In this birth cohort study, 397 children were followed up from pregnancy onward, and the frequency of respiratory symptoms and infections together with information about dog and cat contacts during the first year of life were reported by using weekly diaries and a questionnaire at the age of 1 year. All the children were born in eastern or middle Finland between September 2002 and May 2005. In multivariate analysis, children having dogs at home were healthier (ie, had fewer respiratory tract symptoms or infections) than children with no dog contacts (adjusted odds ratio, [aOR]: 1.31; 95% confidence interval [CI]: 1.13-1.52). Furthermore, children having dog contacts at home had less frequent otitis (aOR: 0.56; 95% CI: 0.38-0.81) and tended to need fewer courses of antibiotics (aOR: 0.71; 95% CI: 0.52-0.96) than children without such contacts. In univariate analysis, both the weekly amount of contact with dogs and cats and the average yearly amount of contact were associated with decreased respiratory infectious disease morbidity. These results suggest that dog contacts may have a protective effect on respiratory tract infections during the first year of life. Our findings support the theory that during the first year of life, animal contacts are important, possibly leading to better resistance to infectious respiratory illnesses during childhood.


Positive selection on the killer whale mitogenome.
Mitochondria produce up to 95 per cent of the eukaryotic cell's energy. The coding genes of the mitochondrial DNA may therefore evolve under selection owing to metabolic requirements. The killer whale, Orcinus orca, is polymorphic, has a global distribution and occupies a range of ecological niches. It is therefore a suitable organism for testing this hypothesis. We compared a global dataset of the complete mitochondrial genomes of 139 individuals for amino acid changes that were associated with radical physico-chemical property changes and were influenced by positive selection. Two such selected non-synonymous amino acid changes were found; one in each of two ecotypes that inhabit the Antarctic pack ice. Both substitutions were associated with changes in local polarity, increased steric constraints and α-helical tendencies that could influence overall metabolic performance, suggesting a functional change.


The role of GABA in human motor learning.
GABA modification plays an important role in motor cortical plasticity. We therefore hypothesized that interindividual variation in the responsiveness of the GABA system to modification influences learning capacity in healthy adults. We assessed GABA responsiveness by transcranial direct current stimulation (tDCS), an intervention known to decrease GABA. The magnitude of M1 GABA decrease induced by anodal tDCS correlated positively with both the degree of motor learning and the degree of fMRI signal change within the left M1 during learning. This study therefore suggests that the responsiveness of the GABAergic system to modification may be relevant to short-term motor learning behavior and learning-related brain activity.


Metabolic co-dependence drives the evolutionarily ancient Hydra-Chlorella symbiosis.
Many multicellular organisms rely on symbiotic associations for support of metabolic activity, protection, or energy. Understanding the mechanisms involved in controlling such interactions remains a major challenge. In an unbiased approach we identified key players that control the symbiosis between Hydra viridissima and its photosynthetic symbiont Chlorella sp. A99. We discovered significant up-regulation of Hydra genes encoding a phosphate transporter and glutamine synthetase suggesting regulated nutrition supply between host and symbionts. Interestingly, supplementing the medium with glutamine temporarily supports in vitro growth of the otherwise obligate symbiotic Chlorella, indicating loss of autonomy and dependence on the host. Genome sequencing of Chlorella sp. A99 revealed a large number of amino acid transporters and a degenerated nitrate assimilation pathway, presumably as consequence of the adaptation to the host environment. Our observations portray ancient symbiotic interactions as a codependent partnership in which exchange of nutrients appears to be the primary driving force.


Basal Ganglia Pathways Associated With Therapeutic Pallidal Deep Brain Stimulation for Tourette Syndrome.
Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) can improve tics and comorbid obsessive-compulsive behavior (OCB) in patients with treatment-refractory Tourette syndrome (TS). However, some patients' symptoms remain unresponsive, the stimulation applied across patients is variable, and the mechanisms underlying improvement are unclear. Identifying the fiber pathways surrounding the GPi that are associated with improvement could provide mechanistic insight and refine targeting strategies to improve outcomes. Retrospective data were collected for 35 patients who underwent bilateral GPi DBS for TS. Computational models of fiber tract activation were constructed using patient-specific lead locations and stimulation settings to evaluate the effects of DBS on basal ganglia pathways and the internal capsule. We first evaluated the relationship between activation of individual pathways and symptom improvement. Next, linear mixed-effects models with combinations of pathways and clinical variables were compared in order to identify the best-fit predictive models of tic and OCB improvement. The best-fit model of tic improvement included baseline severity and the associative pallido-subthalamic pathway. The best-fit model of OCB improvement included baseline severity and the sensorimotor pallido-subthalamic pathway, with substantial evidence also supporting the involvement of the prefrontal, motor, and premotor internal capsule pathways. The best-fit models of tic and OCB improvement predicted outcomes across the cohort and in cross-validation. Differences in fiber pathway activation likely contribute to variable outcomes of DBS for TS. Computational models of pathway activation could be used to develop novel approaches for preoperative targeting and selecting stimulation parameters to improve patient outcomes.


Allergen immunotherapy in allergic rhinitis: current use and future trends.
Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk. Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT. New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy. Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance. New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.


The effect of genetic vs nongenetic parental care on adult children's income and wealth in later life: An evolutionary analysis.
Using Wave IV of the National Longitudinal Study of Adolescent to Adult Health data set, this preregistered study set out to investigate the effect of parental care arrangements (eg, genetically related parents, adoptive, step/ foster, genetic nonparental relative, and no parental figure) on adult children's income and wealth in later life. Consistent with the preregistration plan, multivariate analyses of covariance were first used to examine, separately, the effects of paternal and maternal care arrangements on children's income and wealth in later life. Further post hoc exploratory analyses were carried out to evaluate the robustness of the findings. The results indicate that individual earnings in later life are unrelated to paternal care arrangements, thus questioning a key tenet of kin selection theory. However, children raised by biological fathers and adoptive fathers still enjoy significant economic advantages over nongenetic father figures and homes without fathers in relation to household income and wealth. Prevailing theories suggest that children raised by relatives, nongenetically related parents, and no father or mother suffer from a lack of parental investment that should manifest itself in reduced earnings and assets in adulthood. These theories are only partially correct, with evidence pointing to no deleterious effect of variable parental arrangements on individual earnings.


A simple 3,4-ethylenedioxythiophene based hole-transporting material for perovskite solar cells.
We report a novel electron-rich molecule based on 3,4-ethylenedioxythiophene (H101). When used as the hole-transporting layer in a perovskite-based solar cell, the power-conversion efficiency reached 13.8 % under AM 1.5G solar simulation. This result is comparable with that obtained using the well-known hole transporting material 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD). This is the first heterocycle-containing material achieving >10 % efficiency in such devices, and has great potential to replace the expensive spiro-OMeTAD given its much simpler and cheaper synthesis.


Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.
Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.


The reproduction of centrosomes: nuclear versus cytoplasmic controls.
The tight coordination normally found between nuclear events and the doubling of centrosomes at each cell cycle suggests that nuclear activities may be part of the mechanism that controls the reproduction of centrosomes. To determine if this is the case, we used a micropipette to completely remove the nucleus from eggs of the sea urchin Lytechinus variegatus at prophase of the first mitosis, leaving only one centrosome in the cell. The subsequent behavior of this centrosome was then followed in vivo with the polarization microscope. In all cases the centrosome reproduced in a precise 1:2:4:8 fashion with a periodicity that was slightly slower than the centrosome cycle of control eggs. The cell cycle-related changes in centrosome morphology were identical to those of control eggs in that: (a) the astral birefringence varied cyclically to a normal extent, (b) the astral focus enlarged and then flattened during the telophase equivalent, (c) cleavage furrows were initiated as the astral birefringence faded, and (d) daughter centrosomes separated before the increase in astral birefringence at the onset of each mitosis. To determine if centrioles also reproduced normally, enucleate eggs were followed in vivo until they contained eight centrosomes. They were then individually removed from the preparations, fixed, and embedded. Each egg was serially 0.25-micron sectioned for observation with the high voltage electron microscope. We completely reconstructed 23 centrosomes in four eggs; all centrosomes contained two centrioles apiece. These results demonstrate that the subunits for complete centrosome assembly can be stockpiled ahead of time and that the properly controlled use of these subunits for centrosome reproduction does not require nuclear transcription or nuclear DNA synthesis at each cell cycle.


Dopaminergic and clinical correlates of high-frequency repetitive transcranial magnetic stimulation in gambling addiction: a SPECT case study.
Repetitive Transcranial Magnetic Stimulation (rTMS) shows the potential to modulate local brain activity, thus resulting in a modulatory action on neurocircuitries implicated in the pathophysiology of Gambling Disorder (GD). We report the case of a GD patient treated with two weeks of high frequency (15 Hz) rTMS over the dorsolateral prefrontal cortex (DLPFC). At baseline and after rTMS treatment the patient underwent a SPECT examination with (123)I-FP-CIT tracer, to test changes in dopamine transporter (DAT) availability. The patient was followed up for six months, to explore safety and clinical correlates of a weekly high frequency rTMS maintenance treatment. Over the six-month follow-up the patient reported no episodes of gambling relapse. Also, the patient did not report craving for gambling or gambling-related symptoms. After two weeks of left DLPFC-rTMS treatment, we found a decrease in DAT availability in striatal regions, that represents a putative neurobiological substrate of dopaminergic pathways modulation. This study suggests that high frequency DLPFC-rTMS deserves further investigations in larger samples, using controlled study designs, to assess its real potential as a treatment for GD.


Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.
Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.


Measurements of argon broadened Lorentz width and pressureinduced line shift coefficients in the nu(4) band of (12)CH(4).
Room temperature argon broadened halfwidth and pressure-induced line shift coefficients have been determined for 118 transitions in the nu(4) band of (12)CH(4) from analysis of high resolution laboratory absorption spectra recorded with the McMath Fourier transform spectrometer operated on Kitt Peak by the National Solar Observatory. Transitions up to J''= 12 have been measured using a nonlinear least-squares spectral fitting procedure. The variation of the measured halfwidth coefficients with symmetry type and rotational quantum number is very similar to that measured previously for N(2) and air broadening, but the absolute values of the argon broadening coefficients are all smaller. On average, the ratio of the argon broadened halfwidth coefficient to the corresponding N(2) broadened halfwidth coefficient is 0.877 +/- 0.017 (2sigma). More than 95% of the pressure-induced shifts are negative with values ranging from -0.0081 to +0.0055 cm(-1) atm(-1). The pressure shifts in argon are nearly equal to corresponding values measured previously in N(2) and air.


Managing incidental findings on abdominal CT: white paper of the ACR incidental findings committee.
As multidetector CT has come to play a more central role in medical care and as CT image quality has improved, there has been an increase in the frequency of detecting "incidental findings," defined as findings that are unrelated to the clinical indication for the imaging examination performed. These "incidentalomas," as they are also called, often confound physicians and patients with how to manage them. Although it is known that most incidental findings are likely benign and often have little or no clinical significance, the inclination to evaluate them is often driven by physician and patient unwillingness to accept uncertainty, even given the rare possibility of an important diagnosis. The evaluation and surveillance of incidental findings have also been cited as among the causes for the increased utilization of cross-sectional imaging. Indeed, incidental findings may be serious, and hence, when and how to evaluate them are unclear. The workup of incidentalomas has varied widely by physician and region, and some standardization is desirable in light of the current need to limit costs and reduce risk to patients. Subjecting a patient with an incidentaloma to unnecessary testing and treatment can result in a potentially injurious and expensive cascade of tests and procedures. With the participation of other radiologic organizations listed herein, the ACR formed the Incidental Findings Committee to derive a practical and medically appropriate approach to managing incidental findings on CT scans of the abdomen and pelvis. The committee has used a consensus method based on repeated reviews and revisions of this document and a collective review and interpretation of relevant literature. This white paper provides guidance developed by this committee for addressing incidental findings in the kidneys, liver, adrenal glands, and pancreas.


Floating dielectric slab optical interconnection between metal-dielectric interface surface plasmon polariton waveguides.
A simple and effective optical interconnection which connects two distanced single metal-dielectric interface surface plasmon waveguides by a floating dielectric slab waveguide (slab bridge) is proposed. Transmission characteristics of the suggested structure are numerically studied using rigorous coupled wave analysis, and design rules based on the study are given. In the wave-guiding part, if the slab bridge can support more than the fundamental mode, then the transmission efficiency of the interconnection shows strong periodic dependency on the length of the bridge, due to the multi-mode interference (MMI) effect. Otherwise, only small fluctuation occurs due to the Fabry-Pérot effect. In addition, light beating happens when the slab bridge is relatively short. In the wave-coupling part, on the other hand, gap-assisted transmission occurs at each overlapping region as a consequence of mode hybridization. Periodic dependency on the length of the overlap region also appears due to the MMI effect. According to these results, we propose design principles for achieving both high transmission efficiency and stability with respect to the variation of the interconnection distance, and we show how to obtain the transmission efficiency of 68.3% for the 1mm-long interconnection.


Birth weight and psychological distress at age 45-51 years: results from the Aberdeen Children of the 1950s cohort study.
It is unclear whether the effect of low birth weight on common affective disorders in later life is direct or mediated through childhood factors. To determine whether birth weight has a direct effect on psychological distress in adulthood not mediated by childhood IQ or behavioural problems. Participants (n=5572) of the Aberdeen Children of the 1950s study had data on birth weight for gestational age and adult psychological distress. Logistic regression was used to examine the association between these factors, with adjustment for confounders and potential childhood mediators. Children born full term but weighing less than 5.5 lb had increased odds of psychological distress in later life after adjustment for potential confounders (OR=1.49, 95% CI 1.01-2.20). Further adjustment for childhood IQ and behaviour did not attenuate the association. A 1 s.d. decrease in birth weight for gestational age was associated with a 4% increased odds of psychological distress in adulthood (OR=1.04, 95% CI 0.97-1.12). Low birth weight for gestational age, particularly at term, was associated with adult psychological distress. This was not mediated by childhood factors, suggesting a direct effect of early life factors on adult mental health. A neurodevelopmental pathway may therefore be implicated.


Reading Comprehension Difficulties in Chinese-English Bilingual Children.
The co-occurrence of reading comprehension difficulties for first language (L1) Chinese and second language (L2) English and associated longitudinal cognitive-linguistic correlates in each language were investigated. Sixteen poor comprehenders in English and 16 poor comprehenders in Chinese, 18 poor readers in both, and 18 children with normal performance in both were identified at age 10. The prevalence rate for being poor in both was 52.94%, suggesting that approximately half of children who are at risk for Chinese reading comprehension difficulty are also at risk for English reading comprehension difficulty. Chinese word reading, phonological, and morphological awareness were longitudinal correlates of poor comprehension in Chinese. English word reading and vocabulary were longitudinal correlates of poor comprehension in English. Chinese phonological awareness was an additional correlate of poor comprehension in English. Moreover, poor comprehenders in both Chinese and English showed slower rapid automatized naming scores than the other groups. Findings highlight some factors that might be critical for reading comprehension in L1 Chinese and L2 English; fluency is likely to be a critical part of reading comprehension across languages. Copyright © 2017 John Wiley & Sons, Ltd.


Cost-utility analysis for advanced breast cancer therapy in Germany: results of the fulvestrant sequencing model.
Therapy decisions in advanced breast cancer (ABC) increasingly require assessment not only of treatment efficacy but also of cost-effectiveness. To this end, we performed a cost-utility analysis by comparing treatment sequences including/omitting fulvestrant in a hypothetical population of hormone receptor-positive (HR+) postmenopausal women with ABC. The analysis was performed from the German health care perspective. Using a first-order sequential Markov model, expected costs and utilities were calculated over a time horizon of 10 years for cohorts of patients with HR+ ABC, previously treated for at least 5 years using adjuvant endocrine therapies. Utilities were primarily quantified in terms of quality adjusted life years (QALY). "Base-case" estimates of state transition rates, resource utilization, and other model parameters were derived from published evidence and expert assessment. The impacts of uncertainties in all key model parameters were evaluated by sensitivity analysis. Costs and benefits were discounted at 3% annually. Including second-line fulvestrant in the treatment sequence led to greater estimated health gains (0.021 QALY) and cost savings of 564 euros ($745, 380 pounds) per patient, i.e. the fulvestrant-containing sequence was "dominant". The prediction of a cost savings was robust with respect to variations in all key parameters. The probability of acceptable cost-effectiveness for the fulvestrant sequence was 72% at a willingness to pay (WTP) of 30,000 euros/QALY ($39,621/QALY, 20,198 pounds/QALY); the probability was even higher at lower WTP and substantially exceeded 50% for any realistic WTP. In a representative population of women with HR+ advanced breast cancer, inclusion of fulvestrant in the treatment sequence provides a cost-effective alternative from the German health care perspective. A high probability of cost-effectiveness is maintained under variations in all key parameters. The results reflect a tendency for patients receiving fulvestrant at an early stage to maintain high quality of life for a longer interval.


Antimicrobial Activity of Two Garlic Species (Allium Sativum and A. Tuberosum) Against Staphylococci Infection. In Vivo Study in Rats.
Purpose: This study observed the effect of garlic extracts and amoxicillin against an induced staphylococcal infection model. MIC and MBC were also obtained for aqueous extracts of Allium sativum (Asa) and Allium tuberosum (Atu) against Staphylococcus aureus penicillin-sensitive (PSSA - ATCC 25923) and MRSA (ATCC 33592). Methods: Granulation tissues were induced in the back of 205 rats. After 14 days, 0.5 mL of 108 CFU/mL of PSSA or MRSA were injected inside tissues. After 24h, animals were divided: G1 (Control) - 0.5 mL of NaCl 0.9%; G2 - Asa 100 mg/kg or 400mg/kg; G3 - Atu 100 mg/kg or 400 mg/kg; G4 - amoxicillin suspension 50 mg/kg, considering PSSA infection; and G5 (Control) - 0.5 mL of NaCl 0.9%; G6 - Asa 400mg/kg; G7 - amoxicillin 50 mg/kg; and G8 - Asa 400 mg/kg + amoxicillin 50 mg/kg for MRSA. All treatments were administered P.O. every 6h. Animals were killed at 0, 6, 12 and 24h. Samples were spread on salt-mannitol agar. Colonies were counted after 18 h at 37 °C. Atu was not able to inhibit or kill PSSA and MRSA. Considering Asa, MIC and MBC against PSSA were 2 mg/mL and 4 mg/mL, respectively; and 16 mg/mL and 64 mg/mL against MRSA. Results: No effect was observed in vivo for control, Asa 100 mg/kg and Atu 100 mg/kg, while amoxicillin, Atu 400 mg/kg and Asa 400 mg/kg decreased PSSA counts in all-time points. No effect of any group against MRSA was observed at any time. Conclusion: Thus, A. sativum and A. tuberosum were able to reduce PSSA infection, but not MRSA infection.


Hepatitis B and C Viral Infections in Tihamet Aseer, South-Western Saudi Arabia: Are There Gender Differences?
Hepatitis B virus (HBV) infection is endemic in Saudi Arabia. Many studies have shown varying results in gender differences in HBV and hepatitis C virus (HCV) infection. The objective of this study was to determine if gender differences exist in HBV and HCV infection and to elucidate any related risk factors in Tihamet Aseer, south-western Saudi Arabia. The study was a cross-sectional study of a representative sample of males and females in Tihamet Aseer, south-western Saudi Arabia. A comprehensive questionnaire was completed by all participants. Blood samples were taken and sera were tested for hepatitis B surface antigen and HCV antibodies by fourth-generation enzyme immunoassays. The study included 1532 participants from the Tihamet Aseer area. An overall seroprevalence of 7.9% and 1.7% was found for HBV and HCV infections, respectively. In logistic regression analysis, no gender differences were found for HBV seroprevalence. Identified risk factors for HBV infection included a history of blood transfusion and lack of hepatitis B vaccination. On the other hand, females were more prone to become seropositive for HCV (adjusted odds ratio = 5.034, 95% confidence interval: 1.042-9.321). Other identified risk factors for HCV infection were illiteracy and a history of blood transfusion. The prevalence and HBV and HCV infection is high compared to the national figures. Gender differences were only observed in HCV infection. It is recommended to have an active educational and media campaign. A "catch-up" vaccination program against HBV should be introduced for adults as a strategy to achieve the herd immunity effect in the affected area.


Evaluation of a Package of Behaviour Change Interventions (Baduta Program) to Improve Maternal and Child Nutrition in East Java, Indonesia: Protocol for an Impact Study.
Over the past decade, the prevalence of stunting has been close to 37% in children aged <5 years in Indonesia. The Baduta program, a multicomponent package of interventions developed by the Global Alliance for Improved Nutrition, aims to improve maternal and infant nutrition in Indonesia. This study aims to assess the impact of the Baduta program, a package of health system strengthening and behavior change interventions, compared with the standard village health services on maternal and child nutrition. The impact evaluation uses a cluster randomized controlled trial design with 2 outcome assessments. The first uses cross-sectional surveys of mothers of children aged 0-23 months and pregnant women before and after the interventions. The second is a cohort study of pregnant women followed until their child is 18 months from a subset of clusters. We will also conduct a process evaluation guided by the program impact pathway to assess coverage, fidelity, and acceptance. The study will be conducted in the Malang and Sidoarjo districts of East Java, Indonesia. The unit of randomization is the subdistricts. As random allocation of interventions to only 6 subdistricts is feasible, we will use constrained randomization to ensure balance of baseline covariates. The first intervention will be health system strengthening, including the Baby-Friendly Hospital Initiative, and training on counseling for appropriate infant and young child feeding (IYCF). The second intervention will be nutrition behavior change that includes Emo-Demos; a national television (TV) advertising campaign; local screening TV spots; a free, text message service; and promotion of low-cost water filters and hygiene practices. The primary study outcome is child stunting (low length-for-age), and secondary outcomes include length-for-age Z scores, wasting (low weight-for-length), anemia, child morbidity, IYCF indicators, and maternal and child nutrient intakes. The sample size for each cross-sectional survey is 1400 mothers and their children aged <2 years and 200 pregnant women in each treatment group. The cohort evaluation requires a sample size of 340 mother-infant pairs in each treatment group. We will seek Gatekeeper consent and written informed consent from the participants. The intention-to-treat principle will guide our data analysis, and we will apply Consolidated Standards of Reporting Trials guidelines for clustered randomized trials in the analysis. In February 2015, we conducted a baseline cross-sectional survey on 2435 women with children aged <2 years and 409 pregnant women. In February 2017, we conducted an end-line survey on 2740 mothers with children aged <2 years and 642 pregnant women. The cohort evaluation began in February 2015, with 729 pregnant women, and was completed in December 2016. The results of the program evaluation will help guide policies to support effective packages of behavior change interventions to prevent child stunting in Indonesia. RR1-10.2196/18521.


The effects of interactions between proline and carbon nanostructures on organocatalysis in the Hajos-Parrish-Eder-Sauer-Wiechert reaction.
The non-covalent interactions of S-(-)-proline with the surfaces of carbon nanostructures (fullerene, nanotubes and graphite) change the nucleophilic-electrophilic and acid-base properties of the amino acid, thus tuning its activity and selectivity in the organocatalytic Hajos-Parrish-Eder-Sauer-Wiechert (HPESW) reaction. Whilst our spectroscopy and microscopy measurements show no permanent covalent bonding between S-(-)-proline and carbon nanostructures, a systematic investigation of the catalytic activity and selectivity of the organocatalyst in the HPESW reaction demonstrates a clear correlation between the pyramidalisation angle of carbon nanostructures and the catalytic properties of S-(-)-proline. Carbon nanostructures with larger pyramidalisation angles have a stronger interaction with the nitrogen atom lone pair of electrons of the organocatalyst, thereby simultaneously decreasing the nucleophilicity and increasing the acidity of the organocatalyst. These translate into lower conversion rates but higher selectivities towards the dehydrated product of Aldol addition.


SPIRS: a framework for content-based image retrieval from large biomedical databases.
With the increasing use of medical images in clinical medicine, disease research, and education, the need for methods that effectively archive, query, and retrieve these images by their content is underscored. This paper presents the implementation of a Web-based retrieval system called SPIRS (Spine Pathology & Image Retrieval System) at the U. S. National Library of Medicine that demonstrates recent developments in shape representation and retrieval from a large dataset of 17,000 digitized x-ray images of the spine and associated text records. Users can search these images by providing a sketch of the vertebral outline or selecting an example vertebral image and some relevant text parameters. Pertinent pathology on the image/sketch can be annotated and weighted to indicate importance. This hybrid text-image query yields images containing similar vertebrae along with relevant fields from associated text records, which allows users to examine the pathologies of vertebral abnormalities. Initial experiments with SPIRS have demonstrated the potential for this system, particularly on a large dataset of clinical images.


First detection of a Vssc allele V1016G conferring a high level of insecticide resistance in Aedes albopictus collected from Europe (Italy) and Asia (Vietnam), 2016: a new emerging threat to controlling arboviral diseases.
IntroductionAedes albopictus (Skuse) is an important vector of arboviral diseases, including dengue, chikungunya and Zika virus disease. Monitoring insecticide resistance and mechanisms by which the mosquito develops resistance is crucial to minimise disease transmission.AimTo determine insecticide resistance status and mechanisms in Ae. albopictus from different geographical regions.MethodsWe sampled 33 populations of Ae. albopictus from Asia, Europe and South America, and tested these for susceptibility to permethrin, a pyrethroid insecticide. In resistant populations, the target site for pyrethroids, a voltage-sensitive sodium channel (Vssc) was genotyped. Three resistant sub-strains, each harbouring a resistance allele homozygously, were established and susceptibilities to three different pyrethroids (with and without a cytochrome P450 inhibitor) were assayed.ResultsMost populations of Ae. albopictus tested were highly susceptible to permethrin but a few from Italy and Vietnam (4/33), exhibited high-level resistance. Genotyping studies detected a knockdown resistance (kdr) allele V1016G in Vssc for the first time in Ae. albopictus. Two previously reported kdr alleles, F1534C and F1534S, were also detected. The bioassays indicated that the strain homozygous for the V1016G allele showed much greater levels of pyrethroid resistance than other strains harbouring F1534C or F1534S.ConclusionThe V1016G allele was detected in bothAsian and Italian Ae. albopictus populations, thus a spread of this allele beyond Italy in Europe cannot be ruled out. This study emphasises the necessity to frequently and regularly monitor the V1016G allele in Ae. albopictus, particularly where this mosquito species is the main vector of arboviruses.


Effects of indoor air purification intervention on blood pressure, blood‑oxygen saturation, and heart rate variability: A double-blinded cross-over randomized controlled trial of healthy young adults.
The use of indoor air purifier (IAP) has received growing attention as a mitigation strategy for reducing indoor air pollution, but the evidence on their cardiovascular benefits is unclear. This study aims to evaluate whether the use of IAP can reduce the adverse effects of indoor particulate matter (PM) on cardiovascular health among young healthy population. A randomized, double-blind, cross-over, IAP intervention of 38 college students was conducted. The participants were assigned into two groups to receive the true and sham IAPs for 36 h in random order. Systolic and diastolic blood pressure (SBP; DBP), blood oxygen saturation (SpO2), heart rate variability (HRV) and indoor size-fractioned particulate matter (PM) were real-time monitored throughout the intervention. We found that IAP could reduce indoor PM by 41.7-50.5 %. Using IAP was significantly associated with a reduction of 2.96 mmHg (95 % CI: -5.71, -0.20) in SBP. Increased PM was significantly associated with increased SBP (e.g., 2.17 mmHg [0.53, 3.81], 1.73 mmHg [0.32, 3.14] and 1.51 mmHg [0.28, 2.75] for an IQR increment of PM1 [16.7 μg/m3], PM2.5 [20.6 μg/m3] and PM10 [37.9 μg/m3] at lag 0-2 h, respectively) and decreased SpO2 (-0.44 % [-0.57, -0.29], -0.41 % [-0.53, -0.30] and - 0.40 % [-0.51, -0.30] for PM1, PM2.5 and PM10 at lag 0-1 h, respectively), which could last for about 2 h. Using IAPs could halve indoor PM levels, even in relatively low air pollution settings. The exposure-response relationships suggested that the benefits of IAPs on BP may only be observed when indoor PM exposure is reduced to a certain level.


Effectiveness and Safety of Direct Oral Anticoagulants versus Vitamin K Antagonists for People Aged 75 Years and over with Atrial Fibrillation: A Systematic Review and Meta-Analyses of Observational Studies.
Older people, are underrepresented in randomised controlled trials of direct oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation (AF). The aim of this study was to combine data from observational studies to provide evidence for the treatment of people aged ≥75 years. Medline, Embase, Scopus and Web of Science were searched. The primary effectiveness outcome was ischaemic stroke. Safety outcomes were major bleeding, intracranial haemorrhage, gastrointestinal bleeding, myocardial infarction, and mortality. Twenty-two studies were eligible for inclusion. Two studies related specifically to people ≥75 years but were excluded from meta-analysis due to low quality; all data in the meta-analyses were from subgroups. The pooled risk estimate of ischaemic stroke was slightly lower for DOACs. There was no significant difference in major bleeding, mortality, or myocardial infarction. Risk of intracranial haemorrhage was 44% lower with DOACs, but risk of GI bleeding was 46% higher. Our results suggest that DOACs may be preferable for the majority of older patients with AF, provided they are not at significant risk of a GI bleed. However, these results are based entirely on data from subgroup analyses so should be interpreted cautiously. There is a need for adequately powered research in this patient group.


Ethanol tolerance of sugar transport, and the rectification of stuck wine fermentations.
The incomplete consumption of sugar resulting from stuck wine fermentation is associated with important economic losses. One of the solutions to this serious problem consists of reinoculating the brew with a yeast starter culture that is both alcohol tolerant and a vigorous fructose fermenter. The present work aimed to select yeast strains capable of restarting stuck wine fermentations, and identify key parameters that contribute to the efficiency of the strains. Commercial and non-commercial Saccharomyces wine strains were tested, as well as strains of the fermentative non-Saccharomyces species Zygosaccharomyces bailii and Torulaspora delbrueckii. Although the latter species were shown to be more resistant to a combination of ethanol- and acetic-acid-induced cell death, commercial Saccharomyces cerevisiae strains were the most efficient fructose consumers in medium simulating a stuck fermentation. Stationary-phase S. cerevisiae cells performed better than inocula prepared from exponentially growing cultures, which correlates with the higher resistance to ethanol of non-growing populations. Stationary-phase cells pre-adapted to ethanol did not improve fructose consumption rates; this was in contrast to exponential-phase cells that benefited from prior incubation in ethanol-containing medium. Notably, a correlation was observed between yeast fructose consumption capacity and glucose (or fructose) transport. Our results challenge the current belief that ethanol tolerance, expressed in terms of cell viability, is a reliable criterion for the selection of yeast strains to restart stuck fermentations. Instead, this capacity seems to be based on sugar transport and its resistance to ethanol. In an attempt to further improve cell viability in the presence of high ethanol concentrations, hybrid strains of T. delbrueckii and S. cerevisiae were produced, and they showed high potential as restarter strains. The present work opens perspectives for the application of innovative strategies in the wine-making industry.


A medical locum service as a site for sentinel influenza surveillance.
Surveillance of influenza in the countries of the European Union includes a sentinel network of general practitioners reporting cases of influenza-like illness (ILI), the collection of specimens for virological testing, and laboratory reporting of influenza diagnoses. In Victoria, Australia we have a similar sentinel surveillance system, with ILI defined by fever, cough and fatigue, and influenza seasons described by thresholds. The coordination of sentinel general practices can, however, be time consuming and expensive. For the last two influenza seasons we have used a deputising medical locum service as a sentinel site for influenza surveillance. We are not aware of such a service being used as a sentinel site elsewhere in the world. In both retrospective and prospective comparisons, we have shown that ILI surveillance patterns from sentinel general practices are very similar to those from the locum service. Because of its timeliness, flexibility, patient mix and geographic spread, locum service surveillance is able to supplement sentinel ILI surveillance and may also have a role in the recognition of emerging disease patterns. This is likely to be true not only in Australia but also in countries of the European Union.


Distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy among diabetic patients in Ilorin: Prevalence and predictors.
Peripheral neuropathy contributes to morbidity and mortality among diabetic patients. We aimed to determine the prevalence of distal symmetrical polyneuropathy (DSP) and cardiovascular autonomic neuropathy (CAN) and their predictors among diabetic patients in Ilorin, North-central Nigeria. : This was a cross-sectional study in which 175 consenting diabetic patients were recruited consecutively. We assessed DSP using the Michigan Neuropathy Screening Instrument (MNSI), and it was defined by MNSI symptom score ≥7 or physical examination score ≥2. CAN was assessed using five tests of cardiovascular autonomic function, and abnormalities in ≥2 tests defined CAN. Logistic regression analysis was used to identify the predictors of DSP and CAN. The prevalence of DSP and CAN was 41.7% and 26.9%, respectively, while 19.4% had both. Hypertension (odds ratio [OR]: 2.401; 95% confidence interval [CI]: 1.169-4.930, P = 0.017) and poor glycaemic control (OR: 2.957; 95% CI: 1.488-5.878, P = 0.002) independently predicted DSP. Hypertension (OR: 2.215; 95% CI: 1.023-4.414, P = 0.043) and serum creatinine (OR: 1.035; 95% CI: 1.014-1.056, P ≤ 0.001) were independent predictors of CAN. DSP and CAN are common among diabetic patients, and thus efforts should be made to prevent their occurrence by intensifying blood pressure and glucose control while regularly monitoring renal function.


Measuring pulse-front tilt in ultrashort pulse laser beams without ambiguity of its sign using single-shot tilted pulse-front autocorrelator.
The measurement of pulse-front tilt (PFT) in ultrashort pulse laser beams, without ambiguity of its sign, has been carried out using an in-house built single-shot tilted pulse-front autocorrelator (TPFAC) based on second harmonic generation in non-linear crystal. The experiment is carried out for the beam propagation through a single prism and a pair of prisms. Expressions of PFT angle have been derived to account for beam size, beam propagation effects and for arbitrary incidence of the laser beam. The measured PFT angles were found in accordance with theoretically calculated values. The calculated sensitivity of TPFAC is found to be larger than that offered by the other techniques.


A coupled duration-focused architecture for real-time music-to-score alignment.
The capacity for real-time synchronization and coordination is a common ability among trained musicians performing a music score that presents an interesting challenge for machine intelligence. Compared to speech recognition, which has influenced many music information retrieval systems, music's temporal dynamics and complexity pose challenging problems to common approximations regarding time modeling of data streams. In this paper, we propose a design for a real-time music-to-score alignment system. Given a live recording of a musician playing a music score, the system is capable of following the musician in real time within the score and decoding the tempo (or pace) of its performance. The proposed design features two coupled audio and tempo agents within a unique probabilistic inference framework that adaptively updates its parameters based on the real-time context. Online decoding is achieved through the collaboration of the coupled agents in a Hidden Hybrid Markov/semi-Markov framework, where prediction feedback of one agent affects the behavior of the other. We perform evaluations for both real-time alignment and the proposed temporal model. An implementation of the presented system has been widely used in real concert situations worldwide and the readers are encouraged to access the actual system and experiment the results.


"I'm not the woman I was": Women's perceptions of the effects of fibromyalgia on private life.
In this qualitative study, we explored how gender shapes women's experiences of living with fibromyalgia and how it affects their private lives. Through thematic analysis of data from 13 in-depth interviews in Spain, we identified seven themes which reflect that these women feel remorse and frustration for not being able to continue to fulfill the gender expectation of caring for others and for the home. This research contributes to a better understanding of what suffering from fibromyalgia implies for women and provides insights into how families and providers can support women with fibromyalgia in order to achieve a beneficial lifestyle.


A Case of Cerebral Malaria Managed by Erythrocyte Exchange.
Plasmodium falciparum may cause serious and sometimes even fatal cerebral malaria. Cerebral malaria is a disease characterized by alterations in consciousness and epileptic attacks; therefore, it requires a rapid evaluation and quick intervention. It may progress to a fatal outcome despite administering targeted therapeutic interventions. There are studies indicating that erythrocyte exchange (erythrocytapheresis) can be a treatment modality for managing severe malaria patients. In this case report, the successful management of a cerebral malaria patient by the combination of antimalarial drug therapy and erythrocyte exchange is presented.


Decoding intra-limb and inter-limb kinematics during treadmill walking from scalp electroencephalographic (EEG) signals.
Brain-machine interface (BMI) research has largely been focused on the upper limb. Although restoration of gait function has been a long-standing focus of rehabilitation research, surprisingly very little has been done to decode the cortical neural networks involved in the guidance and control of bipedal locomotion. A notable exception is the work by Nicolelis' group at Duke University that decoded gait kinematics from chronic recordings from ensembles of neurons in primary sensorimotor areas in rhesus monkeys. Recently, we showed that gait kinematics from the ankle, knee, and hip joints during human treadmill walking can be inferred from the electroencephalogram (EEG) with decoding accuracies comparable to those using intracortical recordings. Here we show that both intra- and inter-limb kinematics from human treadmill walking can be achieved with high accuracy from as few as 12 electrodes using scalp EEG. Interestingly, forward and backward predictors from EEG signals lagging or leading the kinematics, respectively, showed different spatial distributions suggesting distinct neural networks for feedforward and feedback control of gait. Of interest is that average decoding accuracy across subjects and decoding modes was ~0.68±0.08, supporting the feasibility of EEG-based BMI systems for restoration of walking in patients with paralysis.