Reformulation and Generalisation of the Cohen and Fleiss Kappas

The assessment of consistency in the categorical or ordinal decisions made by observers or raters is an important problem especially in the medical field. The Fleiss Kappa, Cohen Kappa and Intra-class Correlation (ICC), as commonly used for this purpose, are compared and a generalised approach to these measurements is presented. Differences between the Fleiss Kappa and multi-rater versions of the Cohen Kappa are explained and it is shown how both may be applied to ordinal scoring with linear, quadratic or other weighting. The relationship between quadratically weighted Fleiss and Cohen Kappa and pair-wise ICC is clarified and generalised to multi-rater assessments. The AC1 coefficient is considered as an alternative measure of consistency and the relevance of the Kappas and AC1 to measuring content validity is explore

Benfotiamine in high carbohydrate diet enhances growth and reproductive performance of the Asian native catfish Clarias macrocephalus subadults

Clarias macrocephalus has been extirpated in most regions in the Philippines and as a preliminary study towards its reintroduction, we aimed at enhancing the growth and reproductive performance of the broodstock. Several studies have identified thiamine deficiency as a factor in the extirpation of some important fish species in the wild. The present study aimed to determine the effects of elevated dietary carbohydrates and benfotiamine, a more bioavailable analog of thiamine (vitamin B1). Three diets were used, namely, a commercial diet specific for catfish was used as the control diet (Com), a high carbohydrate (HC) diet, and a benfotiamine-supplemented HC diet (HCB). Results show that survival of the subadult catfish in captivity for 10 weeks was remarkably high, exhibiting an average of 99% for all three treatments (P>0.05). HCB diet resulted in significantly higher final average body weight (FABW), weight gain (WG), specific growth rate (SGR), and significantly best food conversion ratio (FCR) (P0.05). For the reproductive performance, female Asian catfish fed the HCB diet exhibited significantly heavier ovary and liver (P0.05). GSI of the female catfish and fecundity were significantly higher in the HCB group (P0.05). In the male catfish, testes were significantly heavier in the HCB group (P0.05). HSI, male LW, and LL were significantly higher in the HC and HCB groups (P>0.05) than in the Com group (P0.05). In conclusion, elevating dietary carbohydrates in the diet from 7.70% to 22.73% (i.e., Com to HC diet, respectively) did not negatively affect the growth and reproductive performance of the Asian catfish. Further supplementation of benfotiamine at 0.02% to the HC diet enhanced significantly both the growth and reproductive performance of the Asian catfish

Deceleration and trapping of heavy diatomic molecules using a ring-decelerator

We present an analysis of the deceleration and trapping of heavy diatomic molecules in low-field seeking states by a moving electric potential. This moving potential is created by a 'ring-decelerator', which consists of a series of ring-shaped electrodes to which oscillating high voltages are applied. Particle trajectory simulations have been used to analyze the deceleration and trapping efficiency for a group of molecules that is of special interest for precision measurements of fundamental discrete symmetries. For the typical case of the SrF molecule in the (N,M) = (2, 0) state, the ring-decelerator is shown to outperform traditional and alternate-gradient Stark decelerators by at least an order of magnitude. If further cooled by a stage of laser cooling, the decelerated molecules allow for a sensitivity gain in a parity violation measurement, compared to a cryogenic molecular beam experiment, of almost two orders of magnitude

Spin squeezing and pairwise entanglement for symmetric multiqubit states

We show that spin squeezing implies pairwise entanglement for arbitrary symmetric multiqubit states. If the squeezing parameter is less than or equal to 1, we demonstrate a quantitative relation between the squeezing parameter and the concurrence for the even and odd states. We prove that the even states generated from the initial state with all qubits being spin down, via the one-axis twisting Hamiltonian, are spin squeezed if and only if they are pairwise entangled. For the states generated via the one-axis twisting Hamiltonian with an external transverse field for any number of qubits greater than 1 or via the two-axis counter-twisting Hamiltonian for any even number of qubits, the numerical results suggest that such states are spin squeezed if and only if they are pairwise entangled.Comment: 6 pages. Version 3: Small corrections were mad

Cadherin-11 Provides Specific Cellular Adhesion between Fibroblast-like Synoviocytes

Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti–cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11–Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA

Optic nerve head and retinal abnormalities associated with congenital fibrosis of the extraocular muscles

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves

Measurement of νˉμ\bar{\nu}_{\mu} and νμ\nu_{\mu} charged current inclusive cross sections and their ratio with the T2K off-axis near detector

We report a measurement of cross section $\sigma(\nu_{\mu}+{\rm nucleus}\rightarrow\mu^{-}+X)$ and the first measurements of the cross section $\sigma(\bar{\nu}_{\mu}+{\rm nucleus}\rightarrow\mu^{+}+X)$ and their ratio $R(\frac{\sigma(\bar \nu)}{\sigma(\nu)})$ at (anti-)neutrino energies below 1.5 GeV. We determine the single momentum bin cross section measurements, averaged over the T2K $\bar{\nu}/\nu$-flux, for the detector target material (mainly Carbon, Oxygen, Hydrogen and Copper) with phase space restricted laboratory frame kinematics of $\theta_{\mu}$500 MeV/c. The results are $\sigma(\bar{\nu})=\left( 0.900\pm0.029{\rm (stat.)}\pm0.088{\rm (syst.)}\right)\times10^{-39}$ and $\sigma(\nu)=\left( 2.41\ \pm0.022{\rm{(stat.)}}\pm0.231{\rm (syst.)}\ \right)\times10^{-39}$in units of cm$^{2}$/nucleon and$R\left(\frac{\sigma(\bar{\nu})}{\sigma(\nu)}\right)= 0.373\pm0.012{\rm (stat.)}\pm0.015{\rm (syst.)}$.Comment: 18 pages, 8 figure

A new human challenge model for testing heat-stable toxin-based vaccine candidates for enterotoxigenic Escherichia coli diarrhea - dose optimization, clinical outcomes, and CD4+T cell responses

Enterotoxigenic Escherichia coli (ETEC) are a common cause of diarrheal illness in young children and travelers. There is yet no licensed broadly protective vaccine against ETEC. One promising vaccine development strategy is to target strains expressing the heat-stable toxin (ST), particularly the human ST (STh), since infections with these strains are among the leading causes of diarrhea in children in low-and-middle income countries. A human challenge model based on an STh-only ETEC strain will be useful to evaluate the protective efficacy of new ST-based vaccine candidates. To develop this model, we experimentally infected 21 healthy adult volunteers with the epidemiologically relevant STh-only ETEC strain TW10722, identified a suitable dose, assessed safety, and characterized clinical outcomes and immune responses caused by the infection. Doses of 1x10(10) colony-forming units (CFU) of TW10722 gave a suitable attack risk of 67% for moderate or severe diarrhea and an overall diarrhea attack risk of 78%. Non-diarrheal symptoms were mostly mild or moderate, and there were no serious adverse events. During the first month after ingesting the challenge strain, we measured significant increases in both activated CD4+ T cells and levels of serum IgG and IgA antibodies targeting coli surface antigen 5 (CS5) and 6 (CS6), as well as the E. coli mucinase YghJ. The CS5-specific CD4+ T cell and antibody responses were still significantly elevated one year after experimental infection. In conclusion, we have developed a safe STh-only ETEC-based human challenge model which can be efficiently used in Phase 2B trials to evaluate the protective efficacy of new ST-based vaccine candidates

Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics

Published: April 13, 2023With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.Madeline G. Dans, Henni Piirainen, William Nguyen, Sachin Khurana, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Aurelie T. Dawson, Sujaan Das, Molly Parkyn Schneider, Thorey K. Jonsdottir, Mikha Gabriela, Maria R. Gancheva, Christopher J. Tonkin, Vanessa Mollard, Christopher Dean Goodman, Geoffrey I. McFadden, Danny W. Wilson, Kelly L. Rogers, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning-Ward, Brad E. Sleebs, Inari Kursula, Paul R. Gilso

Twelve-year outcomes of watchful waiting versus surgery of mildly symptomatic or asymptomatic inguinal hernia in men aged 50 years and older:a randomised controlled trial

Background: Inguinal hernia belongs to the most common surgical pathology worldwide. Approximately, one third is asymptomatic. The value of watchful waiting (WW) in patients with asymptomatic or mildly symptomatic inguinal hernia has been established in a few randomised controlled trials (RCTs). The aim of this study was to assess long-term outcomes of a RCT comparing WW and elective surgery.Methods: In the original study, men aged ≥50 years with an asymptomatic or mildly symptomatic inguinal hernia were randomly assigned to WW or elective repair. In the present study, the primary outcome was the 12-year crossover rate to surgery, secondary outcomes were time-to-crossover, patient regret, pain, quality of life and incarceration. Dutch Trial Registry: NTR629. Findings: Out of 496 originally analysed patients, 488 (98.4%) were evaluable for chart review (WW: n = 258, surgery: n = 230), and 200 (41.0%) for telephone contact (WW: n = 106, surgery: n = 94) between November 2021 and March 2022 with a median 12 years follow-up (IQR 9–14). After 12 years, the estimated cumulative crossover rate to surgery was 64.2%, which was higher in mildly symptomatic than in asymptomatic patients (71.7% versus 60.4%, HR 1.451, 95% CI: 1.064–1.979). Time-to-crossover was longer in asymptomatic patients (50% after 6.0 years versus 2.0 years, p = 0.019). Patient regret was higher in the WW group (37.7 versus 18.0%, p = 0.002), as well as pain/discomfort (p = 0.031). Quality of life did not differ (p = 0.737). In the WW group, incarceration occurred in 10/255 patients (3.9%). Interpretation: During 12-year follow-up, most WW patients crossed over to surgery, significantly earlier with mildly symptomatic hernia. Considering the relatively low incarceration rate, WW might still be an option in asymptomatic patients with a clear preference and being well-informed about pros and cons.</p