Selection bias: neighbourhood controls and controls selected from those presenting to a Health Unit in a case control study of efficacy of BCG revaccination.

BACKGROUND: In most case control studies the hardest decision is the choice of the control group, as in the ideal control group the proportion exposed is the same as in the population that produced the cases. METHODS: A comparison of two control groups in a case control study of the efficacy of BCG revaccination. One group was selected from subjects presenting to the heath unit the case attended for routine prevention and care; the second group was selected from the neighbourhood of cases. All Health Units from which controls were selected offered BCG revaccination. Efficacy estimated in a randomized control trial of BCG revaccination was used to establish that the neighbourhood control group was the one that gave unbiased results. RESULTS: The proportion of controls with scars indicating BCG revaccination was higher among the control group selected from Health Unit attenders than among neighbourhood controls. This excess was not removed after control for social variables and history of exposure to tuberculosis, and appears to have resulted from the fact that people attending the Health Unit were more likely to have been revaccinated than neighbourhood controls, although we can not exclude an effect of other unmeasured variables. CONCLUSION: In this study, controls selected from people presenting to a Health Unit overrepresented exposure to BCG revaccination. Had the results from the HU attenders control group been accepted this would have resulted in overestimation of vaccine efficacy. When the exposure of interest is offered in a health facility, selection of controls from attenders at the facility may result in over representation of exposure in controls and selection bias

Searches for Long Lived Neutral Particles

An intriguing possibility for TeV scale physics is the existence of neutral long lived particles (LOLIPs) that subsequently decay into SM states. Such particles are many cases indistinguishable from missing transverse energy (MET) at colliders. We propose new methods to search for these particles using neutrino telescopes. We study their detection prospects, assuming production either at the LHC or through dark matter (DM) annihilations in the Sun and the Earth. We find that the sensitivity for LOLIPs produced at the LHC is limited by luminosity and detection energy thresholds. On the other hand, in the case of DM annihilation into LOLIPs, the sensitivity of neutrino telescopes is promising and may extend beyond the reach of upcoming direct detection experiments. In the context of low scale hidden sectors weakly coupled to the SM, such indirect searches allow to probe couplings as small as 10^-15.Comment: 22 pages, 6 figure

Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0–10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus

The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Replication fork stalling and accumulation of single-stranded DNA trigger the S phase checkpoint, a signalling cascade that, in budding yeast, leads to the activation of the Rad53 kinase. Rad53 is essential in maintaining cell viability, but its targets of regulation are still partially unknown. Here we show that Rad53 drives the hyper-SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε, principally following replication forks stalling induced by nucleotide depletion. Pol2 is the main target of SUMOylation within the replisome and its modification requires the SUMO-ligase Mms21, a subunit of the Smc5/6 complex. Moreover, the Smc5/6 complex co-purifies with Pol ε, independently of other replisome components. Finally, we map Pol2 SUMOylation to a single site within the N-terminal catalytic domain and identify a SUMO-interacting motif at the C-terminus of Pol2. These data suggest that the S phase checkpoint regulate Pol ε during replication stress through Pol2 SUMOylation and SUMO-binding abilit

A revision of the status of Lepadogaster lepadogaster (Teleostei : Gobiesocidae): sympatric subspecies or a long misunderstood blend of species?

Molecular (partial mitochondrial 12S ribosomal DNA sequences), morphological and meristic analysis of Lepadogaster lepadogaster lepadogaster, L. l. purpurea and L. zebrina were performed to investigate the relationships between these taxa. On the western shore of mainland Portugal, where the two subspecies of L. lepadogaster occur sympatrically, they differ in microhabitat preferences and their breeding seasons are largely out of phase. This information, combined with data on distribution patterns, led to the following conclusions: Lepadogaster l. purpurea is considered to be a valid species, L. purpurea (Bonnaterre, 1788), different from L. l. lepadogaster, now designated L. lepadogaster (Bonnaterre, 1788). L. zebrina was found to be a synonym of L. lepadogaster. The two newly defined species were found to be in sympatry at Madeira and the Canary islands, the Atlantic coast of the Iberian Peninsula, and the Mediterranean at least as far as Genoa (Italy). Diagnostic characters and a list of synonyms are provided. (C) 2002 The Linnean Society of London, Biological Journal of the Linnean Society, 2002, 76, 327-338

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Revised estimates of leprosy disability weights for assessing the global burden of disease: A systematic review and individual patient data meta-analysis

Background Leprosy is a chronic bacterial infection caused by Mycobacterium leprae, which may lead to physical disability, stigma, and discrimination. The chronicity of the disease and disabilities are the prime contributors to the disease burden of leprosy. The current figures of the disease burden in the 2017 global burden of disease study, however, are considered to be under-estimated. In this study, we aimed to systematically review the literature and perform individual patient data meta-analysis to estimate new disability weights for leprosy, using Health-Related Quality of Life (HRQOL) data. Methodology/principal findings The search strategy included all major databases with no restriction on language, setting, study design, or year of publication. Studies on human populations that have been affected by leprosy and recorded the HRQOL with the Short form tool, were included. A consortium was formed with authors who could share the anonymous individual-level data of their study. Mean disability weight estimates, sorted by the grade of leprosy disability as defined by WHO, were estimated for individual participant data and pooled using multivariate ran-dom-effects meta-analysis. Eight out of 14 studies from the review were included in the meta-analysis due to the availability of individual-level data (667 individuals). The overall estimated disability weight for grade 2 disability was 0.26 (95%CI: 0.18–0.34). For grade 1 disability the estimated weight was 0.19 (95%CI: 0.13–0.26) and for grade 0 disability it was 0.13 (95%CI: 0.06–0.19). The revised disability weight for grade 2 leprosy disability is four times higher than the published GBD 2017 weights for leprosy and the grade 1 disability weight is nearly twenty times higher. Conclusions/significance The global burden of leprosy is grossly underestimated. Revision of the current disability weights and inclusion of disability caused in individuals with grade 0 leprosy disability will contribute towards a more precise estimation of the global burden of leprosy.</p

Automatic Detection of Malignant Masses in Digital Mammograms Based on a MCET-HHO Approach

Digital image processing techniques have become an important process within medical images. These techniques allow the improvement of the images in order to facilitate their interpretation for specialists. Within these are the segmentation methods, which help to divide the images by regions based on different approaches, in order to identify details that may be complex to distinguish initially. In this work, it is proposed the implementation of a multilevel threshold segmentation technique applied to mammography images, based on the Harris Hawks Optimization (HHO) algorithm, in order to identify regions of interest (ROIs) that contain malignant masses. The method of minimum cross entropy thresholding (MCET) is used to select the optimal threshold values for the segmentation. For the development of this work, four mammography images were used (all with presence of a malignant tumor), in their two views, craniocaudal (CC) and mediolateral oblique (MLO), obtained from the Digital Database for Screening Mammography (DDSM). Finally, the ROIs calculated were compared with the original ROIs of the database through a series of metrics, to evaluate the behavior of the algorithm. According to the results obtained, where it is shown that the agreement between the original ROIs and the calculated ROIs is significantly high, it is possible to conclude that the proposal of the MCET-HHO algorithm allows the automatic identification of ROIs containing malignant tumors in mammography images with significant accuracy.Digital image processing techniques have become an important process within medical images. These techniques allow the improvement of the images in order to facilitate their interpretation for specialists. Within these are the segmentation methods, which help to divide the images by regions based on different approaches, in order to identify details that may be complex to distinguish initially. In this work, it is proposed the implementation of a multilevel threshold segmentation technique applied to mammography images, based on the Harris Hawks Optimization (HHO) algorithm, in order to identify regions of interest (ROIs) that contain malignant masses. The method of minimum cross entropy thresholding (MCET) is used to select the optimal threshold values for the segmentation. For the development of this work, four mammography images were used (all with presence of a malignant tumor), in their two views, craniocaudal (CC) and mediolateral oblique (MLO), obtained from the Digital Database for Screening Mammography (DDSM). Finally, the ROIs calculated were compared with the original ROIs of the database through a series of metrics, to evaluate the behavior of the algorithm. According to the results obtained, where it is shown that the agreement between the original ROIs and the calculated ROIs is significantly high, it is possible to conclude that the proposal of the MCET-HHO algorithm allows the automatic identification of ROIs containing malignant tumors in mammography images with significant accuracy

Early epilepsy in children with Zika-related microcephaly in a cohort in Recife, Brazil: Characteristics, electroencephalographic findings, and treatment response.

OBJECTIVE: To estimate the incidence of epilepsy in children with Zika-related microcephaly in the first 24 months of life; to characterize the associated clinical and electrographic findings; and to summarize the treatment responses. METHODS: We followed a cohort of children, born during the 2015-2016 Zika virus (ZIKV) epidemic in Brazil, with congenital microcephaly and evidence of congenital ZIKV infection on neuroimaging and/or laboratory testing. Neurological assessments were performed at ≤3, 6, 12, 15, 18, 21, and 24 months of life. Serial electroencephalograms were performed over the first 24 months. RESULTS: We evaluated 91 children, of whom 48 were female. In this study sample, the cumulative incidence of epilepsy was 71.4% in the first 24 months, and the main type of seizure was infantile spasms (83.1%). The highest incidence of seizures occurred between 3 and 9 months of age, and the risk remained high until 15 months of age. The incidence of infantile spasms peaked between 4 and 7 months and was followed by an increased incidence of focal epilepsy cases after 12 months of age. Neuroimaging results were available for all children, and 100% were abnormal. Cortical abnormalities were identified in 78.4% of the 74 children evaluated by computed tomography and 100% of the 53 children evaluated by magnetic resonance imaging. Overall, only 46.1% of the 65 children with epilepsy responded to treatment. The most commonly used medication was sodium valproate with or without benzodiazepines, levetiracetam, phenobarbital, and vigabatrin. SIGNIFICANCE: Zika-related microcephaly was associated with high risk of early epilepsy. Seizures typically began after the third month of life, usually as infantile spasms, with atypical electroencephalographic abnormalities. The seizure control rate was low. The onset of seizures in the second year was less frequent and, when it occurred, presented as focal epilepsy