Detecting and predicting neutralization of alemtuzumab responses in MS

Objective: To test the hypothesis that anti-drug antibodies against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance. Methods: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding anti-drug antibodies. Alemtuzumab IgG Alexa-Fluor 488 conjugate was used in a competitive-binding cell based assay to detect neutralizing anti-drug antibodies. The assays were used to retrospectively screen, blinded, banked-serum samples from people with multiple sclerosis (n=32) who had received three or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month post-infusion. Results: The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. Anti-drug antibody responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred prior to the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Pre-infusion, anti-drug antibody levels predicted limited, post-infusion lymphocyte depletion. Conclusions: Although anti-drug antibodies to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of, lymphocyte depletion and the anti-drug response may be of practical value in patients requiring additional cycles of alemtuzumab. Anti-drug antibody detection may help to inform on re-treatment or switching to another treatment

Changing indications and socio-demographic determinants of (adeno)tonsillectomy among children in England--are they linked? A retrospective analysis of hospital data.

OBJECTIVE: To assess whether increased awareness and diagnosis of obstructive sleep apnoea syndrome (OSAS) and national guidance on tonsillectomy for recurrent tonsillitis have influenced the socio-demographic profile of children who underwent tonsillectomy over the last decade. METHOD: Retrospective time-trends study of Hospital Episodes Statistics data. We examined the age, sex and deprivation level, alongside OSAS diagnoses, among children aged <16 years who underwent (adeno)tonsillectomy in England between 2001/2 and 2011/12. RESULTS: Among children aged <16 years, there were 29,697 and 27,732 (adeno)tonsillectomies performed in 2001/2 and 2011/12, respectively. The median age at (adeno)tonsillectomy decreased from 7 (IQR: 5-11) to 5 (IQR: 4-9) years over the decade. (Adeno)tonsillectomy rates among children aged 4-15 years decreased by 14% from 350 (95%CI: 346-354) in 2001/2 to 300 (95%CI: 296-303) per 100,000 children in 2011/12. However, (adeno)tonsillectomy rates among children aged <4 years increased by 58% from 135 (95%CI: 131-140) to 213 (95%CI 208-219) per 100,000 children in 2001/2 and 2011/2, respectively. OSAS diagnoses among children aged <4 years who underwent surgery increased from 18% to 39% between these study years and the proportion of children aged <4 years with OSAS from the most deprived areas increased from 5% to 12%, respectively. CONCLUSIONS: (Adeno)tonsillectomy rates declined among children aged 4-15 years, which reflects national guidelines recommending the restriction of the operation to children with more severe recurrent throat infections. However, (adeno)tonsillectomy rates among pre-school children substantially increased over the past decade and one in five children undergoing the operation was aged <4 years in 2011/12.The increase in surgery rates in younger children is likely to have been driven by increased awareness and detection of OSAS, particularly among children from the most deprived areas

The VANDELS Survey: New constraints on the high-mass X-ray binary populations in normal star-forming galaxies at 3 < z < 5.5

We use VANDELS spectroscopic data overlapping with the ≃7 Ms Chandra Deep Field South survey to extend studies of high-mass X-ray binary systems (HMXBs) in 301 normal star-forming galaxies in the redshift range 3 6 may be ≳0.25 dex higher than previously estimated

No strong dependence of Lyman continuum leakage on physical properties of star-forming galaxies at 3.1 ≲ z ≲ 3.5

We present Lyman continuum (LyC) radiation escape fraction (fesc) measurements for 183 spectroscopically confirmed star-forming galaxies in the redshift range 3.11 300 Å. For candidate LyC leakers, we find a weak negative correlation between fesc and galaxy stellar masses, no correlation between fesc and specific star-formation rates (sSFRs) and a positive correlation between fesc and EW0([O III] + Hβ). The weak/no correlations between stellar mass and sSFRs may be explained by misaligned viewing angles and/or non-coincident timescales of starburst activity and periods of high fesc. Alternatively, escaping radiation may predominantly occur in highly localised star-forming regions, or fesc measurements may be impacted by stochasticity of the intervening neutral medium, obscuring any global trends with galaxy properties. These hypotheses have important consequences for models of reionisation

The VANDELS survey: Global properties of CIII]lambda 1908 angstrom emitting star-forming galaxies at z similar to 3

Context. Strong nebular emission is ubiquitous in galaxies that contribute to cosmic reionization at redshift za a 6. High-ionization UV metal lines, such as CIII]λ1908 A, show high equivalent widths (EW) in these early galaxies, suggesting harder radiation fields at low metallicity than low-z galaxies of similar stellar mass. Understanding the physical properties driving the observed UV nebular line emission at high-z requires large and very deep spectroscopic surveys, which are now only accessible out to za a a 4. Aims. We study the mean properties of a large representative sample of 217 galaxies showing CIII] emission at 2a <a za <a 4, selected from a parent sample of a 750 main-sequence star-forming galaxies in the VANDELS survey. These CIII] emitters have a broad range of UV luminosities, allowing for a detailed stacking analysis to characterize their stellar mass, star formation rate (SFR), and metallicity as a function of the UV emission line ratios, EWs, and the carbon-to-oxygen (C/O) abundance ratio. Methods. Stacking provides unprecedented high signal-to-noise (S/N) spectra for CIII] emitters over more than three decades in luminosity, stellar mass, and SFR. This enables a full spectral fitting to derive stellar metallicities for each stack. Moreover, we use diagnostics based on photoionization models and UV line ratios to constrain the ionization sources of the galaxies and derive the C/O abundance. Results. Reliable CIII] detections (S/Na a ¥a 3) represent a 30% of the parent sample. However, stacked spectra of non-detections (S/Na <a 3) show weak (EW a 2 A) CIII] emission, suggesting that this line is common in normal star-forming galaxies at za a a 3. On the other hand, extreme CIII] emitters (EW(CIII]) a 8 A) are exceedingly rare (a 3%) in VANDELS. The UV line ratios of the sample suggest no ionization source other than massive stars. Stacks with larger EW(CIII]) show larger EW(Lyα) and lower metallicity, but not all CIII] emitters are Lyα emitters. The stellar metallicities of CIII] emitters are not significantly different from that of the parent sample, increasing from a 10% to a 40% solar for stellar masses log(Ma/Ma) a 9a? 10.5. The stellar mass-metallicity relation of the CIII] emitters is consistent with previous works, exhibiting a strong evolution from za =a 0 to za a a 3. The C/O abundances of the sample range between 35%a? 150% solar, with a noticeable increase with FUV luminosity and a smooth decrease with the CIII] EW. Here, we discuss the CIII] emitters in the C/Oa Fe/H and the C/Oa O/H planes and we find that they follow stellar and nebular abundance trends consistent with those of Milky Way halo and thick-disk stars and local HII galaxies, respectively. A qualitative agreement is also found with chemical evolution models, which suggests that CIII] emitters at za a a 3 are experiencing an active phase of chemical enrichment. Conclusions. Our results provide new insights into the nature of UV line emitters at za a a 2a 4, paving the way for future studies at higher z using the James Webb Space Telescope

The NIRVANDELS Survey: A robust detection of α-enhancement in star-forming galaxies at z ≃3.4

We present results from the NIRVANDELS survey on the gas-phase metallicity (Zg, tracing O/H) and stellar metallicity (Z∗, tracing Fe/H) of 33 star-forming galaxies at redshifts 2.95 3, finding (O/Fe) = 2.54 ± 0.38 × (O/Fe)⊙, with no clear dependence on M∗

Regional research priorities in brain and nervous system disorders

The characteristics of neurological, psychiatric, developmental and substance-use disorders in low-and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and quality, and genetics. Neurological, psychiatric, developmental and substance-use disorders that result from, or are worsened by, a lack of adequate nutrition and infectious disease still afflict much of sub-Saharan Africa, although disorders related to increasing longevity, such as stroke, are on the rise. In the Middle East and North Africa, major depressive disorders and post-traumatic stress disorder are a primary concern because of the conflict-ridden environment. Consanguinity is a serious concern that leads to the high prevalence of recessive disorders in the Middle East and North Africa and possibly other regions. The burden of these disorders in Latin American and Asian countries largely surrounds stroke and vascular disease, dementia and lifestyle factors that are influenced by genetics. Although much knowledge has been gained over the past 10 years, the epidemiology of the conditions in low-and middle-income countries still needs more research. Prevention and treatments could be better informed with more longitudinal studies of risk factors. Challenges and opportunities for ameliorating nervous-system disorders can benefit from both local and regional research collaborations. The lack of resources and infrastructure for health-care and related research, both in terms of personnel and equipment, along with the stigma associated with the physical or behavioural manifestations of some disorders have hampered progress in understanding the disease burden and improving brain health. Individual countries, and regions within countries, have specific needs in terms of research priorities.Fil: Ravindranath, Vijayalakshmi. Indian Institute of Science; IndiaFil: Dang, Hoang Minh. Vietnam National University; VietnamFil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Mansour, Hader. University of Pittsburgh; Estados Unidos. Mansoura University; EgiptoFil: Nimgaonkar, Vishwajit L.. University of Pittsburgh; Estados UnidosFil: Russell, Vivienne Ann. University of Cape Town; SudáfricaFil: Xin, Yu. Peking University; Chin

Genetic Signatures of Exceptional Longevity in Humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity

Nonlinearity and Topology

The interplay of nonlinearity and topology results in many novel and emergent properties across a number of physical systems such as chiral magnets, nematic liquid crystals, Bose-Einstein condensates, photonics, high energy physics, etc. It also results in a wide variety of topological defects such as solitons, vortices, skyrmions, merons, hopfions, monopoles to name just a few. Interaction among and collision of these nontrivial defects itself is a topic of great interest. Curvature and underlying geometry also affect the shape, interaction and behavior of these defects. Such properties can be studied using techniques such as, e.g. the Bogomolnyi decomposition. Some applications of this interplay, e.g. in nonreciprocal photonics as well as topological materials such as Dirac and Weyl semimetals, are also elucidated