To treat or not to treat? Current attitudes on treatment aimed at modifying the disease burden in clinically suspect arthralgia:a survey among participants of the TREAT EARLIER trial and healthcare professionals

Objectives While awaiting therapies accomplishing rheumatoid arthritis (RA)-prevention in individuals at-risk, recent evidence supports that a 1-year methotrexate treatment may lead to sustained reduction in disease burden and subclinical joint inflammation in patients with clinically suspect arthralgia (CSA). We aimed to study the previously unexplored attitudes of CSA patients and rheumatologists on 1-year DMARD treatment in the arthralgia phase to reduce the disease burden, while not preventing RA.Methods CSA patients who participated in the TREAT EARLIER trial, thus being expert by experience, were informed on the trial results. Thereafter they completed an anonymous questionnaire about their attitudes on treatment in the CSA phase. We used the same approach for Dutch healthcare professionals in rheumatology.Results The majority of trial participants (85%) considered the effects of the 1-year treatment as found in the TREAT EARLIER trial, beneficial in the symptomatic at-risk stage. 79% would recommend a 1-year methotrexate course to others with comparable joint complaints. Two-thirds indicated RA prevention and improving disease burden to be equally important treatment goals in the CSA phase. Most healthcare professionals (88%) were inclined to prescribe 1-year treatment to CSA patients aimed at long-term improvement of symptoms and functioning, while not preventing RA development. 59% believed the profits of a 1-year methotrexate course to outweigh disadvantages, for example, side effects.Conclusions A considerable willingness exists among CSA patients and rheumatologists to start a 1-year treatment resulting in long-term improvement of symptoms and functioning, while not preventing RA. This emphasises the need for more research optimising treatment regimens and disease monitoring in individuals at-risk to facilitate such treatment decisions in the future, while avoiding an intervention, either limited or for a prolonged period, which may have harms that outweigh benefits.Trial registration number The Netherlands Trials Registry (NTR4853-trial-NL4599). EudraCT number: NL2014-004472-35

Identifying intrinsic and reflexive contributions to low-back stabilization

Motor control deficits have been suggested as potential cause and/or effect of a-specific chronic low-back pain and its recurrent behavior. Therefore, the goal of this study is to identify motor control in low-back stabilization by simultaneously quantifying the intrinsic and reflexive contributions. Upper body sway was evoked using continuous force perturbations at the trunk, while subjects performed a resist or relax task. Frequency response functions (FRFs) and coherences of the admittance (kinematics) and reflexes (sEMG) were obtained. In comparison with the relax task, the resist task resulted in a 61% decrease in admittance and a 73% increase in reflex gain below 1.1 Hz. Intrinsic and reflexive contributions were captured by a physiologically-based, neuromuscular model, including proprioceptive feedback from muscle spindles (position and velocity) and Golgi tendon organs (force). This model described on average 90% of the variance in kinematics and 39% of the variance in sEMG, while resulting parameter values were consistent over subjects

Extended hypoxia in the alfalfa leafcutting bee, Megachile rotundata, increases survival but causes sub-lethal effects

AbstractMany insects are tolerant of hypoxic conditions, but survival may come at a cost to long-term health. The alfalfa leaf-cutting bee, Megachile rotundata, develops in brood cells inside natural cavities, and may be exposed to hypoxic conditions for extended periods of time. Whether M. rotundata is tolerant of hypoxia, and whether exposure results in sub-lethal effects, has never been investigated. Overwintering M. rotundata prepupae were exposed to 10%, 13%, 17%, 21% and 24% O2 for 11months. Once adults emerged, five indicators of quality — emergence weight, body size, feeding activity, flight performance, and adult longevity, — were measured to determine whether adult bees that survived past exposure to hypoxia were competent pollinators. M. rotundata prepupae are tolerant of hypoxic condition and have higher survival rates in hypoxia, than in normoxia. Under hypoxia, adult emergence rates did not decrease over the 11months of the experiment. In contrast, bees reared in normoxia had decreased emergence rates by 8months, and were dead by 11months. M. rotundata prepupae exposed to extended hypoxic conditions had similar emergence weight, head width, and cross-thorax distance compared to bees reared in standard 21% oxygen. Despite no significant morphological differences, hypoxia-exposed bees had lower feeding rates and shorter adult lifespans. Hypoxia may play a role in post-diapause physiology of M. rotundata, with prepupae showing better survival under hypoxic conditions. Extended exposure to hypoxia, while not fatal, causes sub-lethal effects in feeding rates and longevity in the adults, indicating that hypoxia tolerance comes at a cost

Joint involvement in RA starts predominantly in the hands:functional, clinical and imaging studies in clinically suspect arthralgia and during progression to RA

Objectives: It is unknown whether rheumatoid arthritis (RA) starts in hands or feet. To investigate this, we performed functional, clinical and imaging studies during progression from clinically suspect arthralgia (CSA) to RA. Additionally, we studied whether functional disabilities of hands/feet at CSA onset contribute to predicting RA development. Methods: 600 patients with CSA were followed for clinical inflammatory arthritis (IA) during median follow-up of 25 months, during which 99 developed IA. Functional disabilities were measured at baseline/4/12/24 months with the Health Assessment Questionnaire Disability Index (HAQ); HAQ items assessing hand disabilities and foot disabilities were selected. The course of disabilities towards IA development (here considered as t=0) was depicted by increasing incidences and analysed using linear mixed models. To evaluate robustness of findings, tender hand/foot joints and subclinical joint inflammation (measured with CE-1.5TMRI) of hand/foot were additionally studied. Associations between disabilities at CSA presentation (here t=0) and future IA development were studied using Cox regression in the total CSA population.Results: During IA development, hand disabilities occurred earlier and more frequently than foot disabilities. Despite both hand disabilities and foot disabilities rose significantly towards IA development, hand disabilities were more severe during this course (mean difference over time: 0.41 units, 95% CI 0.28 to 0.55, pPathophysiology and treatment of rheumatic disease

Optical Properties of Layered Superconductors near the Josephson Plasma Resonance

We study the optical properties of crystals with spatial dispersion and show that the usual Fresnel approach becomes invalid near frequencies where the group velocity of the wave packets inside the crystal vanishes. Near these special frequencies the reflectivity depends on the atomic structure of the crystal provided that disorder and dissipation are very low. This is demonstrated explicitly by a detailed study of layered superconductors with identical or two different alternating junctions in the frequency range near the Josephson plasma resonance. Accounting for both inductive and charge coupling of the intrinsic junctions, we show that multiple modes are excited inside the crystal by the incident light, determine their relative amplitude by the microscopic calculation of the additional boundary conditions and finally obtain the reflectivity. Spatial dispersion also provides a novel method to stop light pulses, which has possible applications for quantum information processing and the artificial creation of event horizons in a solid.Comment: 25 pages, 20 figures, submitted to Phys. Rev.

Molecular assessment of bacterial vaginosis by Lactobacillus abundance and species diversity

__Background:__ To date, women are most often diagnosed with bacterial vaginosis (BV) using microscopy based Nugent scoring or Amsel criteria. However, the accuracy is less than optimal. The aim of the present study was to confirm the identity of known BV-associated composition profiles and evaluate indicators for BV using three molecular methods. __Methods:__ Evaluation of indicators for BV was carried out by 16S rRNA amplicon sequencing of the V5-V7 region, a tailor-made 16S rRNA oligonucleotide-based microarray, and a PCR-based profiling technique termed IS-profiling, which is based on fragment variability of the 16S-23S rRNA intergenic spacer region. An inventory of vaginal bacterial species was obtained from 40 females attending a Dutch sexually transmitted infection outpatient clinic, of which 20 diagnosed with BV (Nugent score 7-10), and 20 BV negative (Nugent score 0-3). __Results:__ Analysis of the bacterial communities by 16S rRNA amplicon sequencing revealed two clusters in the BV negative women, dominated by either Lactobacillus iners or Lactobacillus crispatus and three distinct clusters in the BV positive women. In the former, there was a virtually complete, negative correlation between L. crispatus and L. iners. BV positive subjects showed cluster profiles that were relatively high in bacterial species diversity and dominated by anaerobic species, including Gardnerella vaginalis, an

Impaired fertility in men diagnosed with inflammatory arthritis: results of a large multicentre study (iFAME-Fertility)

Objectives The impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems.Methods We performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: = 41 years (after the peak).Results In total 628 participants diagnosed with IA were included. Men diagnosed = 41 years (1.88 (SD 1.14)). This was statistically significant (p=0.0004). The percentages of men diagnosed = 41 years.Conclusions This is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.Pathophysiology and treatment of rheumatic disease

Unexpected finding of uniparental disomy mosaicism in term placentas: Is it a common feature in trisomic placentas?

Objective: Non-invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed. Method: NIPT was conducted in the course of the Dutch TRIDENT study. Placentas of 10 cases with NIPT results indicating an autosomal trisomy and showing a normal (N = 9) or low mosaic karyotype (N = 1) in amniotic fluid (AF) were investigated. The cytotrophoblast as well as the mesenchymal core of two to four placental chorionic villi biopsies were studied with single nucleotide polymorphism (SNP) array. Clinical outcome data were collected. Results: In 10/10 cases, CPM was proven. In 3/10 cases trisomy/uniparental disomy (UPD)/biparental disomy (BPD) mosaicism was discovered. In 2/3 cases, all three cell lines were present in the placenta, whereas BPD was found in AF. In 1/3 cases trisomy 22/UPD22 was present in AF while trisomy 22/BPD22 mosaicism was found in the placenta. Five of 10 pregnancies were affected with pre-eclampsia, low birth weight, preterm delivery, and/or congenital malformations. Conclusion: The presence of trisomy/UPD/BPD mosaicism in 3/10 cases that we investigated proves that trisomic zygote rescue may involve multiple rescue events during early embryogenesis. UPD mosaicism, when present in crucial fetal tissues, may explain the abnormal phenotype in undiagnosed cases

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease