Systemic immunosuppression depletes peripheral blood regulatory B cells in patients with immune thrombocytopenia.

Regulatory B (Breg) cells are potentially implicated in the pathogenesis of immune thrombocytopenia (ITP). We analysed a prospective cohort of newly diagnosed steroid naïve ITP patients enrolled in the multicentre FLIGHT trial and found that the numbers of Bregs in their peripheral blood were similar to healthy controls. In contrast, Breg numbers were significantly reduced in ITP patients treated with systemic immunosuppression (glucocorticoids or mycophenolate mofetil). We also demonstrate that glucocorticoid treatment impairs Breg interleukin-10 production via an indirect T-cell-mediated mechanism.

Exercise, Sleep Quality, and Physical Health during the COVID-19 Pandemic.

OBJECTIVES: Sufficient exercise and high-quality sleep are important for good health, and they may be particularly crucial during the coronavirus pandemic. Sleeping difficulties and insufficient exercise are prevalent in the United States, however, and data indicate little to no change-or even worsening-of these health behaviors before the pandemic. This study explores how exercise quantity coincides with sleep quality in the United States during the pandemic and how both ultimately relate to physical health. METHODS: We used logistic regression and multinomial logistic regression to analyze data from the 2021 Crime, Health, and Politics Survey sampled from the National Opinion Research Center's AmeriSpeak panel. Survey responses were collected between May and June 2021. RESULTS: Results show that more typical weekly exercise and more exercise during the pandemic are significantly associated with higher odds of better current sleep quality and sleep quality during the pandemic, controlling for a variety of sociodemographic factors. Both exercise activity and sleep quality are also significantly associated with higher odds of good physical health. CONCLUSIONS: These findings support the literature that increases in exercise frequency and improved sleep quality are linked and are also associated with better physical health outcomes, even during a global crisis.

Do Religious Struggles Mediate the Association Between Neighborhood Disorder and Health in the United States?

Over the past two decades, numerous studies have linked the subjective experience of neighborhood disorder (perceptions of crime, dilapidation and ambient strains) with poorer health. We test whether religious struggles (religious doubts and feeling abandoned or punished by God) mediate this association. Our counterfactual mediation analyses of data from the 2021 Crime, Health, and Politics Survey (CHAPS) (n = 1741) revealed consistent indirect effects of neighborhood disorder through religious struggles for anger, psychological distress, sleep disturbance, poorer self-rated health, and shorter subjective life expectancy. This study contributes to previous work by integrating the study of neighborhood context and religion.

UK national survey of anticoagulation in extra-corporeal photopheresis-Is it time for a UK consensus statement?

BACKGROUND: Extra-corporeal photopheresis (ECP) requires anticoagulation to prevent circuit clotting. Unfractionated heparin (UFH) is currently the only anticoagulant licensed for the ECP system in use in the United Kingdom (UK). Acid citrate dextrose-A (ACD-A) is the preferred anticoagulant for most other apheresis procedures. Anecdotal evidence suggested variability in ECP practice across the UK with some providers using off-label ACD-A. AIMS: We developed a survey together with the UK Photopheresis Society to establish current practice. MATERIALS & METHODS: This was distributed to all 17 ECP providers covering 34 UK sites. RESULTS: Significant variability in practice was demonstrated with only 36% of responding providers (5/14) using UFH exclusively and 29% (4/14) using ACD-A as standard. CONCLUSION: This survey highlights the need for a UK consensus.

Teleology first: Goals before knowledge and belief.

Comparing knowledge with belief can go wrong in two dimensions: If the authors employ a wider notion of knowledge, then they do not compare like with like because they assume a narrow notion of belief. If they employ only a narrow notion of knowledge, then their claim is not supported by the evidence. Finally, we sketch a superior teleological view.

The C-Terminus and Third Cytoplasmic Loop Cooperatively Activate Mouse Melanopsin Phototransduction.

Melanopsin, an atypical vertebrate visual pigment, mediates non-image-forming light responses including circadian photoentrainment and pupillary light reflexes and contrast detection for image formation. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells are characterized by sluggish activation and deactivation of their light responses. The molecular determinants of mouse melanopsin's deactivation have been characterized (i.e., C-terminal phosphorylation and ß-arrestin binding), but a detailed analysis of melanopsin's activation is lacking. We propose that an extended third cytoplasmic loop is adjacent to the proximal C-terminal region of mouse melanopsin in the inactive conformation, which is stabilized by the ionic interaction of these two regions. This model is supported by site-directed spin labeling and electron paramagnetic resonance spectroscopy of melanopsin, the results of which suggests a high degree of steric freedom at the third cytoplasmic loop, which is increased upon C-terminus truncation, supporting the idea that these two regions are close in three-dimensional space in wild-type melanopsin. To test for a functionally critical C-terminal conformation, calcium imaging of melanopsin mutants including a proximal C-terminus truncation (at residue 365) and proline mutation of this proximal region (H377P, L380P, Y382P) delayed melanopsin's activation rate. Mutation of all potential phosphorylation sites, including a highly conserved tyrosine residue (Y382), into alanines also delayed the activation rate. A comparison of mouse melanopsin with armadillo melanopsin-which has substitutions of various potential phosphorylation sites and a substitution of the conserved tyrosine-indicates that substitution of these potential phosphorylation sites and the tyrosine residue result in dramatically slower activation kinetics, a finding that also supports the role of phosphorylation in signaling activation. We therefore propose that melanopsin's C-terminus is proximal to intracellular loop 3, and C-terminal phosphorylation permits the ionic interaction between these two regions, thus forming a stable structural conformation that is critical for initiating G-protein signaling.

Examining the factors that affect structural repetition in question answering.

We present two experiments that examine structural priming in the single-trial phone-call paradigm introduced by Levelt and Kelter (Cognitive psychology, 14 (1), 78-106, 1982). Experimenters called businesses and asked either What time do you close? or At what time do you close? Participants were more likely to produce a prepositional response (At 7 o'clock vs. 7 o'clock) following a prepositional question than following a non-prepositional question. Experiments 1 and 2 attempted to strengthen the priming effect by having the experimenters engage in a brief interaction with the participant before asking the What time…? question. The interactions did not reliably affect the observed priming effect. An analysis across experiments demonstrated that the priming effect found in this paradigm is generally smaller than the average structural priming effect (as reported in Mahowald, James, Futrell, & Gibson, Journal of Memory and Language, 91, 5-27, 2016), but within the range of the effects that are observed in different structural priming paradigms.

Characteristics of persistently unhealthy counties: A comparison of white and black mortality over time.

This research examines differences in white and black persistence of mortality in the United States over a period of nearly 50 years. Using data from the National Center for Health Statistics Compressed Mortality File, we calculated race-specific, all-cause age-adjusted mortality rates for ten time periods from 1968 to 2015. Counties ranking in the top 20% of mortality in at least half of the time periods are classified as persistently unhealthy. Race-specific mortality persistence is mapped illustrating geographic disparities in the clustering of unhealthy places. Persistence of white mortality is clustered in several distinct Southern regions, while black persistent mortality is evenly distributed geographically. Socioeconomic characteristics of white and black persistently unhealthy places are also examined, with a focus on rural-urban differences.

Stand-alone intrathecal central nervous system (CNS) prophylaxis provide unclear benefit in reducing CNS relapse risk in elderly DLBCL patients treated with R-CHOP and is associated increased infection-related toxicity.

Central nervous system (CNS) relapse following R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) occurs in 2-5% of patents with diffuse large B-cell lymphoma (DLBCL). Many patients aged ≥70 years are unsuitable for high-dose methotrexate (HDMTX) prophylaxis and therefore often receive stand-alone intrathecal prophylaxis. The CNS international prognostic index (CNS-IPI) is a clinical CNS relapse risk score that has not specifically been validated in elderly patients. The value of CNS prophylaxis in patients aged ≥70 years remains uncertain. Data on 690 consecutively R-CHOP-treated DLBCL patients aged ≥70 years were collected across 8 UK centres (2009-2018). CNS prophylaxis was administered per physician preference. Median age was 77·2 years and median follow-up was 2·8 years. CNS-IPI was 1-3 in 60·1%, 4 in 23·8%, 5 in 13·0% and 6 in 3·3%. Renal and/or adrenal (R/A) involvement occurred in 8·8%. Two-year overall CNS relapse incidence was 2·6% and according to CNS-IPI, 1-3:0·8%, 4:3·6%, 5:3·8% and 6:21·8%. Two-year CNS relapse incidence for R/A was 10·0%. When excluding HDMTX (n = 31) patients, there remained no change in unadjusted/adjusted CNS relapse for intrathecal prophylaxis effect according to CNS-IPI. CNS-IPI is valid in elderly R-CHOP-treated DLBCL patients, with the highest risk in those with CNS-IPI 6 and R/A involvement. We observed no clear benefit for stand-alone intrathecal prophylaxis but observed an independent increased risk of infection-related admission during R-CHOP when intrathecal prophylaxis was administered.

Prospective evaluation of scrotal ultrasound and intratesticular perfusion by color-coded duplex sonography (CCDS) in TESE patients with azoospermia.

PURPOSE: The objective of this study was to assess whether CCDS might improve the outcome of testicular sperm retrieval in patients with azoospermia. Furthermore, we evaluated potential sonographic alterations of the testis before and after trifocal and Micro-TESE. METHODS: 78 patients were enrolled prospectively: 24 with obstructive azoospermia (OA) and 54 with non-obstructive azoospermia (NOA). 31 of 54 patients in the NOA group had negative surgical sperm retrieval. Testicular volume, hormonal parameters and sonographical findings were compared before and after TESE. The spermatogenetic score was determined for all retrieval sites. CCDS was performed at the upper, middle and lower segment of the testis. Ultrasound parameters and peak systolic velocity (PSV) were measured pre- and post-operatively. RESULTS: Testicular volume and epididymal head size were significantly increased in OA patients compared to NOA patients. Ultrasound parameters were comparable between NOA patients with and without successful sperm retrieval. A higher intratesticular PSV was significantly correlated with a better spermatogenic score in the corresponding sonographic position. However, after adjustment for other clinical confounders, PSV does not show a significant influence on the spermatogenic score. Testicular volume decreased significantly in all patients post-operatively after 6 weeks (p < 0.001). Finally, the PSV significantly increased in all patients 24 h after surgery and nearly returned to baseline levels after 6 weeks (p < 0.001). CONCLUSIONS: A higher intratesticular PSV may be helpful as a pre-operative diagnostic parameter in mapping for better sperm retrieval, but CCDS does not help to predict successful testicular sperm retrieval after adjustment for other clinical confounders.

Religion and Sexual Identity Fluidity in a National Three-Wave Panel of U.S. Adults.

Research has shown that cross-sectional estimates of sexual identities overlook fluidity in those identities. Research has also shown that social factors, such as competing identities, can influence sexual identity fluidity. We contributed to this literature in two ways. First, we utilized a representative panel of US adults (N = 1034) surveyed in 2010, 2012, and 2014 by the General Social Survey. The addition of a third observation allowed us to examine more complexity in sexual identity fluidity. We found that 2.40% of US adults reported at least one change in sexual identity across the 4 years, with 1.59% reporting one change and 0.81% reporting two changes. Our second contribution came from examining the role of religion, as past research has suggested that religion can destabilize and prolong sexual identity development. We found that lesbian or gay individuals (N = 17), bisexuals (N = 15), and females (N = 585) showed more sexual identity fluidity compared to heterosexuals (N = 1003) and males (N = 450), respectively. Marital status, age, race, and education did not have significant associations with sexual identity fluidity. Regarding the role of religion, we found that participants identifying as more religious in Wave 1 showed more fluidity in sexual identity across later observations. Further analysis showed that higher levels of religiosity make it more likely that lesbian or gay individuals will be fluid in sexual identity, but this is not the case for heterosexual individuals. This finding reinforces past qualitative research that has suggested that religion can extend or complicate sexual minorities' identity development.

Unexplained recurrent miscarriages are associated with an aberrant sperm protamine mRNA content.

STUDY QUESTION: Are unexplained recurrent miscarriages associated with abnormal protamine-1 and protamine-2 mRNA levels in spermatozoa? SUMMARY ANSWER: Both protamine-1 and protamine-2 mRNA levels as well as the protamine-1 to protamine-2 mRNA ratio in spermatozoa from men whose female partners experienced two or more consecutive miscarriages were significantly different compared to those from both healthy control men and subfertile couples undergoing IVF/ICSI. WHAT IS KNOWN ALREADY: Aberrant sperm protamine ratios are known to be associated with male-factor infertility. Data from this study suggest that the protamine mRNA ratio may additionally affect early embryo development. STUDY DESIGN, SIZE, DURATION: The study population was recruited from men whose female partners presented with two or more consecutive unexplained miscarriages in a consultation for recurrent pregnancy loss between 2014 and 2016. At the research laboratory of the Urological Clinic of the University Giessen, spermatozoa from cases and controls were subjected to reverse transcription quantitative PCR (RTqPCR) using specific primer pairs for protamine-1 and protamine-2. PARTICIPANTS/MATERIALS, SETTING, METHODS: Protamine-1 and protamine-2 mRNA levels were analysed in semen samples from 25 men whose female partners experienced at least two consecutive idiopathic miscarriages before the 20th week of gestation. The couples were recruited during consultation at the Fertility Center of the LMU Munich, Germany, and at the Clinical Division of Gynecologic Endocrinology and Reproductive Medicine of the Medical University of Vienna, Austria. Results were compared with those from 32 healthy donors (WHO, 2010) recruited at the Department of Urology, Pediatric Urology and Andrology, Giessen, Germany, and 107 men whose partners participated in an IVF/ICSI program at the Fertility Center of the LMU Munich, Germany. MAIN RESULTS AND THE ROLE OF CHANCE: Protamine-1 and protamine-2 mRNA levels as well as the protamine mRNA ratio and all routine semen parameters revealed significant differences between recurrent miscarriage couples and healthy volunteers (P < 0.01). When comparing recurrent miscarriage couples with couples undergoing IVF/ICSI, Ct-values of protamine-1 and protamine-2 mRNAs were significantly higher and the protamine mRNA ratio was significantly lower in RM couples (P < 0.01). When comparing protamine mRNA levels and the protamine mRNA ratio with routine semen parameters, a significant negative correlation was evident between progressive motility and the protamine-2 mRNA level (P = 0.015), as well as between non-progressive motility and the protamine mRNA ratio (P = 0.023). LIMITATIONS REASONS FOR CAUTION: Although our data demonstrate significant abnormalities in RM, larger sample sizes will be needed to confirm our results. Larger sample sizes should also balance the fact that we had to focus mainly on median protamine mRNA levels. Finally, men in the healthy control group were younger in age than those in the case group, which might have introduced some bias, at least concerning the classic semen parameters. Moreover, only protamine mRNA instead of protein levels could be measured. WIDER IMPLICATIONS OF THE FINDINGS: Although the exact mechanism remains to be elucidated, our data suggest that protamine mRNA levels in spermatozoa are not only important for successful fertilization, but also for proper development of the early embryo. STUDY FUNDING/COMPETING INTEREST(S): Grant from the University Clinic Giessen and Marburg (UKGM 29/2015GI). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Evaluation of neuropsychological outcome and "quality of life" after glioma surgery.

PURPOSE: Extended tumour resection is imperative to improve the outcome of glioma patients but also carries the risk of increasing morbidity and thus, potentially, of decreasing the patient's quality of life (QOL). In this pilot study, we evaluated how postoperative neurological and neuropsychological alterations impacted on QOL in patients who underwent glioma resection. METHODS: Twenty-two patients were included in this study and tested at three different time points, i.e. 1 day before surgery (t1), on the day of discharge (t2) and 3 months following surgery (T3). National Institutes of Health Stroke Scale (NIHSS) score, Addenbrook's Cognitive Examination-Revised (ACE-R) and a comprehensive battery of established tests were used to assess neurological and neuropsychological profiles. QOL and subjectively experienced health condition were ascertained through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ C30) and EORTC-QLQ BN20 questionnaires. RESULTS: Postoperatively, 5/22 patients worsened and 5/22 patients improved neurologically. Depending on the neuropsychological test, up to 57.1 % of patients experienced deterioration of some sort of neuropsychological function. Most of these functions, however, recovered during the extended observation period (3 months). There was no correlation between QOL and a patient's neurological or neuropsychological condition. CONCLUSIONS: Our study suggests that extended tumour resection is not necessarily linked to a loss in QOL.

Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.

The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic 'optic atrophy plus' phenotypes in several families. First, we unravelled a deep intronic mutation 364 base pairs 3' of exon 4b in OPA1 by in-depth investigation of a family with severe optic atrophy plus syndrome in which conventional OPA1 diagnostics including gene dosage analyses were normal. The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis. In patient fibroblasts we demonstrate nonsense mediated messenger RNA decay, reduced levels of OPA1 protein, and impairment of mitochondrial dynamics. Subsequent site-specific screening of >360 subjects with unexplained inherited optic neuropathy revealed three additional families carrying this deep intronic mutation and a base exchange four nucleotides upstream, respectively, thus confirming the clinical significance of this mutational mechanism. Second, in all severely affected patients of the index family, the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2). The variant alone did not cause a phenotype, even in homozygous state indicating that this long debated OPA1 variant is not pathogenic per se, but acts as a phenotypic modifier if it encounters in trans with an OPA1 mutation. Subsequent screening of whole exomes from >600 index patients identified a second family with severe optic atrophy plus syndrome due to compound heterozygous p.I382M, thus confirming this mechanism. In summary, we provide genetic and functional evidence that deep intronic mutations in OPA1 can cause optic atrophy and explain disease in a substantial share of families with unsolved inherited optic neuropathies. Moreover, we show that an OPA1 modifier variant explains the emergence of optic atrophy plus phenotypes if combined in trans with another OPA1 mutation. Both mutational mechanisms identified in this study-deep intronic mutations and intragenic modifiers-might represent more generalizable mechanisms that could be found also in a wide range of other neurodegenerative and optic neuropathy diseases.

Embedded ultrasonic transducers for active and passive concrete monitoring.

Recently developed new transducers for ultrasonic transmission, which can be embedded right into concrete, are now used for non-destructive permanent monitoring of concrete. They can be installed during construction or thereafter. Large volumes of concrete can be monitored for changes of material properties by a limited number of transducers. The transducer design, the main properties as well as installation procedures are presented. It is shown that compressional waves with a central frequency of 62 kHz are mainly generated around the transducer's axis. The transducer can be used as a transmitter or receiver. Application examples demonstrate that the transducers can be used to monitor concrete conditions parameters (stress, temperature, …) as well as damages in an early state or the detection of acoustic events (e.g., crack opening). Besides application in civil engineering our setups can also be used for model studies in geosciences.