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Rakesh Sebastian, Jegan Arunachalam, Manorajan Rajendran Department of Nephrology, Government Rajaji Hospital, Madurai Medical College, Madurai, Tamil Nadu, IndiaCorrespondence: Jegan ArunachalamDepartment of Nephrology, Government Rajaji Hospital, Madurai Medical College, Madurai, Tamil Nadu, IndiaTel +91 9994373260Email jeganmddm@gmail.comAbstract: Anti-glomerular basement membrane disease (anti-GBM) affects mainly kidneys and lungs. It requires aggressive immunosuppressive treatment. Since the emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), there has been an increased number of new cases of anti-GBM disease presenting as rapidly progressive glomerulonephritis (RPGN). The causal relationship is still speculative. We report a case series of four patients affected with COVID-19 infection presenting later with anti-GBM disease.Keywords: anti glomerular basement membrane disease, COVID-19, case series, plasmapheresis

We have previously shown that the microRNA (miRNA) processor complex consisting of the RNAse Drosha and the DiGeorge Critical Region (DGCR) 8 protein is essential for B cell maturation. To determine whether miRNA processing is required to initiate T cell-mediated antibody responses, we deleted DGCR8 in maturing B2 cells by crossing a mouse with loxP-flanked DGCR8 alleles with a CD23-Cre mouse. As expected, non-immunized mice showed reduced numbers of mature B2 cells and IgG-secreting cells and diminished serum IgG titers. In accordance, germinal centers and antigen-specific IgG-secreting cells were absent in mice immunized with T-dependent antigens. Therefore, DGCR8 is required to mount an efficient T-dependent antibody response. However, DGCR8 deletion in B1 cells was incomplete, resulting in unaltered B1 cell numbers and normal IgM and IgA titers in DGCR8-knock-out mice. Therefore, this mouse model could be used to analyze B1 responses in the absence of functional B2 cells.

Abstract A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had

Tumor associated neutrophils have been correlated with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here the authors show that the tyrosine kinase inhibitor lorlatinib modulates neutrophil development and recruitment in the tumor microenvironment, attenuating PDAC progression in preclinical mouse models.

Objectives: The objective of this study was to evaluate the accuracy of forensic age estimation in a German population by combining clavicle and wisdom teeth assessments based on cone beam computed tomography (CT) data. The study aimed to determine the reliability of this approach in predicting biological age. Material and Methods: A total of 161 CT data sets from 120 males and 41 females with known exact ages were evaluated by three raters. The clavicle was assessed according to stages 1–5 (including substages 2a–c and 3a–c), and the Demirjian stage’s classification method was used for the wisdom teeth. Inter-class correlation (ICC) was calculated to assess the agreement among the three raters. Additionally, ordinary least square regressions were performed to predict chronological age using the clavicle or one of the four teeth. Finally, age prediction models using multiple indicators were developed. Results: The ICCs ranged from 0.82 for the clavicle to 0.86 and 0.88 for the wisdom teeth. Linear estimation tended to overestimate chronological age, especially in subjects over 18 years old. The clavicle showed the strongest overestimation. Combining age estimation from the clavicle with the upper and lower wisdom teeth improved the predictive power, resulting in a 14% and 15% increase in R² for the upper and lower wisdom teeth, respectively. Adding more than one tooth to the prediction did not improve the predictive power (all ΔR² < 1%). Conclusions: Age estimation using CT can be significantly improved by combining information from the analysis of wisdom teeth with age estimation based on the clavicle.

Background: The treatment of head and neck tumors remains a challenge due to their reduced radiosensitivity. Small molecule kinase inhibitors (smKI) that inhibit the DNA damage response, may increase the radiosensitivity of tumor cells. However, little is known about how the immunophenotype of the tumor cells is modulated thereby. Therefore, we investigated whether the combination of ATM or ATR inhibitors with hypo-fractionated radiotherapy (RT) has a different impact on the expression of immune checkpoint markers (extrinsic), the release of cytokines or the transcriptome (intrinsic) of head and neck squamous cell carcinoma (HNSCC) cells. Methods: The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT. Results: Cell death was mainly induced by the combination of RT with both inhibitors, but stronger with ATRi. Further, the immune phenotype of cancer cells, not dying from combination therapy itself, is altered predominantly by RT+ATRi in an immune-stimulatory manner by the up-regulation of ICOS-L. However, the analysis of secreted cytokines after treatment of HNSCC cell lines revealed an ambivalent influence of both inhibitors, as we observed the intensified secretion of IL-6 and IL-8 after RT+ATRi. These findings were confirmed by RNAseq analysis and further the stronger immune-suppressive character of RT+ATMi was enlightened. We detected the down-regulation of a central protein of cytoplasmatic sensing pathways of nucleic acids, RIG-1, and found one immune-suppressive target, EDIL3, strongly up-regulated by RT+ATMi. Conclusion: Independent of a restrictive toxicity, the combination of RT + either ATMi or ATRi leads to comprehensive and immune-modulating alterations in HNSCC. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi. [ABSTRACT FROM AUTHOR]

There are several well-known medical conditions in which posture and gravity interact with natural history, including pregnancy. In this review, we provide a comprehensive overview of interactions between maternal posture and maternal physiology and pathophysiology at rest during pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 644 studies from 1991 through 2021, inclusive, that met our inclusion criteria. We present a narrative review of the resulting literature and highlight discrepancies, research gaps, and potential clinical implications. We organize the results by organ system and, commencing with the neurological system, proceed in our synthesis generally in the craniocaudal direction, concluding with the skin. The circulatory system warranted our greatest and closest consideration-literature concerning the dynamic interplay between physiology (heart rate, stroke volume, cardiac output, blood pressure, and systemic vascular resistance), pathophysiology (e.g., hypertension in pregnancy), and postural changes provide an intricate and fascinating example of the importance of the subject of this review. Other organ systems discussed include respiratory, renal, genitourinary, gastrointestinal, abdominal, and endocrine. In addition to summarizing the existing literature on maternal posture-physiology interactions, we also point out gaps and opportunities for further research and clinical developments in this area. Overall, our review provides both insight into and relevance of maternal posture-physiology interactions vis à vis healthcare's mission to improve health and wellness during pregnancy and beyond. [ABSTRACT FROM AUTHOR]

Abstract Background Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. Methods A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. Results While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). Conclusions Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.

Abstract Background There is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies. Methods A prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope. Results While the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p < 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p < 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation. Conclusions The uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

Abstract Soil water repellency is traditionally expressed as contact angle (CA) and measured destructively on exposed surfaces or derived from flow behavior or measured forces. These approaches cannot map local heterogeneities in CA, which typically exist in intact soil. Here, we explore the potential and limitations of in situ measurements of three‐dimensional CAs with simplified benchmark tests and in intact sand. The method is based on a protocol for the freely available OpenFOAM software and applied to segmented X‐ray computed tomography (X‐ray CT) data. This study scrutinizes its suitability under typical vadose zone conditions, as it was originally developed for rock studies in petroleum engineering. The assets of the method are that it allows for accurate measurement of locally varying, equilibrium contact angles and that they can be linked to pore scale features that cause them. This is demonstrated with rehydrated mucilage structures in sand and the associated change in local CAs, where they touch sand grains. In general, the image acquisition time of polychromatic X‐ray CT (minutes) precludes the assessments of dynamic CAs that may equilibrate within seconds. Another limitation is that acute CAs are overestimated due to the voxel discretization of interfaces and contact lines in combination with image smoothing. The divergence arises around 60° and is most severe in the limit of vanishing water repellency. In summary, the method enables the mapping of local heterogeneities of equilibrium CAs, though the absolute values should be critically assessed.