The role of different acetabular morphologies on patient-reported outcomes following periacetabular osteotomy in borderline hip dysplasia.

INTRODUCTION: The treatment option for borderline hip dysplasia (BHD) includes hip arthroscopy and periacetabular osteotomy (PAO). To the present day the controversial discussion remains, which intervention to prefer. Literature reports supporting an educated choice are scare, based on small patient cohorts and do not address the variability of acetabular morphology. Consequently, we intended to report PAO outcomes, from patients diagnosed with BHD, dependent on acetabular morphology, in a large patient cohort and aimed to define risk factors for poor clinical results and patient satisfaction. MATERIALS AND METHODS: A prospective monocentre study was conducted. Patients enrolled underwent PAO for symptomatic BHD (LCEA, 18°-25°). A total of 107 hips were included with 94 complete data sets were available for evaluation with a minimum follow-up of 1 year and a mean follow-up of 2.3 years. The mean age was 31 ± 8.2 years, and 81.3% were female. As the primary outcome measure, we utilized the modified Harris hip score (mHHS) with minimal clinically important change (MCID) of eight to define clinical failure. Results were compared after a comprehensive radiographic assessment distinguishing between lateral deficient vs. anterior/posterolateral deficient acetabular and stable vs. unstable hip joints. RESULTS: Overall, clinical success was achieved in 91.5% of patients and the mHHS improved significantly (52 vs. 84.7, p < 0.001). Eight hips failed to achieve the MCID and four had radiographic signs of overcorrection. Comparing variable joint morphologies, the rate of clinical success was higher in patients with an anterior/posterolateral deficient acetabular covarage compared to lateral deficient acetabular (95.2% vs. 90.4%). tThe highest rate of clinical failure was recorded in unstable hip joints (85.7% vs. 92.5% in stable hips). CONCLUSIONS: This study demonstrates that PAO is an effective means to treat symptomatic BHD with variable acetabular morphologies, achieving a clinical success in 91.5% of all patients. To maintain a high level of safety and patient satisfaction technical accuracy appears crucial.

[Information and Counseling needs Regarding Parenthood Decisions: Are Existing Services Sufficient and what Role does Depression Play?] / Informations- und Beratungsbedarf bei Elternschaftsentscheidungen: Genügen bestehende Angebote und welche Rolle spielen Depressionen?

OBJECTIVE: Support needs in parenting decisions and the associated desire for information and counseling services are insufficiently researched, especially in relation to groups of people with mental health burdens. The aim of this study was to assess information and counseling needs in parenting decisions. In addition, we investigated whether more severe depressive symptomatology is associated with increased needs. METHODS: A sample of 187 individuals between the ages of 20 and 44 was surveyed in an online study. RESULTS: Not having enough information on the topic was expressed by 45% of participants, and the desire for information related to multiple topics. A larger offer of professional coun-seling was desired by 65% of the participants, 74% (rather) did not know where to get it. Existing counseling services were used infrequently in relation to needs and with predominantly moderate satisfaction. Greater depressive symptomatology was not associated with increased information or counseling needs. DISCUSSION AND CONCLUSION: Findings suggest an expansion of support services on parenting decisions. Further research into the needs of different groups and barriers to using existing services is essential.

Advanced optical imaging techniques for bladder cancer detection and diagnosis: a systematic review.

OBJECTIVES: To systematically assess the current available literature concerning advanced optical imaging methods for the detection and diagnosis of bladder cancer (BCa), focusing particularly on the sensitivity and specificity of these techniques. METHODS: First a scoping search was performed to identify all available optical techniques for BCa detection and diagnosis. The optical imaging techniques used for detecting BCa are: the Storz professional image enhancement system (IMAGE1 S), narrow-band imaging (NBI), photoacoustic imaging (PAI), autofluorescence imaging (AFI), photodynamic diagnosis (PDD), and scanning fibre endoscopy (SFE). The staging and grading techniques for BCa are: optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), Raman spectroscopy, endocytoscopy, and non-linear optical microscopy (NLO). Then a systematic literature search was conducted using MEDLINE, EMBASE and Web of Science from inception to 21 November 2023. Articles were screened and selected by two independent reviewers. Inclusion criteria were: reporting on both the sensitivity and specificity of a particular technique and comparison to histopathology, and in the case of a detection technique comparison to white light cystoscopy (WLC). RESULTS: Out of 6707 articles, 189 underwent full-text review, resulting in 52 inclusions. No articles met criteria for IMAGE1 S, PAI, SFE, Raman spectroscopy, and endocytoscopy. All detection techniques showed higher sensitivity than WLC, with NBI leading (87.8-100%). Overall, detection technique specificity was comparable to WLC, with PDD being most specific (23.3-100%). CLE and OCT varied in sensitivity and specificity, with OCT showing higher specificity for BCa diagnosis, notably for carcinoma in situ (97-99%) compared to CLE (62.5-81.3%). NLO demonstrated high sensitivity and specificity (90-97% and 77-100%, respectively) based on limited data from two small ex vivo studies. CONCLUSIONS: Optical techniques with the most potential are PDD for detecting and OCT for staging and grading BCa. Further research is crucial to validate their integration into routine practice and explore the value of other imaging techniques.

In silico screening identifies SHPRH as a novel nucleosome acidic patch interactor.

Nucleosomes are the fundamental unit of eukaryotic chromatin. Diverse factors interact with nucleosomes to modulate chromatin architecture and facilitate DNA repair, replication, transcription, and other cellular processes. An important platform for chromatin binding is the H2A-H2B acidic patch. Here, we used AlphaFold-Multimer to screen over 7000 human proteins for nucleosomal acidic patch binding and identify 41 potential acidic patch binders. We determined the cryo-EM structure of one hit, SHPRH, with the nucleosome at 2.8 Å. The structure confirms the predicted acidic patch interaction, reveals that the SHPRH ATPase engages a different nucleosomal DNA location than other SF2-type ATPases, and clarifies the roles of SHPRH's domains in nucleosome recognition. Our results illustrate the use of in silico screening as a high throughput method to identify specific interaction types and expands the set of potential acidic patch binding factors. All the screening data is freely available at: https://predictomes.org/view/acidicpatch.

Adherence to single inhaler triple therapy and digital inhalers in Chronic Obstructive Pulmonary Disease: a literature review and protocol for a randomized controlled trial (TRICOLON study).

BACKGROUND: Medication non-adherence is a significant problem in patients with Chronic Obstructive Pulmonary Disease (COPD). Efforts to address this issue are receiving increased attention. Simplifying treatment by prescribing single-inhaler triple therapy (SITT) as an alternative to multi-inhaler triple therapy (MITT) or with smart inhalers are often considered potential solutions. However, the actual impact of these innovations on adherence and clinical outcomes is unclear. METHODS: To address this knowledge gap we first conducted a literature review focusing on two research questions: 1) the difference in adherence between SITT and MITT users in COPD, and 2) the effect of smart inhalers on adherence in COPD. Separate searches were conducted in PubMed and two authors independently assessed the articles. In addition, we present a protocol for a study to acquire knowledge for the gaps identified. RESULTS: To address the first research question, 8 trials were selected for further review. All trials were observational, i.e. randomized controlled trials were lacking. Seven of these trials showed higher adherence and/or persistence in patients on SITT compared with patients on MITT. In addition, four studies showed a positive effect of SITT on various clinical outcomes. For the second research question, 11 trials were selected for review. While most of the studies showed a positive effect of smart inhalers on adherence, there was considerable variation in the results regarding their effect on other clinical outcomes. The TRICOLON (TRIple therapy COnvenience by the use of one or multipLe Inhalers and digital support in ChrONic Obstructive Pulmonary Disease) trial aims to improve understanding regarding the effectiveness of SITT and smart inhalers in enhancing adherence. This open-label, randomized, multi-center study will enroll COPD patients requiring triple therapy at ten participating hospitals. In total, 300 patients will be randomized into three groups: 1) MITT; 2) SITT; 3) SITT with digital support through a smart inhaler and an e-health platform. The follow-up period will be one year, during which three methods of measuring adherence will be used: smart inhaler data, self-reported data using the Test of Adherence to Inhalers (TAI) questionnaire, and drug analysis in scalp hair samples. Finally, differences in clinical outcomes between the study groups will be compared. DISCUSSION: Our review suggests promising results concerning the effect of SITT, as opposed to MITT, and smart inhalers on adherence. However, the quality of evidence is limited due to the absence of randomized controlled trials and/or the short duration of follow-up in many studies. Moreover, its impact on clinical outcomes shows considerable variation. The TRICOLON trial aims to provide solid data on these frequently mentioned solutions to non-adherence in COPD. Collecting data in a well-designed randomized controlled trial is challenging, but the design of this trial addresses both the usefulness of SITT and smart inhalers while ensuring minimal interference in participants' daily lives. TRIAL REGISTRATION: NCT05495698 (Clinicaltrials.gov), registered at 08-08-2022. Protocol version: version 5, date 27-02-2023.

Influence of Neoadjuvant Therapy on Success of Endoscopic Vacuum Therapy in Anastomotic Leakage after Rectal Resection Because of Rectal Cancer.

Background: For locally advanced rectal cancer, neoadjuvant therapy (NT) is an established element of therapy. Endoscopic vacuum therapy (EVT) has been a relevant treatment option for anastomotic leakage after rectal resection since 2008. The aim was to evaluate the influence of NT on the duration and success of EVT in anastomotic leakage after rectal resection for rectal cancer. Methods: This was a monocentric, retrospective cohort study including patients who underwent rectal resection with primary anastomosis because of histologically proven carcinoma of the rectum in the Department for General and Visceral Surgery of Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin over a period of ten years (2012 to 2022). Results: Overall, 243 patients were included, of which 47 patients (19.3%) suffered from anastomotic leakage grade B with consecutive EVT. A total of 29 (61.7%) patients received NT and 18 patients (38.3%) did not. The median duration of EVT until the removal of the sponge did not differ between patients with and without NT: 24.0 days (95% CI 6.44-41.56) versus 20.0 days (95% CI 17.03-22.97); p = 0.273. The median duration from insertion of EVT until complete healing was 74.0 days with NT (95% CI 10.07-137.93) versus 62.0 days without NT (95% CI 45.99-78.01); p = 0.490. Treatment failure-including early persistence and late onset of recurrent anastomotic leakage-was evident in 27.6% of patients with NT versus 27.8% without NT; p = 0.989. Ostomy was reversed in 19 patients (79.2%) with NT compared to 11 patients (68.8%) without NT; p = 0.456. Overall, continuity was restored in 75% of patients in the long term after EVT. Conclusion: This trial comprised-to our knowledge-the largest study cohort to analyze the outcome of EVT in anastomotic leakage after rectal resection for rectal cancer. We conclude that neoadjuvant therapy neither prolongs EVT nor the time to healing from anastomotic leakage. The rates of treatment failure of EVT and permanent ostomy were not higher when neoadjuvant therapy was used.

CD74 is a functional MIF receptor on activated CD4+ T cells.

Next to its classical role in MHC II-mediated antigen presentation, CD74 was identified as a high-affinity receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine and major determinant of various acute and chronic inflammatory conditions, cardiovascular diseases and cancer. Recent evidence suggests that CD74 is expressed in T cells, but the functional relevance of this observation is poorly understood. Here, we characterized the regulation of CD74 expression and that of the MIF chemokine receptors during activation of human CD4+ T cells and studied links to MIF-induced T-cell migration, function, and COVID-19 disease stage. MIF receptor profiling of resting primary human CD4+ T cells via flow cytometry revealed high surface expression of CXCR4, while CD74, CXCR2 and ACKR3/CXCR7 were not measurably expressed. However, CD4+ T cells constitutively expressed CD74 intracellularly, which upon T-cell activation was significantly upregulated, post-translationally modified by chondroitin sulfate and could be detected on the cell surface, as determined by flow cytometry, Western blot, immunohistochemistry, and re-analysis of available RNA-sequencing and proteomic data sets. Applying 3D-matrix-based live cell-imaging and receptor pathway-specific inhibitors, we determined a causal involvement of CD74 and CXCR4 in MIF-induced CD4+ T-cell migration. Mechanistically, proximity ligation assay visualized CD74/CXCR4 heterocomplexes on activated CD4+ T cells, which were significantly diminished after MIF treatment, pointing towards a MIF-mediated internalization process. Lastly, in a cohort of 30 COVID-19 patients, CD74 surface expression was found to be significantly upregulated on CD4+ and CD8+ T cells in patients with severe compared to patients with only mild disease course. Together, our study characterizes the MIF receptor network in the course of T-cell activation and reveals CD74 as a novel functional MIF receptor and MHC II-independent activation marker of primary human CD4+ T cells.

Controlled Study of Pre- and Postoperative Headache in Patients with Sellar Masses (HEADs-uP Study).

INTRODUCTION: Sellar masses are common intracranial neoplasms. Their clinical manifestations vary widely and include headache. We aimed to determine whether the prevalence and characteristics of headache in patients with sellar tumours differ from the general population and to investigate the effect of tumour resection on this complaint. METHODS: We performed a prospective, controlled study in a single tertiary centre and included 57 patients that underwent transsphenoidal resection for a sellar mass (53% females, mean age 53.5 ± 16.4) and 29 of their partners (controls; 45% females, mean age 54.8 ± 14.9). Outcome measures were prevalence, characteristics and impact of headache 1 month preoperatively and at neurosurgical follow-up 3 months postoperatively. RESULTS: Preoperatively, the prevalence of regular headache (≥1 time per month) was higher in patients than in controls (54% vs. 17%, p < 0.001), and patients scored higher on headache impact questionnaires (all p ≤ 0.01). At postoperative follow-up, headache prevalence decreased in both groups, but the decrease in regular headache frequency and impact was larger in patients than in controls, and no between-group differences remained. CONCLUSIONS: More than half of patients with sellar tumours suffer from at least once-monthly headaches, and both regular headache occurrence and impact are higher compared with controls. The more pronounced decrease in headache complaints in patients versus controls at postoperative follow-up suggests an additional effect of tumour resection next to the factor time.

Which Social Media Platforms Provide the Most Informative Data for Monitoring the Opioid Crisis?

Background and Aims: Social media can provide real-time insight into trends in substance use, addiction, and recovery. Prior studies have leveraged data from platforms such as Reddit and X (formerly Twitter), but evolving policies around data access have threatened their usability in opioid overdose surveillance systems. Here, we evaluate the potential of a broad set of platforms to detect emerging trends in the opioid crisis. Design: We identified 72 online platforms with a substantial global user base or prior citations in opioid-related research. We evaluated each platform's fit with our definition of social media, size of North American user base, and volume of opioid-related discourse. We created a shortlist of 11 platforms that met our criteria. We documented basic characteristics, volume and nature of opioid discussion, official policies regulating drug-related discussion, and data accessibility of shortlisted platforms. Setting: USA and Canada. Measurements: We quantified the volume of opioid discussion by number of platform-specific Google search hits for opioid terms. We captured informal language by including slang generated using a large language model. We report the number of opioid-related hits and proportion of opioid-related hits to hits for common nouns. Findings: We found that TikTok, YouTube, and Facebook have the most potential for use in opioid-related surveillance. TikTok and Facebook have the highest relative amount of drug-related discussions. Language on TikTok was predominantly informal. Many platforms offer data access tools for research, but changing company policies and user norms create instability. The demographics of users varies substantially across platforms. Conclusions: Social media data sources hold promise for detecting trends in opioid use, but researchers must consider the utility, accessibility, and stability of data on each platform. A strategy mixing several platforms may be required to cover all demographics suffering in the epidemic.

Effect of body condition score on the interobserver variability of vertebral heart scale assessment in dogs.

The vertebral heart scale (VHS) is widely known and used as an objective standard for the evaluation of cardiomegaly on thoracic radiographs. It, therefore, plays an important role in assessing the severity of canine heart disease. The body condition score (BCS) is a nine-scale body condition scoring system used to objectively document the body condition in dogs. Obese animals have widened precardiac and postcardiac mediastinum, fat deposits between the sternum and lungs or heart, as well as increased pericardial fat. These conditions could complicate cardiac silhouette evaluation and could, therefore, result in higher interobserver variability in the assessment of VHS. The purpose of this study was to investigate whether overweight dogs (BCS 6/9, 7/9, 8/9, and 9/9) have more variability in the interobserver VHS measurement compared with dogs with a normal BCS (BCS 4/9 and 5/9). The dogs were admitted to a private referral center for different medical reasons. The VHS was measured by three trained observers in right lateral radiographs of 18 overweight dogs and 33 dogs with a normal BCS. Bland-Altmann plots were constructed, and limits of agreement were calculated to show the variability of VHS measurements. No statistically significant differences in VHS variability were found between BCS categories, observers, sex, or age categories. In conclusion, BCS does not affect the reliability of VHS assessment among trained veterinarians.

Single-cell profiling of sarcomas from archival tissue reveals programs associated with resistance to immune checkpoint blockade.

PURPOSE: Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-seq, thus hampering progress in understanding these understudied cancers. EXPERIMENTAL DESIGN: Here, we demonstrate feasibility of producing multi-modal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic (UPS) and three intimal sarcomas (INS) samples, including paired specimens from two patients treated with ICB. RESULTS: We find that genomic diversity decreases in patients with response to ICB, and, in unbiased analyses, identify cancer cell programs associated with therapy resistance. Although interactions of tumor-infiltrating T lymphocytes within the tumor ecosystem increase in ICB responders, clonal expansion of CD8+ T cells alone was insufficient to predict drug responses. CONCLUSION: This study provides a framework for studying rare tumors and identifies salient and treatment-associated cancer cell intrinsic and tumor-microenvironmental features in sarcomas.

Endovascular thrombectomy for acute ischaemic stroke with established large infarct (TENSION): 12-month outcomes of a multicentre, open-label, randomised trial.

BACKGROUND: Long-term data showing the benefits of endovascular thrombectomy for stroke with large infarct are scarce. The TENSION trial showed the safety and efficacy of endovascular thrombectomy in patients with ischaemic stroke and large infarct at 90 days. We aimed to investigate the safety and efficacy at 12 months of endovascular thrombectomy in patients who were enrolled in the TENSION trial. METHODS: TENSION was an open-label, blinded endpoint, randomised trial done at 40 hospitals across Europe and one hospital in Canada. We included patients (aged ≥18 years) with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and who had a large infarct, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 on standard-of-care stroke imaging. We randomly assigned patients (1:1) to receive either endovascular thrombectomy with medical treatment or medical treatment only up to 12 h from stroke onset. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days. Here, we report the prespecified 12-month follow-up analyses for functional outcome (using the simplified modified Rankin Scale questionnaire), quality of life (using the Patient-Reported Outcomes Measurement Information System 10-item [PROMIS-10] and EQ-5D questionnaires), post-stroke anxiety and depression (using the Patient Health Questionnaire-4 [PHQ-4]), and overall survival. Outcomes (except survival) were assessed in the intention-to-treat population; the survival analysis was based on treatment received. This trial is registered with ClinicalTrials.gov, NCT03094715, and is completed. FINDINGS: We enrolled patients between July 17, 2018, and Feb 21, 2023, when the trial was stopped early for efficacy. 253 patients were randomly assigned, 125 (49%) to endovascular thrombectomy and 128 (51%) to medical treatment only. Median follow-up was 8·36 months (IQR 0·02-12·00). Endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better functional outcome at 12 months (adjusted common odds ratio 2·39 [95% CI 1·47-3·90]). Endovascular thrombectomy was also associated with a better quality of life compared with medical treatment only, as reflected by median scores on the EQ-5D questionnaire index (0·7 [IQR 0·4-0·9] vs 0·4 [0·2-0·7]), median scores for health status on the EQ-5D questionnaire visual analogue scale (50 [IQR 35-70] vs 30 [5-60]), and median global physical health scores on the PROMIS-10 questionnaire (T-score 39·8 [IQR 37·4-50·8] vs 37·4 [32·4-44·9]); although there was not enough evidence to suggest a difference between groups in global mental health scores on PROMIS-10 (41·1 [IQR 36·3-48·3] vs 38·8 [31·3-44·7]) or the numbers of patients reporting anxiety (13 [22%] of 58 vs 15 [42%] of 36) and depression (18 [31%] vs 18 [50%]) on PHQ-4. Overall survival was slightly better in the endovascular thrombectomy group compared with medical treatment only (adjusted hazard ratio 0·70 [95% CI 0·50-0·99]). INTERPRETATION: In patients with acute ischaemic stroke from large vessel occlusion with established large infarct, compared with medical treatment only, endovascular thrombectomy was associated at 12 months after stroke with better functional outcome, quality of life, and overall survival. These findings suggest that the benefits of endovascular thrombectomy in patients with an ischaemic stroke and a large infarct are sustained in the long term and support the use of endovascular thrombectomy in these patients. FUNDING: European Union Horizon 2020 Research and Innovation Programme.

Learning Collective Variables with Synthetic Data Augmentation through Physics-Inspired Geodesic Interpolation.

In molecular dynamics simulations, rare events, such as protein folding, are typically studied using enhanced sampling techniques, most of which are based on the definition of a collective variable (CV) along which acceleration occurs. Obtaining an expressive CV is crucial, but often hindered by the lack of information about the particular event, e.g., the transition from unfolded to folded conformation. We propose a simulation-free data augmentation strategy using physics-inspired metrics to generate geodesic interpolations resembling protein folding transitions, thereby improving sampling efficiency without true transition state samples. This new data can be used to improve the accuracy of classifier-based methods. Alternatively, a regression-based learning scheme for CV models can be adopted by leveraging the interpolation progress parameter.

micronuclAI: Automated quantification of micronuclei for assessment of chromosomal instability.

Chromosomal instability (CIN) is a hallmark of cancer that drives metastasis, immune evasion and treatment resistance. CIN results from chromosome mis-segregation events during anaphase, as excessive chromatin is packaged in micronuclei (MN), that can be enumerated to quantify CIN. Despite recent advancements in automation through computer vision and machine learning, the assessment of CIN remains a predominantly manual and time-consuming task, thus hampering important work in the field. Here, we present micronuclAI , a novel pipeline for automated and reliable quantification of MN of varying size, morphology and location from DNA-only stained images. In micronucleAI , single-cell crops are extracted from high-resolution microscopy images with the help of segmentation masks, which are then used to train a convolutional neural network (CNN) to output the number of MN associated with each cell. The pipeline was evaluated against manual single-cell level counts by experts and against routinely used MN ratio within the complete image. The classifier was able to achieve a weighted F1 score of 0.937 on the test dataset and the complete pipeline can achieve close to human-level performance on various datasets derived from multiple human and murine cancer cell lines. The pipeline achieved a root-mean-square deviation (RMSE) value of 0.0041, an R 2 of 0.87 and a Pearson's correlation of 0.938 on images obtained at 10X magnification. We tested the approach in otherwise isogenic cell lines in which we genetically dialed up or down CIN rates, and also on a publicly available image data set (obtained at 100X) and achieved an RMSE value of 0.0159, an R 2 of 0.90, and a Pearson's correlation of 0.951. Given the increasing interest in developing therapies for CIN-driven cancers, this method provides an important, scalable, and rapid approach to quantifying CIN on routinely obtained images. We release a GUI-implementation for easy access and utilization of the pipeline.

Comparison of pregnancy outcomes between indigenous and non-indigenous lupus patients.

AIM: To compare pregnancy outcomes between IA and non IA lupus patients. BACKGROUND: Pregnancy in lupus patients confers an increased risk of maternal and fetal morbidity. There are no data on pregnancy outcomes for indigenous Australian (IA) patients with lupus. METHODS: Using state-wide longitudinal hospital morbidity data, we studied 702 pregnancies in IA (n = 31) and non-indigenous (NI) patients with lupus (n = 357) in Western Australia and compared rates for live birth (LB), preterm birth (PB) and gestational complications in the period 1985-2015. Results are presented as medians or frequency. RESULTS: IA patients had proportionally more pre-existing renal disease (35 vs 13%, P < 0.01) and lower socio-economic status (P = 0.02). Age at first pregnancy was lower in IA patients (27 vs 30 years, P < 0.001), recorded gravidity was similar (2 vs 2, P > 0.6) and elective termination (n = 138) was more frequent in NI than IA pregnancies (21.1 vs 4.8%, P < 0.01). For continued pregnancies (59 in IA and 505 in NI), respective outcomes were as follows: LB 84.7% versus 91.5% (P = 0.15), spontaneous abortion 13.5% versus 6.9% (P = 0.13), (pre-)eclampsia 8% versus 9.9% (P = 0.89), PB 12% versus 13.4% (P = 0.98) and caesarean delivery 30% versus 47.2% (P = 0.02). Gestational diabetes (26% vs 6.1%), renal flares (20% vs 5.6%) and infections (22% vs 6.3%) were all more frequent in IA lupus pregnancies (all P < 0.001). CONCLUSIONS: The burden of comorbidities was higher in IA patients with lupus due to renal flares, gestational DM and infections. Although PB rates were overall high, they were, however, similar for IA and NI lupus pregnancies, as were LB rates.

Upper Limb Robots for Recovery of Motor Arm Function in Patients With Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Robot technology to support upper limb (UL) rehabilitation poststroke has rapidly developed over the past 3 decades. We aimed to assess the effects of UL-robots (UL-RTs) on recovery of UL motor functioning and capacity poststroke when compared with any non-UL-RT and to identify variables that are associated with the found effect sizes (ESs). METHODS: Randomized controlled trials (RCTs) comparing UL-RTs with any other intervention on patients with UL limitations poststroke were identified in electronic searches from PubMed, Wiley/Cochrane Libraries, Embase, Cumulative Index of Nursing and Allied Health Literature, Web of Science, SportDISCUS, Physiotherapy Evidence Database (PEDro), and Google Scholar from inception until August 1, 2022. Two reviewers independently extracted relevant data using a Microsoft Excel spreadsheet. Meta-analyses were performed for measures of UL-muscle synergism, muscle power, muscle tone, capacity, self-reported motor performance, and basic activities of daily living (ADLs). Subgroup, sensitivity, and meta-regression analyses were applied to identify factors potentially associated with found ESs. Analyses were performed using Review Manager version 5.4 or IBM SPSS statistics version 27. RESULTS: Ninety RCTs (N = 4,311) were included (median PEDro score 6 [6-7]). Meta-analyses of 86 trials (N = 4,240) showed small significant improvements in UL-muscle synergism (Fugl-Meyer Assessment of the UL [FM-UL]) (mean difference 2.23 [1.11-3.35]), muscle power (standardized mean difference [SMD] 0.39 [0.16-0.61]), motor performance (SMD 0.11 [0.00-0.21]), and basic ADLs (SMD 0.28 [0.10-0.45]). No overall effects were found for muscle tone (SMD -0.1 [-0.26 to 0.07]) or UL-capacity (SMD 0.04 [-0.10 to 0.18]), except with exoskeletons (SMD 0.27 [0.10-0.43]). Meta-regressions showed a significant positive association between baseline mean FM-UL and ESs for UL-capacity (r = 0.339; p = 0.03), in particular in the acute and early-subacute phases poststroke (r = 0.65; p = 0.01). No further significant subgroup differences or associations were found in our analyses. DISCUSSION: The small significant effects found at the level of motor impairment do not show generalization to clinically meaningful effects at the level of UL-capacity. Meta-regressions suggest that selected participants with some potential of UL-recovery may benefit most from UL-RT, especially earlier poststroke. The robustness and consistency of our findings suggest that the development of the next generation of UL-RT needs to be guided by a better mechanistic understanding about assumed underlying interaction effects between motor learning and motor recovery poststroke. TRIAL REGISTRATION INFORMATION: A prospectively registered study protocol is available in the PROSPERO database under ID CRD42020197450.

Structure and repair of replication-coupled DNA breaks.

Using CRISPR/Cas9 nicking enzymes, we examine the interaction between the replication machinery and single strand breaks, one of the most common forms of endogenous DNA damage. We show that replication fork collapse at leading strand nicks generates resected single-ended double-strand breaks (seDSBs) that are repaired by homologous recombination (HR). If these seDSBs are not promptly repaired, arrival of adjacent forks creates double ended DSBs (deDSBs), which could drive genomic scarring in HR-deficient cancers. deDSBs can also be generated directly when the replication fork bypasses lagging strand nicks. Unlike deDSBs produced independently of replication, end-resection at nick-induced se/deDSBs is BRCA1-independent. Nevertheless, BRCA1 antagonizes 53BP1 suppression of RAD51 filament formation. These results highlight unique mechanisms that maintain replication fork stability.

Synthetic hematocrit from virtual non-contrast images for myocardial extracellular volume evaluation with photon-counting detector CT.

OBJECTIVES: To assess the accuracy of a synthetic hematocrit derived from virtual non-contrast (VNC) and virtual non-iodine images (VNI) for myocardial extracellular volume (ECV) computation with photon-counting detector computed tomography (PCD-CT). MATERIALS AND METHODS: Consecutive patients undergoing PCD-CT including a coronary CT angiography (CCTA) and a late enhancement (LE) scan and having a blood hematocrit were retrospectively included. In the first 75 patients (derivation cohort), CCTA and LE scans were reconstructed as VNI at 60, 70, and 80 keV and as VNC with quantum iterative reconstruction (QIR) strengths 2, 3, and 4. Blood pool attenuation (BPmean) was correlated to blood hematocrit. In the next 50 patients (validation cohort), synthetic hematocrit was calculated using BPmean. Myocardial ECV was computed using the synthetic hematocrit and compared with the ECV using the blood hematocrit as a reference. RESULTS: In the derivation cohort (49 men, mean age 79 ± 8 years), a correlation between BPmean and blood hematocrit ranged from poor for VNI of CCTA at 80 keV, QIR2 (R2 = 0.12) to moderate for VNI of LE at 60 keV, QIR4; 70 keV, QIR3 and 4; and VNC of LE, QIR3 and 4 (all, R2 = 0.58). In the validation cohort (29 men, age 75 ± 14 years), synthetic hematocrit was calculated from VNC of the LE scan, QIR3. Median ECV was 26.9% (interquartile range (IQR), 25.5%, 28.8%) using the blood hematocrit and 26.8% (IQR, 25.4%, 29.7%) using synthetic hematocrit (VNC, QIR3; mean difference, -0.2%; limits of agreement, -2.4%, 2.0%; p = 0.33). CONCLUSION: Synthetic hematocrit calculated from VNC images enables an accurate computation of myocardial ECV with PCD-CT. CLINICAL RELEVANCE STATEMENT: Virtual non-contrast images from cardiac late enhancement scans with photon-counting detector CT allow the calculation of a synthetic hematocrit, which enables accurate computation of myocardial extracellular volume. KEY POINTS: Blood hematocrit is mandatory for conventional myocardial extracellular volume computation. Synthetic hematocrit can be calculated from virtual non-iodine and non-contrast photon-counting detector CT images. Synthetic hematocrit from virtual non-contrast images enables computation of the myocardial extracellular volume.

Dopamine-driven Increase in IL-1ß in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1ß in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1ß in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1ß, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1ß. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1ß gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1ß signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1ß in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1ß, will be critical to effectively tailor medication regimens.