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Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions.

PurposeAnterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation.Materials and methodsMen with aUSD undergoing urethroplasty were recruited from one of 5 participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient-reported outcome measure questionnaires both pre- and postoperatively. The initial study had 3 aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire, (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue, and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation.ResultsOf 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts (P < .001 for each). The highest BMIs and the longest strictures were observed in the LS cohort. SRPT exposures did not significantly differ between etiology cohorts, with > 60% of each reporting low/mild risk. Stricture inflammation significantly differed between cohorts, with mild to severe inflammation present in 27% of trauma-related strictures, 54% of idiopathic strictures, and 48% of LS strictures (P = .036). Stricture fibrosis did not significantly differ between cohorts (P = .7). Three serum cytokines were significantly higher in patients with strictures compared to stricture-free controls: interleukin-9 (IL-9; P = .001), platelet-derived growth factor-BB (P = .004), and CCL5 (P = .01). No differences were observed in the levels of these cytokines based on stricture etiology. However, IL-9 levels were significantly higher in patients with inflamed strictures than in patients with strictures lacking inflammation (P = .019). Degree of stricture inflammation positively correlated with serum levels of IL-9 (Spearman's rho 0.224, P = .014).ConclusionsThe most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, platelet-derived growth factor-BB, and CCL5, which were elevated in patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition.

The sources and sinks of nitrous oxide, as control emissions to the atmosphere, are generally poorly constrained for most environmental systems. Initial depth-resolved analysis of nitrous oxide flux from observation wells and the proximal surface within a nitrate contaminated aquifer system revealed high subsurface production but little escape from the surface. To better understand the environmental controls of production and emission at this site, we used a combination of isotopic, geochemical, and molecular analyses to show that chemodenitrification and bacterial denitrification are major sources of nitrous oxide in this subsurface, where low DO, low pH, and high nitrate are correlated with significant nitrous oxide production. Depth-resolved metagenomes showed that consumption of nitrous oxide near the surface was correlated with an enrichment of Clade II nitrous oxide reducers, consistent with a growing appreciation of their importance in controlling release of nitrous oxide to the atmosphere. Our work also provides evidence for the reduction of nitrous oxide at a pH of 4, well below the generally accepted limit of pH 5.

Unhealthy alcohol use, which encompasses heavy episodic drinking to alcohol use disorder, has been identified as a modifiable barrier to optimal HIV care continuum outcomes. Despite the demonstrated efficacy of couples-based interventions for addressing unhealthy alcohol use, there are no existing couples-based alcohol interventions designed specifically for people living with HIV. This study presents the development and refinement of a three-session couples-based motivational intervention (ReACH2Gether) to address unhealthy alcohol use among a sample of 17 sexual minority men living with HIV and their partners living in the United States. To increase potential population reach, the intervention was delivered entirely remotely. Throughout an original and a modified version, results indicated that the ReACH2Gether intervention was acceptable and there were no reports of intimate partner violence or adverse events. Session engagement and retention were high. In pre-post-test analyses, the ReACH2Gether intervention showed trends in reducing Alcohol Use Disorder Identification Test scores and increasing relationship-promoting dynamics, such as positive support behaviors and goal congruence around alcohol use. Results support the need for continued work to evaluate the ReACH2Gether intervention.

Exudative (wet) age-related macular degeneration can be treated with the vascular endothelial growth factor (VEGF)-inhibiting monoclonal antibody bevacizumab. Currently, bevacizumab therapy is associated with known skin-related side effects, such as rash, mucosal hemorrhage, and hemorrhagic ulcers. While subungual "splinter" hemorrhage is a documented side effect of VEGF receptor antagonists and Raf protein inhibitors, there are no prior reports of bevacizumab-induced subungual hemorrhage to the best of our knowledge. Thus, we present the case of a 71-year-old female diagnosed with bilateral age-related macular degeneration, who, during six months of intravitreal bevacizumab treatment, began noticing fingernail discoloration, described as similar to that of a bruise. Given our patient's history of bevacizumab therapy and the documented reports of bevacizumab-associated mucosal and ulcerative hemorrhage, we hypothesize that the discoloration and hemorrhage are likely unreported adverse effects associated with bevacizumab therapy.

Resource partitioning is central to the incredible productivity of microbial communities, including gigatons in annual methane emissions through syntrophic interactions. Previous work revealed how a sulfate reducer (Desulfovibrio vulgaris, Dv) and a methanogen (Methanococcus maripaludis, Mm) underwent evolutionary diversification in a planktonic context, improving stability, cooperativity, and productivity within 300-1000 generations. Here, we show that mutations in just 15 Dv and 7 Mm genes within a minimal assemblage of this evolved community gave rise to co-existing ecotypes that were spatially enriched within a few days of culturing in a fluidized bed reactor. The spatially segregated communities partitioned resources in the simulated subsurface environment, with greater lactate utilization by attached Dv but partial utilization of resulting H2 by low affinity hydrogenases of Mm in the same phase. The unutilized H2 was scavenged by high affinity hydrogenases of planktonic Mm, producing copious amounts of methane. Our findings show how a few mutations can drive resource partitioning amongst niche-differentiated ecotypes, whose interplay synergistically improves productivity of the entire mutualistic community.

Superior mesenteric artery syndrome, or Wilkie's syndrome, is one of the rarest gastrointestinal disorders known to medical science. It is characterized by the vascular clamp of the third portion of the duodenum, between the superior mesenteric artery and the aorta. It presents as an uncommon cause of upper intestinal obstruction. Imaging is required, preferably with a contrast-enhanced CT or an MRI; conservative management is preferred, leaving surgery for the most complex cases.We present the case of a 34-year-old man with Duchenne's muscular dystrophy and a history of substantial weight loss after hospital admission for aspiration pneumonia. He underwent an abdominal CT scan that showed enlargement of the stomach, the second and third parts of the duodenum; without observing masses, the patient received conservative management with a nasojejunal feeding tube. At the outpatient reevaluation, 1 month postdischarge, he became asymptomatic and had progressive weight gain.

Abstract The rapid growth in consumer-facing mobile and sensor technologies has created tremendous opportunities for patient-driven personalized health management. The diagnosis and management of cardiac arrhythmias are particularly well suited to benefit from these easily accessible consumer health technologies. In particular, smartphone-based and wrist-worn wearable electrocardiogram (ECG) and photoplethysmography (PPG) technology can facilitate relatively inexpensive, long-term rhythm monitoring. Here we review the practical utility of the currently available and emerging mobile health technologies relevant to cardiac arrhythmia care. We discuss the applications of these tools, which vary with respect to diagnostic performance, target populations, and indications. We also highlight that requirements for successful integration into clinical practice require adaptations to regulatory approval, data management, electronic medical record integration, quality oversight, and efforts to minimize the additional burden to health care professionals.

Abstract In order to assess the perceptions and expectations of the radiology staff about artificial intelligence (AI), we conducted an online survey among ESR members (January–March 2024). It was designed considering that conducted in 2018, updated according to recent advancements and emerging topics, consisting of seven questions regarding demographics and professional background and 28 AI questions. Of 28,000 members contacted, 572 (2%) completed the survey. AI impact was predominantly expected on breast and oncologic imaging, primarily involving CT, mammography, and MRI, and in the detection of abnormalities in asymptomatic subjects. About half of responders did not foresee an impact of AI on job opportunities. For 273/572 respondents (48%), AI-only reports would not be accepted by patients; and 242/572 respondents (42%) think that the use of AI systems will not change the relationship between the radiological team and the patient. According to 255/572 respondents (45%), radiologists will take responsibility for any AI output that may influence clinical decision-making. Of 572 respondents, 274 (48%) are currently using AI, 153 (27%) are not, and 145 (25%) are planning to do so. In conclusion, ESR members declare familiarity with AI technologies, as well as recognition of their potential benefits and challenges. Compared to the 2018 survey, the perception of AI's impact on job opportunities is in general slightly less optimistic (more positive from AI users/researchers), while the radiologist’s responsibility for AI outputs is confirmed. The use of large language models is declared not only limited to research, highlighting the need for education in AI and its regulations. Critical relevance statement This study critically evaluates the current impact of AI on radiology, revealing significant usage patterns and clinical implications, thereby guiding future integration strategies to enhance efficiency and patient care in clinical radiology. Key Points The survey examines ESR member's views about the impact of AI on radiology practice. AI use is relevant in CT and MRI, with varying impacts on job roles. AI tools enhance clinical efficiency but require radiologist oversight for patient acceptance. Graphical Abstract

Abstract Background While falls are the leading cause of accidental injury among older people, the current fall prevention strategies have not resulted in a remarkable reduction in fall rates. An alternative novel approach, teaching older adults how to fall safely to prevent injury, has been recently implemented in the FAlling Safely Training (FAST) trial. The current study aimed to explore the views and perceptions of older people about their participation in the safe-falling training program. Methods Focus groups were conducted with eight community-dwelling older adults (age range: 66 to 76 years, five females) at risk of falling who completed the FAST program. Two focus groups involving four participants each were conducted. Recordings were transcribed verbatim and analyzed using thematic analysis. Results Three themes were identified following the analysis: (1) Before the training; with subthemes: Previous fall prevention strategies and Motivation to participate. Motivations to take part in the training included worries about falling, an awareness of an increased risk of falling, and a desire to decrease the chances of sustaining an injury. (2) Training itself; with subthemes: General impressions of the training and Learning the techniques. Older people highlighted that the training was well-designed and executed. (3) Going forward; with subthemes: Training increased confidence, Incorporating in a community setting, and Proposing improvements to the study. It was reported that the training enhanced participants’ confidence about falling without injury. Incorporating the training into a community context was discussed, and suggestions for program enhancements were made. The individual nature of the training was valued, but participants also provided suggestions for how they would see the program taking place successfully in small groups. Conclusions The results indicated that the safe-falling training was acceptable to older adults. The perceived ability to fall without injury was reported to have increased. Individuals who experienced a fall after the training ended reported being able to use the techniques learned in their daily life. The findings have implications for the training to be refined and implemented in the community. Trial registration The article is linked to a randomized controlled trial registered at http://ClinicalTrials.gov (NCT05260034).

Abstract The cytogenetic abnormality inv(2)(p23q13) in acute myeloid leukemia (AML) results in a fusion of RANBP2 with ALK. This fusion makes ALK constitutively active and acts as a driver for the proliferation of AML cell lines. Gilteritinib, a FLT3 inhibitor approved in AML, also can inhibit ALK among other receptor tyrosine kinases. A 75-year-old-woman with a history of essential thrombocythemia (ET) and a presumed germline DDX41 mutation developed ALK-fusion positive AML and despite standard therapies was transfusion-dependent and globally declining. The patient has been on gilteritinib with an ongoing response of more than one year with near normal blood counts and no evidence of AML. The fact that she was found to harbor a presumed germline DDX41 alteration may account for why she developed, and yet survived, two myeloid neoplasms (ET and AML). Additionally, this demonstrates that gilteritinib is clinically active as an ALK inhibitor, and could be considered for use in any AML patient presenting with an inv(2(p23q13)) translocation. Finally, it is an example of using a disease-agnostic, precision medicine approach to arrive at a beneficial treatment.

Background and aim: Many children with an FH mutation also exhibit elevated lipoprotein(a) levels, which is an independent risk factor for atherosclerotic cardiovascular disease. Studies have reported higher levels of lipoprotein(a) in adult and middle-aged women than men. There is limited knowledge on the concentration and change of lipoprotein(a) levels in children with genetic FH, and therefore we investigated sex-differences in lipoprotein(a) level and change in lipoprotein(a) in girls and boys with genetically confirmed FH. Methods: Medical records were reviewed retrospectively in 438 subjects with heterozygous FH that started follow-up below the age of 19 years at the Lipid Clinic, Oslo University Hospital in Norway, and of these we included 386 subjects with at least one Lp(a) measurement. Results: Mean (SD) age at baseline was 13.8 (7.3) years and the age was similar between sexes. Girls had a higher lipoprotein(a) level than boys at baseline: median (25–75 percentile) 223 (108–487) vs. 154 (78–360) mg/L, respectively (p 0.05). Conclusions: We found an increase in Lp(a) levels in children with genetic FH with age, and higher levels in girls than boys, which could impact risk assessment and future ASCVD. Further research is needed to elucidate whether subjects with FH could benefit from lipoprotein(a)-lowering therapies that are under current investigations.

Abstract Resource partitioning is central to the incredible productivity of microbial communities, including gigatons in annual methane emissions through syntrophic interactions. Previous work revealed how a sulfate reducer (Desulfovibrio vulgaris, Dv) and a methanogen (Methanococcus maripaludis, Mm) underwent evolutionary diversification in a planktonic context, improving stability, cooperativity, and productivity within 300–1000 generations. Here, we show that mutations in just 15 Dv and 7 Mm genes within a minimal assemblage of this evolved community gave rise to co-existing ecotypes that were spatially enriched within a few days of culturing in a fluidized bed reactor. The spatially segregated communities partitioned resources in the simulated subsurface environment, with greater lactate utilization by attached Dv but partial utilization of resulting H2 by low affinity hydrogenases of Mm in the same phase. The unutilized H2 was scavenged by high affinity hydrogenases of planktonic Mm, producing copious amounts of methane. Our findings show how a few mutations can drive resource partitioning amongst niche-differentiated ecotypes, whose interplay synergistically improves productivity of the entire mutualistic community.

Abstract Background Widespread antibiotic prescribing contributes to globally emerging antimicrobial resistance (AMR). Despite stewardship recommendations by the Infectious Diseases Society of America, there is a lack of literature identifying barriers and facilitators to antimicrobial stewardship programs (ASPs) in United States (U.S.) carceral settings. Methods Guided by the Theoretic Domains Framework, we performed in-depth interviews with 68 key stakeholders in Massachusetts carceral settings to contextualize barriers and facilitators to ASP implementation. We recruited 32 people incarcerated in Massachusetts jails and 36 carceral clinicians, correctional officers/administrators in Massachusetts and other U.S. states, and Massachusetts community clinicians for interviews. Results From the completed semi-structured in-depth interviews, we identified seven salient themes—four barriers and three facilitators—both specific to and across stakeholder groups. Barriers included the following: (1) jail being viewed as a “dirty place” that increases the risk of infections; (2) variable awareness and knowledge of AMR and ASPs; (3) clinicians’ opposition to change and oversight of their antibiotic prescribing; (4) competing priorities taking precedence over ASP implementation. Facilitators included (5) interest in changing the narrative about carceral healthcare through ASP implementation; (6) opportunities for education about ASP and AMR; and (7) the development of systems, policies, and regulations to improve antibiotic prescribing. Conclusions To our knowledge, this is the first qualitative study to leverage broad criminal-legal stakeholder groups to inform the next steps in developing and implementing ASPs in carceral settings in the U.S.

Background and objective: Visceral metastatic disease in prostate cancer patients conveys a poor prognosis. Using advanced imaging techniques, studies have demonstrated increasing detection rates of visceral metastasis. Visceral metastases are now seen in up to 30–60% of prostate cancer patients. Survival patterns of site-specific visceral metastasis are described poorly in the literature. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. Methods: Retrospectively, we identified 203 prostate cancer patients with visceral metastases from the Mayo Clinic Advanced Prostate Cancer Registry. Patients were divided into three groups according to the first site of visceral metastases detected: lung, brain, or liver. Visceral metastases were detected primarily on either metabolic imaging (C-11 choline) or prostate-specific membrane antigen positron emission tomography computed tomography (CT) scan. Confirmation of visceral metastasis diagnosis was established with either biopsy when feasible or focused conventional imaging, including focused CT or magnetic resonance imaging. Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression model was conducted to assess different variables that affect overall and cancer-specific survival. Key findings and limitations: Over a median (interquartile range) follow-up duration of 16.2 (3.9–49.8) mo, the overall and cancer-specific survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases than in patients with first-site brain or liver metastases (p

Abstract In this study we present the first in vivo clinical study of patients with eczema and psoriasis using terahertz (THz) sensing. Eczema and psoriasis patients were measured using a handheld THz scanner, both before and after the application of moisturiser. We show that THz sensing can distinguish between dry and healthy skin in different regions of the body. Furthermore, the impact of applying moisturiser on the skin can also be observed and potentially evaluated using THz light.

Abstract Background Maternal rectovaginal colonization by group B Streptococcus (GBS) increases the risk of perinatal GBS disease that can lead to death or long-term neurological impairment. Factors that increase the risk of rectovaginal GBS carriage are incompletely understood resulting in missed opportunities for detecting GBS in risk-based clinical approaches. There is a lacking consensus on whether gestational diabetes mellitus (GDM) is a risk factor for rectovaginal GBS. This systematic review and meta-analysis aims to address current conflicting findings and determine whether GDM should be clinically considered as a risk factor for maternal GBS colonization. Methods Peer-reviewed studies that provided GDM prevalence and documented GBS vaginal and/or rectal colonization in women with and without GDM were included in this analysis. From study inception to October 30, 2023, we identified 6,275 relevant studies from EMBASE and PUBMED of which 19 were eligible for inclusion. Eligible studies were analyzed and thoroughly assessed for risk of bias with a modified Newcastle-Ottawa Scale that interrogated representativeness and comparability of cohorts, quality of reporting for GDM and GBS status, and potential bias from other metabolic diseases. Results were synthesized using STATA 18 and analyzed using random-effects meta-analyses. Results Studies encompassed 266,706 women from 10 different countries, with study periods spanning from 1981 to 2020. Meta-analysis revealed that gestational diabetes is associated with a 16% increased risk of rectovaginal GBS carriage (OR 1.16, CI 1.07–1.26, P = 0.003). We also performed subgroup analyses to assess independent effects of pregestational vs. gestational diabetes on risk of maternal GBS carriage. Pregestational diabetes (Type 1 or Type 2 diabetes mellitus) was also associated with an increased risk of 76% (pooled OR 1.76, CI 1.27–2.45, P = 0.0008). Conclusions This study achieved a consensus among previously discrepant observations and demonstrated that gestational diabetes and pregestational diabetes are significant risk factors for maternal rectovaginal carriage of GBS. Recognition of GDM as a risk factor during clinical decisions about GBS screening and intrapartum antibiotic prophylaxis may decrease the global burden of GBS on maternal-perinatal health.

Abstract Mental fitness is a construct that goes beyond a simple focus on subjective emotional wellbeing to encompass more broadly our ability to think, feel, and act to achieve what we want in our daily lives. The measurement and monitoring of multiple (often interacting) domains is crucial to gain a holistic and complete insight into an individual’s mental fitness. We aimed to demonstrate the capability of a new mobile app to characterise the mental fitness of a general population of Australians and to quantify the interrelationships among different domains of mental fitness. Cross-sectional data were collected from 4901 adults from the general population of Australians engaged in work or education who used a mobile app (Innowell) between September 2021 and November 2022. Individuals completed a baseline questionnaire comprised of 26 questions across seven domains of mental fitness (i.e., physical activity, sleep and circadian rhythms, nutrition, substance use, daily activities, social connection, psychological distress). Network analysis was applied at both a domain-level (e.g., 7 nodes representing each cluster of items) and an individual item-level (i.e., 26 nodes representing all questionnaire items). Only 612 people (12%) were functioning well across all domains. One quarter (n = 1204, 25%) had only one problem domain and most (n = 3085, 63%) had multiple problem domains. The two most problematic domains were physical activity (n = 2631, 54%) and social connection (n = 2151, 44%), followed closely by daily activity (n = 1914, 39%). At the domain-level, the strongest association emerged between psychological distress and daily activity (r = 0.301). Psychological distress was the most central node in the network (as measured by strength and expected influence), followed closely by daily activity, sleep and circadian rhythms and then social connection. The item-level network revealed that the nodes with the highest centrality in the network were: hopelessness, depression, functional impairment, effortfulness, subjective energy, worthlessness, and social connectedness. Social connection, sleep and circadian rhythms, and daily activities may be critical targets for intervention due to their widespread associations in the overall network. While psychological distress was not among the most common problems, its centrality may indicate its importance for indicated prevention and early intervention. We showcase the capability of a new mobile app to monitor mental fitness and identify the interrelationships among multiple domains, which may help people develop more personalised insights and approaches.

Abstract Immunotherapies are revolutionizing cancer care, but many patients do not achieve durable responses and immune-related adverse events are difficult to predict. Quantifying the hundreds of proteins involved in cancer immunity has the potential to provide biomarkers to monitor and predict tumor response. We previously developed robust, multiplexed quantitative assays for immunomodulatory proteins using targeted mass spectrometry, providing measurements that can be performed reproducibly and harmonized across laboratories. Here, we expand upon those efforts in presenting data from a multiplexed immuno-oncology (IO)-3 assay panel targeting 43 peptides representing 39 immune- and inflammation-related proteins. A suite of novel monoclonal antibodies was generated as assay reagents, and the fully characterized antibodies are made available as a resource to the community. The publicly available dataset contains complete characterization of the assay performance, as well as the mass spectrometer parameters and reagent information necessary for implementation of the assay. Quantification of the proteins will provide benefit to correlative studies in clinical trials, identification of new biomarkers, and improve understanding of the immune response in cancer.