Rapid adaptation to a novel pathogen through disease tolerance in a wild songbird.

Animal hosts can adapt to emerging infectious disease through both disease resistance, which decreases pathogen numbers, and disease tolerance, which limits damage during infection without limiting pathogen replication. Both resistance and tolerance mechanisms can drive pathogen transmission dynamics. However, it is not well understood how quickly host tolerance evolves in response to novel pathogens or what physiological mechanisms underlie this defense. Using natural populations of house finches (Haemorhous mexicanus) across the temporal invasion gradient of a recently emerged bacterial pathogen (Mycoplasma gallisepticum), we find rapid evolution of tolerance (<25 years). In particular, populations with a longer history of MG endemism have less pathology but similar pathogen loads compared with populations with a shorter history of MG endemism. Further, gene expression data reveal that more-targeted immune responses early in infection are associated with tolerance. These results suggest an important role for tolerance in host adaptation to emerging infectious diseases, a phenomenon with broad implications for pathogen spread and evolution.

Evaluation of the impact of letters to GP practices to promote asthma prescription uptake in school-age children during summer (TRAINS study): a pragmatic cluster-randomised controlled trial.

BACKGROUND: Asthma exacerbations peak in school-aged children after the return to school in September. Previous studies have shown a decline in collections of asthma prescriptions during August. The PLEASANT trial demonstrated that sending a reminder letter to parents increased prescription uptake; reduced unscheduled care, and was cost saving to the health service. We aimed to assess whether informing general practitioner (GP) practices about the PLEASANT trial and its results could lead to its implementation in routine practice. METHODS: The trial to assess implementation of new research in a primary care setting (TRAINS) was a pragmatic cluster-randomised (1:1) trial conducted in England involving GP practices contributing to the Clinical Practice Research Datalink (CPRD). The intervention was a letter informing the GP practice of the PLEASANT trial results with recommendations for implementation. GP practices in the control group continued with usual care without receiving any letters about PLEASANT trial. The intervention was distributed via CPRD by both mail and email in June 2021. The trial received both University of Sheffield Ethics approval and Independent Scientific Advisory Committee (ISAC) approval. The primary outcome was the proportion of children with asthma (aged 4-15 years) who had a prescription for a preventer between Aug 1 and Sept 30, 2021. This trial is registered with ClinicalTrials.gov, NCT05226091. FINDINGS: A total of 1326 GP practices, including 90 583 children with asthma, were included in the study. These practices were randomly allocated to the intervention group (664 practices, 44 708 children) or the control group (662 practices, 45 875 children). In assessing the impact of the intervention on the proportion of children collecting a preventer prescription, 15 716 (35·3%) of 44 708 children from the intervention group and 16 001 (35·1%) of 45 559 children from the control group picked up a prescription. There was no statistically significant difference observed (odds ratio [OR] 1·01, 95% CI 0·97-1·05), indicating that the intervention had no effect. INTERPRETATION: The study findings suggest that passive intervention of providing a letter to GPs did not achieve the intended outcomes. To bridge the gap between evidence and practice, alternative, more proactive strategies could be explored to address the identified issues. FUNDING: Jazan University.

Deletion of myeloid HDAC3 promotes efferocytosis to ameliorate retinal ischemic injury.

Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult.

Role of myeloid cells in ischemic retinopathies: recent advances and unanswered questions.

Myeloid cells including microglia and macrophages play crucial roles in retinal homeostasis by clearing cellular debris and regulating inflammation. These cells are activated in several blinding ischemic retinal diseases including diabetic retinopathy, where they may exert both beneficial and detrimental effects on neurovascular function and angiogenesis. Myeloid cells impact the progression of retinal pathologies and recent studies suggest that targeting myeloid cells is a promising therapeutic strategy to mitigate diabetic retinopathy and other ischemic retinal diseases. This review summarizes the recent advances in our understanding of the role of microglia and macrophages in retinal diseases and focuses on the effects of myeloid cells on neurovascular injury and angiogenesis in ischemic retinopathies. We highlight gaps in knowledge and advocate for a more detailed understanding of the role of myeloid cells in retinal ischemic injury to fully unlock the potential of targeting myeloid cells as a therapeutic strategy for retinal ischemia.

Exploring the Impact of Cardiac Rehabilitation Programs on Health-Related Quality of Life and Physiological Outcomes in Patients Post Coronary Artery Bypass Grafts: A Systematic Review.

Background: This systematic review explores the impact of cardiac rehabilitation programs (CRPs) on health-related quality of life (HRQoL) and physiological outcomes post-coronary artery bypass graft (CABG) surgery. Acknowledging the increasing importance of CRPs in post-CABG care, the study emphasizes the need for a comprehensive evaluation of their effectiveness. The primary objective is to investigate how CRPs influence HRQoL and physiological outcomes in post-CABG patients, offering insights into the multifaceted impact of these rehabilitation programs. Methods: A systematic literature review approach was employed to identify relevant studies published between 2013 and 2023. Inclusion criteria encompassed clinical randomized trials and quasi-experimental studies, with a focus on CRP interventions and their impact on HRQoL and physiological parameters. Results: The review reveals a diverse array of CRP approaches, including exercise training, home-based programs, and telemonitored interventions. Despite methodological variations, a consistent positive impact on HRQoL and physiological outcomes is observed across studies. Noteworthy interventions, such as those incorporating family caregivers, demonstrate holistic benefits. However, limitations include methodological variability and the exclusion of qualitative studies. Conclusions: This systematic review underscores the substantial positive impact of CRPs on HRQoL and physiological outcomes in post-CABG patients. The diverse approaches and consistent improvements across studies provide a robust foundation for healthcare practitioners and researchers. Future efforts should focus on standardizing CRP interventions and conducting well-designed trials to further enhance the evidence base, facilitating more targeted and effective rehabilitation strategies for CABG patients.

Educating the public about toxic chemicals that we unknowingly consume: A potential important role for the practicing pharmacists.

Although lifestyle factors are important in determining the overall health of the general public, the impact of endocrine-disrupting chemicals and other environmental toxins is often underestimated. There is growing evidence indicating that these substances have a significant influence on metabolic health, cancer risks, and fertility. Therefore, it is the shared responsibility of public health officials and health care professionals, including pharmacists, to educate the public about the potential exposure to harmful toxins present in our immediate surroundings, particularly toxic chemicals that we unknowingly consume. Pharmacists play a crucial role in promoting and maintaining public health. This article reviews a selection of common toxins and their significant health risks. Pharmacists can prepare educational materials, hold presentations at public libraries, and participate in scientific meetings to disseminate knowledge about the potential exposure to these toxins, their detrimental impact on health, and strategies and recommendations to minimize exposure.

Exploring the causes and consequences of non-nursing tasks among nurses in Jordan: An in-depth qualitative investigation.

AIM: To investigate the perceptions of Jordanian nurses regarding Non-Nursing Tasks (NNTs) and their consequences, as well as the underlying factors that contribute to the occurrence of NNTs. BACKGROUND: Nurses play a crucial role in providing high-quality patient care, but they often engage in NNTs, which can hinder their ability to deliver care effectively. Western countries have primarily conducted research on NNTs, while Middle Eastern countries such as Jordan have received limited attention. Expanding our understanding of NNTs is essential for improving nursing care. METHODS: A qualitative-exploratory approach was adopted. The research was conducted at three hospitals in Amman, Jordan. A purposeful sampling approach was used to select the participant and a focus group-interview method was used to gather the data. The derived data were analyzed using a thematic analysis approach. RESULTS: The final sample of this study included 38 participants. The findings highlighted that nurses often perform NNTs due to staff shortages and limited resources, as well as weaknesses in nursing administration and education. The finding also highlights the consequences of NNTs on nurses' professional lives, including impaired nursing care, physical and mental health strain, and a lack of efficiency and productivity. CONCLUSIONS: The present study's results provide valuable insights into the impact of NNTs on nurses in Jordan. These findings underscore the need for healthcare stakeholders to actively address the issue of NNTs. It also emphasized the need for more explicit job descriptions and processes, along with support for nurses to fulfilling their responsibilities and prioritizing patient care.

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

PURPOSE: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. METHODS: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro. RESULTS: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.

Survey in radiation oncology departments in Germany, Austria, and Switzerland: state of digitalization by 2023.

PURPOSE: The aim of this work was to assess the current state of digitalization in radiation oncology departments in Germany, Austria, and Switzerland. METHODS: A comprehensive survey was conducted in a digital format, consisting of 53 questions that covered various aspects of digitalization including patient workflow, departmental organization, radiotherapy planning, and employee-related aspects. RESULTS: Overall, 120 forms were eligible for evaluation. Participants were mainly physicians or medical physicists responsible for digitalization aspects in their departments. Nearly 70% of the institutions used electronic patient records, with 50% being completely paperless. However, the use of smartphone apps for electronic patient reported outcomes (ePROMs) and digital health applications (DIGA) was limited (9% and 4.9%, respectively). In total, 70.8% of the radio-oncology departments had interfaces with diagnostic departments, and 36% had digital interchanges with other clinics. Communication with external partners was realized mainly through fax (72%), e­mails (55%), postal letters (63%), or other digital exchange formats (28%). Almost half of the institutions (49%) had dedicated IT staff for their operations. CONCLUSION: To the best of our knowledge, this survey is the first of its kind conducted in German-speaking radiation oncology departments within the medical field. The findings suggest that there is a varied level of digitalization implementation within these departments, with certain areas exhibiting lower rates of digitalization that could benefit from targeted improvement initiatives.

Oncologic treatment support via a dedicated mobile app: a prospective feasibility evaluation (OPTIMISE-1).

BACKGROUND: Mobile health (mhealth) is gaining interest, with mobile devices and apps being ever more available among medical facilities and patients. However, in the field of radiation oncology, the medical benefits of mhealth apps are still underexplored. As an additional approach to patient care during radiotherapy, we designed a mobile treatment surveillance app based on patient-reported outcomes. OBJECTIVE: We aimed to examine the feasibility of app-based treatment surveillance in patients undergoing radiotherapy (RT). Alongside technical practicability and acceptance, we assessed patient satisfaction and quality of life during treatment. METHODS: This prospective single-center study was performed at Heidelberg University Hospital between August 2018 and January 2020. During RT we measured patients' quality of life, symptoms, and treatment satisfaction. Respective questionnaires (EORTC QLQ-C30 with diagnosis-specific modules, RAND PSQ-18) were presented to patients via a mobile app running on a designated tablet device. The primary endpoint was determined by the fraction of patients who completed at least 80% of the items. Secondary endpoints were disease-related quality of life and patient satisfaction. RESULTS: A total of 49 cancer patients (14 breast, 13 pelvic, 12 lung, 10 prostate) were eligible for analysis. 79.6% (95% confidence interval: 66.4-88.5%; n = 39) of all patients completed at least 80% of the items received by the mobile app. A mean of 227.5 ± 48.25 questions were answered per patient. Breast cancer patients showed the highest rate of answered questions, with 92.9% (n = 13) completing at least 80% of the items. CONCLUSION: Patients showed high acceptance, with 79.6% (n = 39) completing at least 80% of the given items. The use of a mobile app for reporting symptoms and quality of life during RT is feasible and well accepted by patients. It may allow for resource-efficient, detailed feedback to the medical staff and assist in the assessment of side effects over time.

Mobile applications in radiation oncology-current choices and future potentials.

PURPOSE: To review existing scientific literature on mobile applications (apps) in the field of radiation oncology and to evaluate characteristics of commercially available apps across different platforms. METHODS: A systematic review of the literature for publications presenting apps in the field of radiation oncology was carried out using the PubMed database, Cochrane library, Google Scholar, and annual meetings of major radiation oncology societies. Additionally, the two major marketplaces for apps, App Store and Play Store, were searched for available radiation oncology apps for patients and health care professionals (HCP). RESULTS: A total of 38 original publications which met the inclusion criteria were identified. Within those publications, 32 apps were developed for patients and 6 for HCP. The vast majority of patient apps focused on documenting electronic patient-reported outcomes (ePROs). In the two major marketplaces, 26 apps were found, mainly supporting HCP with dose calculations. CONCLUSION: Apps used in (and for) scientific research in radiation oncology are rarely available for patients and HCP in common marketplaces.

Effect of a Home-Based Mobile Health App Intervention on Physical Activity Levels in Patients With Heart Failure: A Randomized Controlled Trial.

BACKGROUND: The use of mobile health applications (apps) is an effective strategy in supporting patients' self-management of heart failure (HF) in home settings, but it remains unclear whether they can be used to reduce sedentary behaviors and increase overall physical activity levels. AIM: The aims of this study were to determine the effect of an 8-week home-based mobile health app intervention on physical activity levels and to assess its effects on symptom burden and health-related quality of life. METHOD: In this study, we collected repeated-measures data from 132 participants with HF (60.8 ± 10.47 years) randomized into a usual care group (n = 67) or an 8-week home-based mobile health app intervention group (n = 65). The intervention was tailored to decrease the time spent in sedentary behavior and to increase the time spent in physical activities performed at light or greater intensity levels. Physical activity levels were monitored for 2 weeks before the intervention and during the 8-week intervention using the Samsung mobile health app. Heart failure symptom burden and health-related quality of life were assessed at baseline, 2 weeks from baseline assessment, and immediately post intervention. RESULTS: At week 8, all participants in the intervention group demonstrated an increase in the average daily step counts above the preintervention counts (range of increase: 2351-7925 steps/d). Only 29 participants (45%) achieved an average daily step count of 10 000 or higher by week 6 and maintained their achievement to week 8 of the intervention. Repeated-measures analysis of variance showed a significant group-by-time interaction, indicating that the intervention group had a greater improvement in physical activity levels, symptom burden, and health-related quality of life than the usual care group. CONCLUSION: Home-based mobile health app-based interventions can increase physical activity levels and can play an important role in promoting better HF outcomes.

The effect of therapeutic footwear on the recurrence and new formation of foot ulcers in previously affected diabetic patients in Jeddah, Saudi Arabia.

AIM: Diabetic foot ulcers (DFUs), which are a common serious complication of diabetes mellitus, (lifetime occurrence, 19%-34%) account for at least 85% of all lower-limb amputations in diabetic patients. Special footwear (therapeutic footwear) is frequently recommended for such patients to adapt to changes in their foot structure. We aimed to, measure the effect of therapeutic footwear on DFU development and recurrence among previously affected patients in Saudi Arabia. MATERIALS AND METHODS: A cross-sectional study was performed between June and September 2022. The study targeted patients aged ≥18 years previously diagnosed with DFU. Participants were contacted by telephone to complete a questionnaire assessing footwear use and foot care. RESULTS: This study included 115 participants with a mean age of 61.9 ± 11.63; overall, 47% of participants used therapeutic footwear and 46% were adherent with wearing it. The DFU recurrence rate among patients who used therapeutic footwear was 27.8% versus 52.5% among patients who did not (p = 0.013). While using therapeutic footwear, patients with foot deformities reported a lower ulcer healing rate than those who did not (50% vs. 81.8%, p = 0.04). Patients who examined their feet had a lower recurrence rate than those who did not (38.5% vs. 50%, p = 0.43). CONCLUSION: Therapeutic footwear use was significantly associated with decreased DFU recurrence. Further investigation to enhance the evidence for the effectiveness of therapeutic footwear in DFUs is warranted.

A multi-step education model for advancing competencies in geriatrics and interprofessional collaboration for health students.

At a time when the older adult population is increasing exponentially and health care agencies are fraught with crisis-level short-handedness and burnout, addressing the Quadruple Aim of enhancing patient experience, improving population health, reducing costs, and improving the work life of health care providers is more crucial than ever. A multi-step education model was designed to advance competencies in geriatrics and Interprofessional Collaborative Practice (IPCP) for health profession students focused on each element of the Quadruple Aim. The goals of this education were to equip students with knowledge and experience to provide team-based care for older adults and achieve satisfaction with the education program. The education steps consisted of online didactics, team icebreaker, skills practice, professional huddles, and interprofessional simulation with debriefing. Over 2,300 students and 87 facilitators from 16 professions completed the training over three years. A positive statistically significant increase was found between pre- and post-measures of IPCP competency, knowledge, and attitudes. Additionally, high satisfaction with the education was reported by students and facilitators. By providing positive geriatric education and experiences for health students to work in interprofessional teams, it can translate into future improvements in older adult population health, health care provider job satisfaction, and reduced health care costs.

WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly.

Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders.

De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.

Stereotactic radiotherapy of brain metastases: clinical impact of three-dimensional SPACE imaging for 3T-MRI-based treatment planning.

PURPOSE: For planning CyberKnife stereotactic radiosurgery (CK SRS) of brain metastases (BM), it is essential to precisely determine the exact number and location of BM in MRI. Recent MR studies suggest the superiority of contrast-enhanced 3D fast spin echo SPACE (sampling perfection with application-optimized contrast by using different flip angle evolutions) images over 3D gradient echo (GE) T1-weighted MPRAGE (magnetization-prepared rapid gradient echo) images for detecting small BM. The aim of this study is to test the usability of the SPACE sequence for MRI-based radiation treatment planning and its impact on changing treatment. METHODS: For MRI-based radiation treatment planning using 3T MRI in 199 patients with cerebral oligometastases, we compared the detectability of BM in post-gadolinium SPACE images, post-gadolinium MPRAGE images, and post-gadolinium late-phase MPRAGE images. RESULTS: When SPACE images were used for MRI-based radiation treatment planning, 29.8% and 16.9% more BM, respectively, were detected and included in treatment planning than in the post-gadolinium MPRAGE images and the post-gadolinium late-phase MPRAGE images (post-gadolinium MPRAGE imaging: ntotal = 681, mean ± SD 3.4 ± 4.2; post-gadolinium SPACE imaging: ntotal = 884, mean ± SD 4.4 ± 6.0; post-gadolinium late-phase MPRAGE imaging: ntotal = 796, mean ± SD 4.0 ± 5.3; Ppost-gadolinium SPACE imaging versus post-gadolinium MPRAGE imaging < 0.0001, Ppost-gadolinium SPACE imaging versus post-gadolinium late-phase MPRAGE imaging< 0.0001). CONCLUSION: For 3T MRI-based treatment planning of stereotactic radiosurgery of BM, we recommend the use of post-gadolinium SPACE imaging rather than post-gadolinium MPRAGE imaging.

Symptom relief, prognostic factors, and outcome in patients receiving urgent radiation therapy for superior vena cava syndrome : A single-center retrospective analysis of 21 years' practice.

PURPOSE: Superior vena cava syndrome (SVCS) often results from external vessel compression due to tumor growth. Urgent symptom-guided radiotherapy (RT) remains a major treatment approach in histologically proven, rapidly progressive disease. Despite several publications, recent data concerning symptom relief and oncological outcome as well as potential confounders in treatment response are still scarce. METHODS: We performed a retrospective single-center analysis of patients receiving urgent RT between 2000 and 2021 at the University Medical Center Göttingen. Symptom relief was evaluated by CTCAE score during the RT course. Effects of variables on symptom relief were assessed by logistic regression. The impact of parameters on overall survival (OS) was evaluated using Kaplan-Meier plot along with the log-rank test and by Cox regression analyses. Statistically significant (p-value < 0.05) confounders were tested in multivariable analyses. RESULTS: A total of 79 patients were included. Symptom relief was achieved in 68.4%. Mean OS was 59 days, 7.6% (n = 6) of patients showed long-term survival (> 2 years). Applied RT dose > 39 Gy, clinical target volume (CTV) size < 387 ml, concomitant chemotherapy, and completion of the prescribed RT course were found to be statistically significant for OS; applied RT dose and completion of the prescribed RT course were found to be statistically significant for symptom relief. CONCLUSION: Symptom relief by urgent RT for SVCS was achieved in the majority of patients. RT dose and completion of the RT course were documented as predictors for OS and symptom relief, CTV < 387 ml and concomitant chemotherapy were predictive for OS.

Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis.

Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood-brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7-/- mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3ß signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation.

Statins for Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformations syndrome caused by defective cholesterol biosynthesis. Affected individuals show cholesterol deficiency and accumulation of various precursor molecules, mainly 7-dehydrocholesterol and 8-dehydrocholesterol. There is currently no cure for SLOS, with cholesterol supplementation being primarily a biochemical therapy of limited evidence. However, several anecdotal reports and preclinical studies have highlighted statins as a potential therapy for SLOS. OBJECTIVES: To evaluate the effects of statins, either alone or in combination with other non-statin therapies (e.g. cholesterol, bile acid, or vitamin co-supplementation), compared to cholesterol supplementation alone or in combination with other non-statin therapies (e.g. bile acid or vitamin supplementation) on several important outcomes including overall survival, neurobehavioral features, and adverse effects in individuals with SLOS. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases and three trials registers on 15 February 2022, together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs with parallel or cross-over designs, and non-randomized studies of interventions (NRSIs) including non-randomized trials, cohort studies, and controlled before-and-after studies, were eligible for inclusion in this review if they met our prespecified inclusion criteria, i.e. involved human participants with biochemically or genetically diagnosed SLOS receiving statin therapy or cholesterol supplementation, or both. DATA COLLECTION AND ANALYSIS: Two authors screened titles and abstracts and subsequently full-texts for all potentially-relevant references. Both authors independently extracted relevant data from included studies and assessed the risks of bias. We analyzed the data extracted from the included NRSIs and cohort studies separately from the data extracted from the single included RCT. We used a random-effects model to account for the inherent heterogeneity and methodological variation between these different study designs. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included six studies (61 participants with SLOS); one RCT (N = 18), three prospective NRSIs (N = 20), and two retrospective NRSIs (N = 22). Five studies included only children, and two limited their participant inclusion by disease severity. Overall, there were nearly twice as many males as females. All six studies compared add-on statin therapy to cholesterol supplementation alone. However, the dosages, formulations, and durations of treatment were highly variable across studies. We judged the RCT as having a high risk of bias due to missing data and selective reporting. All included NRSIs had a serious or critical overall risk of bias assessed by the Risk Of Bias In Non-randomized Studies of Interventions tool (ROBINS-I). None of the included studies evaluated survival or reported quality of life (QoL). Only the included RCT formally assessed changes in the neurobehavioral manifestations of SLOS, and we are uncertain whether statin therapy improves this outcome (very low-certainty evidence). We are also uncertain whether the adverse events reported in the RCT were statin-related (very low-certainty evidence). In contrast, the adverse events reported in the NRSIs seem to be possibly due to statin therapy (risk ratio 13.00, 95% confidence interval 1.85 to 91.49; P = 0.01; low-certainty evidence), with only one of the NRSIs retrospectively mentioning changes in the irritability of two of their participants. We are uncertain whether statins affect growth based on the RCT or NRSI results (very low-certainty evidence). The RCT showed that statins may make little or no difference to plasma biomarker levels (low-certainty evidence), while we are uncertain of their effects on such parameters in the NRSIs (very low-certainty evidence). AUTHORS' CONCLUSIONS: Currently, there is no evidence on the potential effects of statin therapy in people with SLOS regarding survival or QoL, and very limited evidence on the effects on neurobehavioral manifestations. Likewise, current evidence is insufficient and of very low certainty regarding the effects of statins on growth parameters in children with SLOS and plasma or cerebrospinal fluid (CSF) levels of various disease biomarkers. Despite these limitations, current evidence seemingly suggests that statins may increase the risk of adverse reactions in individuals with SLOS receiving statins compared to those who are not. Given the insufficient evidence on potential benefits of statins in individuals with SLOS, and their potential for causing adverse reactions, anyone considering this therapy should take these findings into consideration. Future studies should address the highlighted gaps in evidence on the use of statins in individuals with SLOS by collecting prospective data on survival and performing serial standardized assessments of neurobehavioral features, QoL, anthropometric measures, and plasma and CSF biomarker levels after statin introduction. Future studies should also attempt to use consistent dosages, formulations and durations of cholesterol and statin therapy.