Ranking reprogramming factors for cell differentiation.

Transcription factor over-expression is a proven method for reprogramming cells to a desired cell type for regenerative medicine and therapeutic discovery. However, a general method for the identification of reprogramming factors to create an arbitrary cell type is an open problem. Here we examine the success rate of methods and data for differentiation by testing the ability of nine computational methods (CellNet, GarNet, EBseq, AME, DREME, HOMER, KMAC, diffTF and DeepAccess) to discover and rank candidate factors for eight target cell types with known reprogramming solutions. We compare methods that use gene expression, biological networks and chromatin accessibility data, and comprehensively test parameter and preprocessing of input data to optimize performance. We find the best factor identification methods can identify an average of 50-60% of reprogramming factors within the top ten candidates, and methods that use chromatin accessibility perform the best. Among the chromatin accessibility methods, complex methods DeepAccess and diffTF have higher correlation with the ranked significance of transcription factor candidates within reprogramming protocols for differentiation. We provide evidence that AME and diffTF are optimal methods for transcription factor recovery that will allow for systematic prioritization of transcription factor candidates to aid in the design of new reprogramming protocols.

Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 Severity.

OBJECTIVE: To characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients. METHODS: Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021. RESULTS: PNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were "brain fog" (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients. INTERPRETATION: PNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. ANN NEUROL 2023;94:146-159.

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Fifteen-minute consultation: An overview of major incidents.

Major incidents are rare but require a large amount of preparation, co-ordination and communication across different emergency services and specialities. This ensures that casualties are efficiently managed within the constraints of limited clinical resources. This article aims to provide a brief understanding of what constitutes as a major incident, how it is declared and the chain of command in communication and action, focusing specifically on the paediatric process. It also aims to highlight important considerations that could potentially be missed (eg, the mental health impact, forensic evidence and so on).

Influence of the COVID-19 pandemic on learning preferences and perspectives of generation Y and Z students in dental education.

OBJECTIVES: For the first time in history, the COVID-19 pandemic required students at The University of Texas School of Dentistry (UTSD) to move to remote education. Based on a literature review, it was assumed that younger generations of students would prefer virtual teaching models over in-classroom formats. The purpose of this study is to assess students' perspectives of remote learning during COVID-19 in dental education relative to their generation and programme. METHODS: An electronic survey was administered to all UTSD dental and dental hygiene students via Qualtrics. The survey collected information on demographics, pre-pandemic learning preferences, remote learning experiences during the pandemic, and a free response section. Descriptive statistics and Fisher's exact test were used to analyse data. RESULTS: The survey received a 60% response rate (n = 290). Over 95% of respondents belonged to Generations Y and Z. There were no significant differences in responses between generations. However, significant differences in responses between programmes arose with more dental hygiene students agreed that they liked learning in a classroom setting compared to dental students (p < 0.01). Significantly more dental students agreed that they stayed organized, were less stressed, and felt that the transition to online learning was easy compared to dental hygiene students (p < 0.01). CONCLUSION: Although the majority of students surveyed belong to Generations Y and Z, there are still preferences for traditional, in-person learning. Both cohorts recognized the benefits and challenges of distance learning, and the findings from this study shed light on how students are handling remote learning in dental education.

Trends in Hospital Care for Intentional Assault Gunshot Wounds Among Residents of Cook County, Illinois, 2018-2020.

Objectives. To examine gun violence with respect to hospital visits for treatment of intentional assault gunshot wounds (IGWs). Methods. IGW-coded visits among residents of Cook County, Illinois, were matched to census zip code tabulation areas (ZCTAs) to map changes in IGW visit frequencies between 2018 and 2020. Patient characteristics were compared across years, and Poisson regression models for the likelihood of an inpatient admission or in-hospital death were estimated. Results. Over the study period, Cook County residents made 7122 IGW-coded hospital visits to 89 Illinois hospitals, resulting in $342 million in charges and 24 894 hospital days. The number of visits almost doubled between 2018 and 2020, from 1553 to 3031; 6 ZCTAs had increases of more than 60 visits. Approximately one third of patients with a visit were admitted, and 6.5% died. Conclusions. Hospital statistics do not include the full toll of nonfatal gun injuries or the costs of related community-level trauma. The health care system remains crucial in implementing epidemiological approaches to violence prevention. Addressing the national spike in shootings will require large investments in community economic development and a professional public safety workforce. (Am J Public Health. 2022;112(5):795-802. https://doi.org/10.2105/AJPH.2022.306747).

Etiopathophysiological role of the renin-angiotensin-aldosterone system in age-related muscular weakening: RAAS-independent beneficial role of ACE2 in muscle weakness.

Aging is accompanied by major changes in body composition that can negatively affect functional status in older adults, including a progressive decrease in muscle mass, strength, and quality. The prevalence of sarcopenia has varied considerably, depending on the definition used and the population surveyed-a 2014 meta-analysis across several countries found estimates ranging from 1% to 29% for people aged 60 years or older, who live independently. The potentially relevant studies were retrieved from the ScienceDirect/Medline/PubMed/Public library of science/Mendeley/Springer link and Google Scholar. Multiple keywords were used for the literature search both alone and in combination. Some of the important keywords used for literature search were as follows: "Epidemiology of muscle weakness/muscle disorders," "Pathogenesis of RAAS in muscle weakness," "Role of Angiotensin 1-7/ACE-2/Mas R axis in muscle weakness," and "Correction pathophysiology of muscle weakness via ACE2." The renin-angiotensin system (RAAS), a major blood pressure regulatory system, is a candidate mediator that may promote aging-associated muscle weakness. Previously, studies explored the proof concept for RAAS inhibition as a therapeutic target. Furthermore, in RAAS, angiotensin II, and angiotensin-converting enzyme 2 (ACE2) have been reported to induce endoplasmic reticulum (ER) stress via glucose-regulated protein 78/eukaryotic translation initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/CHOP axis in the liver. In addition, other mitochondria and ER physical interactions contribute to skeletal muscle dysfunction. However, very few studies have investigated the relationship between RAAS and ER stress-associated pathophysiological events and ACE2-mediated biological consequences in muscle weakness. Thus, the study has been designed to investigate the RAAS-independent beneficial role of ACE2 in muscle weakness.

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization.

The fumarate ester dimethyl fumarate (DMF) has been introduced recently as a treatment for relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition that results in neuronal demyelination and axonal loss. DMF is known to act by depleting intracellular glutathione and modifying thiols on Keap1 protein, resulting in the stabilization of the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. We have previously shown that DMF reacts with a wide range of protein thiols, suggesting that the complete mechanisms of action of DMF are unknown. Here, we investigated other intracellular thiol residues that may also be irreversibly modified by DMF in neurons and astrocytes. Using mass spectrometry, we identified 24 novel proteins that were modified by DMF in neurons and astrocytes, including cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). Using an in vitro functional assay, we demonstrated that DMF-modified cofilin-1 loses its activity and generates less monomeric actin, potentially inhibiting its cytoskeletal remodeling activity, which could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. We found that the oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, our work provides new insights into the mechanisms supporting the neuroprotective and remyelination benefits associated with DMF treatment in addition to the antioxidant response by Nrf2.

Venous Thromboembolism Treatment and Prevention in Cancer Patients: Can We Use Pills Yet?

OPINION STATEMENT: Cancer increases a patient's risk for developing a venous thromboembolism (VTE) and is a relatively common finding in this population. Traditionally, anticoagulants used to treat VTE have included low molecular weight heparin (LMWH) or vitamin K antagonists (VKA). However, within the last several years, a newer class of anticoagulant, the direct oral anticoagulants (DOACs), has emerged as a potential option for pharmacologic thromboprophylaxis and for treatment of VTE in patients with cancer. While data is still limited and evolving, DOACs offer several benefits that are worth considering, including ease of administration and similar efficacy compared to LMWH in preventing recurrent VTE. However, some studies have reported a notable risk of increased bleeding associated with the use of DOACs. Additional studies are underway to evaluate the role of DOACs compared to LMWH in the setting of cancer. In our practice, based on existing data, we have been using DOACs for the chronic treatment of acute VTE and prevention of recurrent VTE in patients who do not have contraindications to anticoagulation and do not have severe renal insufficiency (creatinine clearance < 30 mL/min). For cancer patients admitted to the hospital with an acute medical illness, we use LMWH for primary prevention of VTE. In the perioperative setting, for patients undergoing major surgery with an active cancer, we prefer pharmacologic thromboprophylaxis with LMWH, although there is some emerging evidence that DOACs may be safe in this setting.

A comparison study: Periodontal practice approach of dentists and dental hygienists.

OBJECTIVES: The aim of this study was to investigate periodontal practice methods of dentists and dental hygienists to compare their knowledge and treatment approach in managing periodontal disease. METHODS: An electronic survey was designed to assess and capture three aspects of data: (a) knowledge of periodontics; (b) practice approaches in non-surgical periodontal therapy; and (c) factors affecting clinical care. The survey was distributed to dentists and dental hygienists who graduated from the same dental school within 5 years (2012-2016). Results were analysed by chi-square test, Fisher's exact test and logistic regression model. RESULTS: Out of total 117 participants, 111 of them reported their profession (n = 77 in the dental programme, n = 34 in the dental hygiene programme). The results showed no statistical difference in basic periodontal knowledge between dentists and dental hygienists (P = .12). Only 13% of the surveyed population identified appropriate recall intervals for periodontal maintenance and more dental hygienists reported periodontal re-evaluations being performed within their offices compared with dentists (91% vs 70%, P = .02). Almost half of the participants who reportedly performed periodontal re-evaluations (46%) charged for the re-evaluation procedure, despite it not being covered by dental insurance. More hygienists reported being familiar with and performing adjunct therapy compared to dentists in the study (P < .01). CONCLUSION: In general, dentists and hygienists in the study were found to have similar periodontal knowledge and practice approaches. However, differences in performing periodontal re-evaluation and adjunct therapy were significant. Further studies are needed to investigate clinical barriers that impact evidence-based periodontal care.

Informed consent in medical decision-making in commercial gestational surrogacy: a mixed methods study in New Delhi, India.

OBJECTIVE: To investigate ethical issues in informed consent for decisions regarding embryo transfer and fetal reduction in commercial gestational surrogacy. DESIGN: Mixed methods study employing observations, an interview-guide and semi-structured interviews. SETTING: Fertility clinics and agencies in Delhi, India, between December 2011 and December 2012. POPULATION: Doctors providing conceptive technologies to commissioning couples and carrying out surrogacy procedures; surrogate mothers; agents functioning as links for surrogacy. METHODS: Interviews using semi-structured interview guides were carried out among 20 doctors in 18 fertility clinics, five agents from four agencies and 14 surrogate mothers. Surrogate mothers were interviewed both individually and in the presence of doctors and agents. Data on socio-economic context and experiences among and between various actors in the surrogacy process were coded to identify categories of ethical concern. Numerical and grounded theory-oriented analyses were used. MAIN OUTCOME MEASURES: Informed consent, number of embryos transferred, fetal reduction, conflict of interest among the involved parties. RESULTS: None of the 14 surrogate mothers were able to explain the risks involved in embryo transfer and fetal reduction. The majority of the doctors took unilateral decisions about embryo transfer and fetal reduction. The commissioning parents were usually only indirectly involved. In the qualitative analysis, difficulties in explaining procedures, autonomy, self-payment of fertility treatment and conflicts of interest were the main themes. CONCLUSIONS: Clinical procedural decisions were primarily made by the doctors. Surrogate mothers were not adequately informed. There is a need for regulation on decision-making procedures to safeguard the interests of surrogate mothers.

Warfarin dosing and body mass index.

BACKGROUND: Warfarin is still the most commonly used anticoagulant for the treatment of venous thromboembolism and other hypercoagulable states. Warfarin metabolism is affected by multiple factors, including diet, medications, and individual patient characteristics. As both underdosing and overdosing can increase risks to patients, several studies have attempted to develop dosing protocols. However, few have investigated how patient weight and body mass index (BMI) affect warfarin dosing. OBJECTIVE: The objective of this study was to determine the association between BMI and the total weekly dose (TWD) of warfarin. METHODS: In this retrospective study, we identified patients taking warfarin who had an international normalized ratio (INR) within the therapeutic range to assess if there was a significant correlation between TWD, that is, maintenance warfarin dosing, and BMI in obese and nonobese patients. RESULTS: A total of 831 patients were studied, with a BMI range between 13.4 and 63.1 kg/m(2). We found that BMI is positively correlated with the total weekly warfarin dose. Our study showed that for each 1-point increase in BMI, the weekly warfarin dose increased by 0.69 mg. We found that the average warfarin weekly dose in this population can be estimated using the formula: 12.34 + 0.69 × BMI. CONCLUSION: There is an association between BMI and the TWD of warfarin. This could have dosing implications for both patients and prescribers, as patients with a high BMI will be expected to require higher doses of warfarin to maintain a therapeutic INR.

Successful thrombolysis of a late acute thrombotic occlusion of an aortic prosthesis after endovascular aneurysm repair.

A 79-year-old man with a previous endovascular aneurysm repair (EVAR) for a 5.4-cm abdominal aortic aneurysm presented 3 years after the procedure with sudden onset lower limb paralysis and pain. The diagnosis of acute aortic thrombosis within the aortic prosthesis graft was made and confirmed on computed tomography. Thrombolysis delivered into the graft via a radiologically placed catheter successfully dissolved the thrombus and resulted in improvement of the patient's symptoms. We discuss the presentation of, and role in management of thrombolysis in, this rare complication of aneurysm repair.

A comparison study: The use of digital and conventional impression techniques in dental hygiene education.

PURPOSE/OBJECTIVES: The study aimed to assess the applicability of digital intraoral scanning in dental hygiene education and compare the quality, efficiency, and ease of use to conventional impression techniques. METHODS: Twenty-eight first-year dental hygiene students (DH1) at UTHealth Houston School of Dentistry (UTSD) participated in this 2022 study. Each student participated in two 4-h lab sessions. Students took traditional alginate impressions and digital intraoral scans using Planmeca Romexis on standardized teeth during the first and second sessions. Both techniques were assessed by faculty for quality and efficiency using a standardized rubric. Participants completed a post-survey providing insight into their perceptions of both techniques and ease of use. RESULTS: The study had 100% participation in the lab sessions and survey responses (N = 28). The results showed digital scanning produced a statistically higher quality product than conventional alginate impressions (p = 0.023). The study found no statistical difference in the efficiency between the two methods. The majority of students (82%) agreed that digital intraoral scanning was easy to use (p = 0.001), and 89% agreed they would use digital intraoral scanning in clinical courses to help with patient care (p = 0.03). CONCLUSION: In this study, dental hygiene students with limited clinical experience learned new technology and used it to produce quality impressions compared to the conventional technique, indicating the value of introducing digital dentistry early in dental hygiene education.

Clandestine abortion resulting in uterine perforation and a retained foreign body led to generalized peritonitis: a case report from Lilongwe, Malawi.

Abortion is criminalized in Malawi in the absence of a life-threatening condition. Consequently, women often undergo unsafe abortions. A large proportion of abortions performed in Malawi require subsequent treatment at a healthcare facility. We describe the case of a 17-year-old who presented with generalized peritonitis and was found intraoperatively to have a necrotic and perforated uterus with a stick retained in her abdominopelvic cavity from a clandestine abortion. This case demonstrates the need for awareness and vigilance among healthcare providers in all specialties to suspect surgical abortion complications as a cause of generalized peritonitis and points to the need for further studies on the optimal management of such patients.

Mainz II urinary diversion in low-resource settings: patient outcomes in women with irreparable fistula in Malawi.

BACKGROUND: Obstructed labor leading to a vesicovaginal fistula remains a devastating outcome of childbirth in low-resource countries. Women with an irreparable vesicovaginal fistula may be candidates for a urinary diversion, such as the Mainz II modified ureterosigmoidostomy procedure. Previous reviews state that the procedure should be considered in low-resource countries. However, given the limited duration of postoperative follow-up, these studies do not adequately represent the long-term morbidity and mortality that is likely associated with this procedure. We present data that strongly support avoiding the procedure in low-resource countries. OBJECTIVE: This study aimed to evaluate the postoperative status of the patient (dead, alive, lost to follow-up) and time to death following the Mainz II procedure. STUDY DESIGN: This is a case series including 21 patients who underwent a Mainz II urinary diversion from April 2013 to June 2015 for management of irreparable vesicovaginal fistula at the Fistula Care Centre in Lilongwe, Malawi. Patients were seen postoperatively at 3, 6, 9, and 12 months, followed by every 6 to 12 months thereafter. Descriptive statistics were performed to summarize the data. RESULTS: During the postoperative period, 8 (38.1%; 8/21) patients died, 5 (23.8%; 5/21) were lost to follow-up, and 8 (38.1%; 8/21) are currently alive and followed up at the Fistula Care Centre. We strongly suspect that 7 of the 8 deaths were related to the procedure given that the patients had illnesses that exacerbated the metabolic consequences of the procedure. The eighth patient died after being attacked by robbers. Unfortunately, the exact cause of death could not be determined for these patients. Given that most of the suspected illnesses would be treatable in an otherwise healthy patient, even in this low-resource setting, we surmised that the metabolic compromise from the Mainz II procedure likely contributed to their untimely death. The average time from procedure to death was 58 months, with the earliest death at 10 months and the most recent at 7 years after the procedure. CONCLUSION: The Mainz II procedure is an option for patients with irreparable fistula. However, it should likely not be performed in low-resource countries given the long-term complications that often cannot be adequately addressed in these settings, leading to significant morbidity and mortality.

Use of Electronic Health Record-Based Measures to Assess Quality of Care for Pediatric Agitation.

OBJECTIVES: Acute agitation during pediatric mental health emergency department (ED) visits presents safety risks to patients and staff. We previously convened multidisciplinary stakeholders who prioritized 20 proposed quality measures for pediatric acute agitation management. Our objectives were to assess feasibility of evaluating performance on these quality measures using electronic health record (EHR) data and to examine performance variation across 3 EDs. METHODS: At a children's hospital and 2 nonchildren's hospitals, we assessed feasibility of evaluating quality measures for pediatric acute agitation management using structured EHR data elements. We retrospectively evaluated measure performance during ED visits by children 5 to 17 years old who presented for a mental health condition, received medication for agitation, or received physical restraints from July 2020 to June 2021. Bivariate and multivariable regression were used to examine measure performance by patient characteristics and hospital. RESULTS: We identified 2785 mental health ED visits, 275 visits with medication given for agitation, and 35 visits with physical restraints. Performance was feasible to measure using EHR data for 10 measures. Nine measures varied by patient characteristics, including 4.87 times higher adjusted odds (95% confidence interval 1.28-18.54) of physical restraint use among children with versus without autism spectrum disorder. Four measures varied by hospital, with physical restraint use varying from 0.5% to 3.3% of mental health ED visits across hospitals. CONCLUSIONS: Quality of care for pediatric acute agitation management was feasible to evaluate using EHR-derived quality measures. Variation in performance across patient characteristics and hospitals highlights opportunities to improve care quality.

Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons.

Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by re-expression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral re-expression of ISL1 and LHX3 reactivates aspects of the youthful gene expression program in mature motor neurons and alleviates key disease-relevant phenotypes in the SOD1G93A mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.

Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease.

Current Trends in Immuno-Oncology.

Surgery, radiation, chemotherapy, and targeted therapy were the four basic kinds of cancer treatment until recently. Immuno-oncology (IO), or the concept that cancer cells were damaged by activating the body's immune system, has emerged and is explained as a unique and crucial method for treating different cancers over the last decade. The US Food and Drug Administration and the European Medicines Agency both approved this newly recognized way of treating cancer in 2020. Within IO, different therapeutic classes have arisen, which are the subject of this article. Immune checkpoint inhibitors are currently the most well-known therapeutic class of immuno-oncology medications due to their amazing ability to show efficacy in a variety of tumor types. Biomarkers were tested for different tumors like gastrointestinal cancer, whole Head, lower and upper part Neck cancer, and also cervical cancer by programmed death-ligand 1 (PD-L1) check point and their targets and are currently being utilized prior to treatment by using Pembrolizumab. However, the significance of PD-L1 expression for immune check point reticence therapy in other/different onco-cancer types remains unclear. Homogenized immuneoncology drugs with regular therapy have been recently studied and clinical efficacy outcomes have shown to be significantly improved. While IO agents are fast transforming the marketed treatment for cancer patients, there are still a number of obstacles to overcome in terms of associating their adverse effects and confirming those different healthcare systems, such as financing these expensive therapies. In addition to cancer vaccines and chimeric antigen receptor T-cell treatments, other IO drugs are in pipeline containing chimeric antigen receptor T-cell therapies; earlier ones have their own set of toxicities and high cost related challenges.