Discrepancy in medications reported by elderly patients in the dental office and in their electronic medical records: A pilot study.

AIMS: This study's main objective was to analyze the discrepancy between the dental medication record (DMR) and the physician-prescribed active medications recorded in the medical medication record (MMR). METHODS: The study group consisted of 100 adults who attended the University Dental Clinic (Santiago de Compostela, Spain) requesting dental care. A dental history was created for all participants that included the DMR. The MMR were compiled from their electronic medical records. RESULTS: About 80% of the patients consumed at least one drug (94.2% of those >65 years) and 19% took more than five drugs (26.4% of those > 65 years). In total, 54% of the patients had some discrepancy between the medications recorded in the DMR and those in the MMR (48.4% for those ≤65 years and 64.7% for those >65 years). The rate of participants who omitted some drugs was higher for those >65 years. The drugs most omitted from the DMR were analgesics/opioids, antihypertensives and anxiolytics/hypnotics/sedatives. CONCLUSIONS: It is imperative to access the MMR of patients requesting dental care because a significant number of medications are not reflected in their DMR. These discrepancies may be particularly common and relevant in elderly patients, in whom multimorbidity and polypharmacy are more frequent.

Base Editor Scanning Reveals Activating Mutations of DNMT3A.

DNA methyltransferase 3A (DNMT3A) is a de novo cytosine methyltransferase responsible for establishing proper DNA methylation during mammalian development. Loss-of-function (LOF) mutations to DNMT3A, including the hotspot mutation R882H, frequently occur in developmental growth disorders and hematological diseases, including clonal hematopoiesis and acute myeloid leukemia. Accordingly, identifying mechanisms that activate DNMT3A is of both fundamental and therapeutic interest. Here, we applied a base editor mutational scanning strategy with an improved DNA methylation reporter to systematically identify DNMT3A activating mutations in cells. By integrating an optimized cellular recruitment strategy with paired isogenic cell lines with or without the LOF hotspot R882H mutation, we identify and validate three distinct hyperactivating mutations within or interacting with the regulatory ADD domain of DNMT3A, nominating these regions as potential functional target sites for pharmacological intervention. Notably, these mutations are still activating in the context of a heterozygous R882H mutation. Altogether, we showcase the utility of base editor scanning for discovering functional regions of target proteins.

Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery.

Allostery enables dynamic control of protein function. A paradigmatic example is the tightly orchestrated process of DNA methylation maintenance. Despite the fundamental importance of allosteric sites, their identification remains highly challenging. Here, we perform CRISPR scanning on the essential maintenance methylation machinery-DNMT1 and its partner UHRF1-with the activity-based inhibitor decitabine to uncover allosteric mechanisms regulating DNMT1. In contrast to non-covalent DNMT1 inhibition, activity-based selection implicates numerous regions outside the catalytic domain in DNMT1 function. Through computational analyses, we identify putative mutational hotspots in DNMT1 distal from the active site that encompass mutations spanning a multi-domain autoinhibitory interface and the uncharacterized BAH2 domain. We biochemically characterize these mutations as gain-of-function, exhibiting increased DNMT1 activity. Extrapolating our analysis to UHRF1, we discern putative gain-of-function mutations in multiple domains, including key residues across the autoinhibitory TTD-PBR interface. Collectively, our study highlights the utility of activity-based CRISPR scanning for nominating candidate allosteric sites, and more broadly, introduces new analytical tools that further refine the CRISPR scanning framework.

Base editor scanning charts the DNMT3A activity landscape.

DNA methylation is critical for regulating gene expression, necessitating its accurate placement by enzymes such as the DNA methyltransferase DNMT3A. Dysregulation of this process is known to cause aberrant development and oncogenesis, yet how DNMT3A is regulated holistically by its three domains remains challenging to study. Here, we integrate base editing with a DNA methylation reporter to perform in situ mutational scanning of DNMT3A in cells. We identify mutations throughout the protein that perturb function, including ones at an interdomain interface that block allosteric activation. Unexpectedly, we also find mutations in the PWWP domain, a histone reader, that modulate enzyme activity despite preserving histone recognition and protein stability. These effects arise from altered PWWP domain DNA affinity, which we show is a noncanonical function required for full activity in cells. Our findings highlight mechanisms of interdomain crosstalk and demonstrate a generalizable strategy to probe sequence-activity relationships of nonessential chromatin regulators.

Longitudinal Characterization of a Neutralizing and Total Antibody Response in Patients with Severe COVID-19 and Fatal Outcomes.

The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations in severe COVID-19 cases. Until now, the importance of developing a neutralizing antibody response in the acute phase and its relationship with progression to severe disease or fatal outcome among hospitalized patients remains unclear. In this study, we aim to characterize and compare longitudinally the primary humoral immune host response in the early stages of the disease, looking for an association between neutralization, antibody titers, infective viral lineage, and the clinical outcome in hospitalized and non-hospitalized patients. A total of 111 patients admitted at INER from November 2021 to June 2022 were included. We found that patients with negative or low neutralization showed a significant reduction in survival probability compared to patients with medium or high neutralization. We observed a significant decrease in the median of neutralization in patients infected with viral variants with changes in RBD of the spike protein. Our results suggest that developing an early and robust neutralizing response against SARS-CoV-2 may increase survival probability in critical patients.

Usefulness of ultrasound-guided tibio-pedal access in patients with critical limb ischemia.

INTRODUCTION: Retrograde access performed guided by fluoroscopy or ultrasound. We aimed to analyze the usefulness of ultrasound in retrograde access in patients with critical limb ischemia. METHODS: Observational analytical study. From December 2013 to June 2019. We included all retrograde accesses that were guided by ultrasound. Our register assesses demographic and clinical data, the vessel used as retrograde access, the procedure performed, the amount of contrast agent used and time of fluoroscopy, access failure, and local complications. RESULTS: On 715 procedures performed, was used ultrasound-guided retrograde access in 25 patients (64% men). The mean age was 74.8 years (45-90), with 92% of diabetics and 32% of chronic renal failure. Two patients with Rutherford stage 4 and 23 with stage 5-6. In 24 (96%) patients the ultrasound-guided puncture was successful, while in one (4%) of them, it was not possible to enter the target vessel. After the punch, was achieved the technical success of revascularization in 19 (79.2%) patients, with 5 (20.8%) in whom did not the arterial injury was not overcome. The arteries used as retrograde access were: anterior tibial 11, posterior tibial 10, and peroneal in 4. The mean of contrast used was 63 mL (9-100 mL) with an average time of 43 min (15-76 min). Complications related did not observe in retrograde access. CONCLUSIONS: Ultrasound-guided retrograde distal access is an effective method that may use as a bailout method in those endovascular procedures in which it is not possible to cross the lesion anterogradely.

A practical approach to dental care for patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome is a polymalformative chromosomal disorder caused by a deletion in the distal region of the short arm of chromosome 4. The disease is considered rare (1/50,000 births) and predominantly affects females (2:1). In addition to the characteristic facial phenotype ("Greek warrior helmet"), its clinical manifestations include epilepsy, developmental and psychomotor delay, intellectual disability, cardiac and respiratory complications, and eating problems. The most prevalent oral manifestations are hypodontia, delayed tooth eruption, morphological dental abnormalities, dental malocclusions, cleft lip/palate and ogival palate. Based on our clinical experience, Wolf-Hirschhorn syndrome does not represent an absolute contraindication for any type of dental procedure. The feasibility of dental treatment will depend mainly on the degree of epilepsy control and on the level of collaboration, this latter conditioned by the severity of the intellectual disability and communication difficulties.

Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson's disease.

In Parkinson's disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN- or VTA-like DA lineage and models their distinct vulnerabilities. We show that the level of WNT activity is critical for the induction of the SN- and VTA-lineage transcription factors Sox6 and Otx2, respectively. Both WNT signaling modulation and forced expression of these transcription factors can drive DA neurons toward the SN- or VTA-like fate. Importantly, the SN-like lineage enriched DA cultures recapitulate the selective sensitivity to mitochondrial toxins as observed in PD, while VTA-like neuron-enriched cultures are more resistant. Furthermore, a proteomics approach led to the identification of compounds that alter SN neuronal survival, demonstrating the utility of our strategy for disease modeling and drug discovery.

Dysbiosis and structural disruption of the respiratory microbiota in COVID-19 patients with severe and fatal outcomes.

The COVID-19 outbreak has caused over three million deaths worldwide. Understanding the pathology of the disease and the factors that drive severe and fatal clinical outcomes is of special relevance. Studying the role of the respiratory microbiota in COVID-19 is especially important as the respiratory microbiota is known to interact with the host immune system, contributing to clinical outcomes in chronic and acute respiratory diseases. Here, we characterized the microbiota in the respiratory tract of patients with mild, severe, or fatal COVID-19, and compared it to healthy controls and patients with non-COVID-19-pneumonia. We comparatively studied the microbial composition, diversity, and microbiota structure between the study groups and correlated the results with clinical data. We found differences in the microbial composition for COVID-19 patients, healthy controls, and non-COVID-19 pneumonia controls. In particular, we detected a high number of potentially opportunistic pathogens associated with severe and fatal levels of the disease. Also, we found higher levels of dysbiosis in the respiratory microbiota of patients with COVID-19 compared to the healthy controls. In addition, we detected differences in diversity structure between the microbiota of patients with mild, severe, and fatal COVID-19, as well as the presence of specific bacteria that correlated with clinical variables associated with increased risk of mortality. In summary, our results demonstrate that increased dysbiosis of the respiratory tract microbiota in patients with COVID-19 along with a continuous loss of microbial complexity structure found in mild to fatal COVID-19 cases may potentially alter clinical outcomes in patients. Taken together, our findings identify the respiratory microbiota as a factor potentially associated with the severity of COVID-19.

Usefulness of ultrasound-guided tibio-pedal access in patients with critical limb ischemia. / Utilidad de la ecografía en la punción retrógrada distal en la isquemia crítica de extremidades inferiores.

INTRODUCTION: Retrograde access performed guided by fluoroscopy or ultrasound. We aimed to analyze the usefulness of ultrasound in retrograde access in patients with critical limb ischemia. METHODS: Observational analytical study. From December 2013 to June 2019. We included all retrograde accesses that were guided by ultrasound. Our register assesses demographic and clinical data, the vessel used as retrograde access, the procedure performed, the amount of contrast agent used and time of fluoroscopy, access failure, and local complications. RESULTS: On 715 procedures performed, was used ultrasound-guided retrograde access in 25 patients (64% men). The mean age was 74.8 years (45-90), with 92% of diabetics and 32% of chronic renal failure. Two patients with Rutherford stage 4 and 23 with stage 5-6. In 24 (96%) patients the ultrasound-guided puncture was successful, while in one (4%) of them, it was not possible to enter the target vessel. After the punch, was achieved the technical success of revascularization in 19 (79.2%) patients, with 5(20.8%) in whom did not the arterial injury was not overcome. The arteries used as retrograde access were: anterior tibial 11, posterior tibial 10, and peroneal in 4. The mean of contrast used was 63 mL (9-100 ml) with an average time of 43 minutes (15- 76 min). Complications related did not observe in retrograde access. CONCLUSIONS: Ultrasound- guided retrograde distal access is an effective method that may use as a bailout method in those endovascular procedures in which it is not possible to cross the lesion anterogradely.

Validation testing to determine the sensitivity of lateral flow testing for asymptomatic SARS-CoV-2 detection in low prevalence settings: Testing frequency and public health messaging is key.

Lateral flow devices (LFDs) are quickly being implemented for use in large-scale population surveillance programs for SARS-CoV-2 infection in the United Kingdom. These programs have been piloted in city-wide screening in the city of Liverpool and are now being rolled out to support care home visits and the return home of University students for the Christmas break. Here, we present data on the performance of LFDs to test almost 8,000 students at the University of Birmingham between December 2 and December 9, 2020. The performance is validated against almost 800 samples using PCR performed in the University Pillar 2 testing lab and theoretically validated on thousands of Pillar 2 PCR testing results performed on low-prevalence care home testing samples. Our data show that LFDs do not detect infections presenting with PCR Ct values over 29 to 30 as determined using the Thermo Fisher TaqPath asssay. This may be of particular importance in detecting individuals that are either at the early, or late stages of infection, and reinforces the need for frequent, recurrent testing.

S-Variant SARS-CoV-2 Lineage B1.1.7 Is Associated With Significantly Higher Viral Load in Samples Tested by TaqPath Polymerase Chain Reaction.

A SARS-CoV-2 variant B1.1.7 containing mutation Δ69/70 has spread rapidly in the United Kingdom and shows an identifiable profile in ThermoFisher TaqPath RT-qPCR, S gene target failure (SGTF). We analyzed recent test data for trends and significance. Linked cycle threshold (Ct) values for respiratory samples showed that a low Ct for ORF1ab and N were clearly associated with SGTF. Significantly more SGTF samples had higher inferred viral loads between 1×107 and 1×108. Our conclusion is that patients whose samples exhibit the SGTF profile are more likely to have high viral loads, which may explain higher infectivity and rapidity of spread.

Infection of arteriovenous fistula for hemodialysis: An uncommon etiology / Infección de fístula arteriovenosa protésica para hemodiálisis de causa inusual

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Clinical relevance of an intervention assessed by a meta-analysis of randomized clinical trials.

OBJECTIVES: Many meta-analyses usually omit the number needed to treat, or perform the calculation incorrectly, despite its importance in clinical decision-making. Accordingly, we will explain in an easily understandable way how to perform this procedure to assess the clinical relevance of the intervention. STUDY DESIGN AND SETTING: The expressions of the Cochrane Library and the concepts of clinical relevance and evidence-based medicine were applied. Simple cutoff points were also established to facilitate the task of interpreting results. The method was applied to two published meta-analyses to illustrate its application to real cases (treatment nonadherence). RESULTS: In the first example, with a risk in the control group ranging from 0.22 to 0.70, sending mobile phone messages to remind chronic patients to take their medication is clinically relevant with a high degree of evidence. For the second example (single-pill regimen in patients suffering from hypertension and/or dyslipidemia after 6 months), the range of the assumed control risk was between 0.28 and 0.57. CONCLUSION: The constructed algorithm could be applied to published meta-analyses or incorporated systematically in all meta-analyses with these characteristics.

The Victorian Institute of Sport Assessment Scale for Patellar Tendinopathy (VISA-P): A Reliability Generalization Meta-analysis.

OBJECTIVE: The Victorian Institute of Sport Assessment-Patella (VISA-P) is a questionnaire to assess the severity of patellar tendinopathies. Its use requires good reliability indicators: internal consistency, test-retest and parallel forms. Several studies have been published examining this question, but to date the reliability of this questionnaire (meta-analysis) has not been generalized. The aim of this study was to perform a meta-analysis to generalize the reliability of the VISA-P. DATA SOURCES: MEDLINE, EMBASE, and Scopus. STUDY SELECTION: Studies included were those examining the reliability coefficients of the VISA-P: Cronbach alpha, intraclass correlation coefficient (ICC), and parallel-forms (correlation coefficients compared with other scales). DATA EXTRACTION: All coefficients were extracted and the mean reliability was obtained using fixed- or random-effects models. Sensitivity (leave-one-out analysis) was analyzed. Quality assessment was performed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. DATA SYNTHESIS: Of 364 scientific articles, 12 fulfilled meta-analysis criteria. The summary statistic was 0.86 [95% confidence interval (CI): 0.78-0.92] for Cronbach alpha and 0.94 (95% CI: 0.89-0.97) for the ICC. Parallel forms depended on the comparative test used, ranging from -0.83 to 0.68. The sensitivity analysis found an influential study for the parallel-forms reliability in the Blazina score. We were unable to analyze the asymmetry of funnel plots and meta-regression models because of the number of studies. CONCLUSIONS: The reliability of VISA-P for assessing the severity of patellar tendinopathies requires greater evaluation with more scientific evidence before it can be implemented in clinical practice.

Clinical effectiveness of a cardiology outpatient management plan to reduce inefficiency in consultations.

Objectives: Longer delays in carrying out complementary tests in cardiology services have resulted in patients arriving for consultation without these tests being performed (inefficient consultations). To ameliorate this situation, a management-based intervention was designed, optimizing the available resources and modifying the appointment system. Therefore, our objective was to determine the effectiveness of this intervention to reduce the number of inefficient consultations and improve the clinical care process.Methods: A non-randomized experimental study comparing two periods (pre- and post-intervention) was designed, analyzing a total of 473 outpatients attending cardiology consultations in a Spanish region in February 2014 (pre-intervention) and 441 patients attending cardiology consultations in November 2014 (post-intervention). The outcome of management measures aimed at optimizing coordination in outpatient care to reduce inefficient consultations was analyzed. After the visit, treatment modifications, requests for new examinations or tests, outpatient discharges, and new diagnoses were evaluated.Results: In the pre-intervention period, 37.2% of the patients had not had the tests performed, while in the post-intervention period, this figure dropped to 10.7% (p < 0.001). When the patients had all the tests completed, there was an increase in the number of new examinations (p < 0.001), outpatient discharges (p < 0.001) and new diagnoses (p = 0.004). Treatment modifications were not significant (p = 0.223).Conclusions: The intervention proved effective, clinically relevant, and statistically significant in reducing the proportion of inefficient consultations, thereby enabling continuation of the clinical care process.

Development, and Internal, and External Validation of a Scoring System to Predict 30-Day Mortality after Having a Traffic Accident Traveling by Private Car or Van: An Analysis of 164,790 Subjects and 79,664 Accidents.

Predictive factors for fatal traffic accidents have been determined, but not addressed collectively through a predictive model to help determine the probability of mortality and thereby ascertain key points for intervening and decreasing that probability. Data on all road traffic accidents with victims involving a private car or van occurring in Spain in 2015 (164,790 subjects and 79,664 accidents) were analyzed, evaluating 30-day mortality following the accident. As candidate predictors of mortality, variables associated with the accident (weekend, time, number of vehicles, road, brightness, and weather) associated with the vehicle (type and age of vehicle, and other types of vehicles in the accident) and associated with individuals (gender, age, seat belt, and position in the vehicle) were examined. The sample was divided into two groups. In one group, a logistic regression model adapted to a points system was constructed and internally validated, and in the other group the model was externally validated. The points system obtained good discrimination and calibration in both the internal and the external validation. Consequently, a simple tool is available to determine the risk of mortality following a traffic accident, which could be validated in other countries.

Nolz1 expression is required in dopaminergic axon guidance and striatal innervation.

Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite the importance of DA striatal innervation, processes involved in establishment of DA axonal connectivity remain largely unknown. Here we demonstrate a striatal-specific requirement of transcriptional regulator Nolz1 in establishing DA circuitry formation. DA projections are misguided and fail to innervate the striatum in both constitutive and striatal-specific Nolz1 mutant embryos. The lack of striatal Nolz1 expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes. This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. Furthermore, transcriptomic analysis of wild-type and Nolz1-/- mutant striatal tissue led to the identification of several secreted factors that underlie the observed guidance defects and proteins that promote DA axonal outgrowth. Together, our data demonstrate the involvement of the striatum in orchestrating dopaminergic circuitry formation.