A high-throughput response to the SARS-CoV-2 pandemic.

Four years after the beginning of the COVID-19 pandemic, it is important to reflect on the events that have occurred during that time and the knowledge that has been gained. The response to the pandemic was rapid and highly resourced; it was also built upon a foundation of decades of federally funded basic and applied research. Laboratories in government, pharmaceutical, academic, and non-profit institutions all played roles in advancing pre-2020 discoveries to produce clinical treatments. This perspective provides a summary of how the development of high-throughput screening methods in a biosafety level 3 (BSL-3) environment at Southern Research Institute (SR) contributed to pandemic response efforts. The challenges encountered are described, including those of a technical nature as well as those of working under the pressures of an unpredictable virus and pandemic.

Occipito-Cervico-Dorsal Flap for Neck Reconstruction After Postburn Contractures: A Case Report and Literature Review.

Because the head and neck are one of the most frequent locations of burns, it is of paramount importance that plastic surgeons and plastic surgical nurses understand the most effective surgical methods for treating neck contractures and the reconstructive technique required for each case. We introduce the case of a 42-year-old woman who presented with a severe postburn neck contracture that was reconstructed with a pedicled occipito-cervico-dorsal flap. We closed the donor-site wound primarily and completely covered the defect with good results. In addition to conventional skin grafts, dermal matrices, and microsurgical techniques, using an occipito-cervico-dorsal flap should be considered for reconstructing postburn neck contractures as it offers good aesthetic and functional outcomes, provides enough tissue and pliable skin, and results in minimal donor-site morbidity.

Role of pH-sensing receptors in colitis.

Low pH in the gut is associated with severe inflammation, fibrosis, and colorectal cancer (CRC) and is a hallmark of active inflammatory bowel disease (IBD). Subsequently, pH-sensing mechanisms are of interest for the understanding of IBD pathophysiology. Tissue hypoxia and acidosis-two contributing factors to disease pathophysiology-are linked to IBD, and understanding their interplay is highly relevant for the development of new therapeutic options. One member of the proton-sensing G protein-coupled receptor (GPCR) family, GPR65 (T-cell death-associated gene 8, TDAG8), was identified as a susceptibility gene for IBD in a large genome-wide association study. In response to acidic extracellular pH, GPR65 induces an anti-inflammatory response, whereas the two other proton-sensing receptors, GPR4 and GPR68 (ovarian cancer G protein-coupled receptor 1, OGR1), mediate pro-inflammatory responses. Here, we review the current knowledge on the role of these proton-sensing receptors in IBD and IBD-associated fibrosis and cancer, as well as colitis-associated cancer (CAC). We also describe emerging small molecule modulators of these receptors as therapeutic opportunities for the treatment of IBD.

The role of genetics in the treatment of dystonia with deep brain stimulation: Systematic review and Meta-analysis.

BACKGROUND: Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that lead to involuntary postures or repetitive movements. Genetic mutations are being increasingly recognized as a cause of dystonia. Deep brain stimulation (DBS) is one of the limited treatment options available. However, there are varying reports on its efficacy in genetic dystonias. This systematic review of the characteristics of genetic dystonias treated with DBS and their outcomes aims to aid in the evaluation of eligibility for such treatment. METHODS: We performed a PUBMED search of all papers related to genetic dystonias and DBS up until April 2022. In addition to performing a systematic review, we also performed a meta-analysis to assess the role of the mutation on DBS response. We included cases that had a confirmed genetic mutation and DBS along with pre-and post-operative BFMDRS. RESULTS: Ninety-one reports met our inclusion criteria and from them, 235 cases were analyzed. Based on our analysis DYT-TOR1A dystonia had the best evidence for DBS response and Rapid-Onset Dystonia Parkinsonism was among the least responsive to DBS. CONCLUSION: While our report supports the role of genetics in DBS selection and response, it is limited by the rarity of the individual genetic conditions, the reliance on case reports and case series, and the limited ability to obtain genetic testing on a large scale in real-time as opposed to retrospectively as in many cases.

Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-ß toxicity and network hyperexcitability.

Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-ß-induced dysfunction in preclinical models of AD and also prevents amyloid-ß-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain-containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain-containing proteins ameliorates amyloid-ß-induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-ß-induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.

Experimental and Modeling High-Pressure Study of Ammonia-Methane Oxidation in a Flow Reactor.

The present work deals with an experimental and modeling analysis of the oxidation of ammonia-methane mixtures at high pressure (up to 40 bar) in the 550-1250 K temperature range using a quartz tubular reactor and argon as a diluent. The impact of temperature, pressure, oxygen stoichiometry, and CH4/NH3 ratio has been analyzed on the concentrations of NH3, NO2, N2O, NO, N2, HCN, CH4, CO, and CO2 obtained as main products of the ammonia-methane mixture oxidation. The main results obtained indicate that increasing either the pressure, CH4/NH3 ratio, or stoichiometry results in a shift of NH3 and CH4 conversion to lower temperatures. The effect of pressure is particularly significant in the low range of pressures studied. The main products of ammonia oxidation are N2, NO, and N2O while NO2 concentrations are below the detection limit for all of the conditions considered. The N2O formation is favored by increasing the CH4/NH3 ratio and stoichiometry. The experimental results are simulated and interpreted in terms of an updated detailed chemical kinetic mechanism, which, in general, is able to describe well the conversion of both NH3 and CH4 under almost all of the studied conditions. Nevertheless, some discrepancies are found between the experimental results and model calculations.

High-Throughput cell-based immunofluorescence assays against influenza.

A rapid drug discovery response to influenza outbreaks with the potential to reach pandemic status could help minimize the virus's impact by reducing the time to identify anti-influenza drugs. Although several anti-influenza strategies have been considered in the search for new drugs, only a few therapeutic agents are approved for clinical use. The cytopathic effect induced by the influenza virus in Madin Darby canine kidney (MDCK) cells has been widely used for high-throughput anti-influenza drug screening, but the fact that the MDCK cells are not human cells constitutes a disadvantage when searching for new therapeutic agents for human use. We have developed a highly sensitive cell-based imaging assay for the identification of inhibitors of influenza A and B virus that is high-throughput compatible using the A549 human cell line. The assay has also been optimized for the assessment of the neutralizing effect of anti-influenza antibodies in the absence of trypsin, which allows testing of purified antibodies and serum samples. This assay platform can be applied to full high-throughput screening campaigns or later stages requiring quantitative potency determinations for structure-activity relationships.

Periodontal health of a low socioeconomic level population in Yucatan (Mexico): A cross-sectional study.

With the objective of assessing the periodontal health status, treatment needs, and oral hygiene habits of the population of Mérida, in Mexico, a descriptive cross-sectional study was performed. Four hundred forty individuals individually completed a questionnaire on oral health, oral hygiene habits, and quality of life. Additionally, a complete clinical dental examination was performed for each. For the statistical analysis, continuous variables (means and standard deviation) and categorical variables (frequencies) were studied. The associations were made using the analysis of variance test for continuous variables and the Chi-square test for categorical variables. The critical value to identify statistically significant differences was P < .05. The main concern of the population was the possible untreated caries they thought they had, with 36.21% followed by pain with 14.62%. Possible periodontal issues were the main discomfort for only 9%. The percentage of the sample that required periodontal intervention by a specialist was 21.14%. Statistically significant differences were found between age, place of residence, socioeconomic level, and schooling. There are great deficiencies in oral health in the studied group, which is accompanied by a great need for periodontal treatment. Periodontal health is closely related to oral hygiene, so the related sociocultural level should also be taken into account for the study of oral health in the most vulnerable populations. It is crucial to establish strategies to promote oral health.

OGR1 (GPR68) and TDAG8 (GPR65) Have Antagonistic Effects in Models of Colonic Inflammation.

G-protein-coupled receptors (GPRs), including pro-inflammatory ovarian cancer GPR1 (OGR1/GPR68) and anti-inflammatory T cell death-associated gene 8 (TDAG8/GPR65), are involved in pH sensing and linked to inflammatory bowel disease (IBD). OGR1 and TDAG8 show opposite effects. To determine which effect is predominant or physiologically more relevant, we deleted both receptors in models of intestinal inflammation. Combined Ogr1 and Tdag8 deficiency was assessed in spontaneous and acute murine colitis models. Disease severity was assessed using clinical scores. Colon samples were analyzed using quantitative polymerase chain reaction (qPCR) and flow cytometry (FACS). In acute colitis, Ogr1-deficient mice showed significantly decreased clinical scores compared with wildtype (WT) mice, while Tdag8-deficient mice and double knockout (KO) mice presented similar scores to WT. In Il-10-spontaneous colitis, Ogr1-deficient mice presented significantly decreased, and Tdag8-deficient mice had increased inflammation. In the Il10-/- × Ogr1-/- × Tdag8-/- triple KO mice, inflammation was significantly decreased compared with Tdag8-/-. Absence of Ogr1 reduced pro-inflammatory cytokines in Tdag8-deficient mice. Tdag8-/- had significantly more IFNγ+ T-lymphocytes and IL-23 T-helper cells in the colon compared with WT. The absence of OGR1 significantly alleviates the intestinal damage mediated by the lack of functional TDAG8. Both OGR1 and TDAG8 represent potential new targets for therapeutic intervention.

Do we really know if they are in pain? A cross-sectional study in hospitalised adult patients in Spain.

AIMS: To describe the prevalence and characteristics of pain in adult hospitalised patients, as well as to analyse the concordance between patient-reported and recorded pain and its impact on analgesic management. DESIGN: A cross sectional study. METHODS: The study was performed on a sample of 611 patients, from October to December 2017. Data were obtained from patient interviews, review of medical and nursing records and review of electronic prescribing. RESULTS: The prevalence of pain at the time of the interview was 36.7%. The median VAS score was 4. 90% of the patients had their pain assessed within the last 24 h; however, concordance between patient-reported pain and recorded pain in the nursing record was slight. CONCLUSION: Pain is still often documented inadequately. Despite the wide use of analgesics, half of the patients with moderate to severe pain do not have adequate pain management. A systematic assessment and recording of pain promotes appropriate analgesic prescription. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: The findings of our study provide insight into the main gaps in the correct management of pain in hospitalised patients. A systematic assessment and recording of the pain suffered by the patient facilitates its control and allows a better management of the analgesic prescription by the physician. This information could help hospital managers to develop training programmes on pain assessment and on the importance of doctor-nurse collaboration to improve pain management, increasing the quality of care and reducing hospital costs. REPORTING METHOD: The study has adhered to the relevant EQUATOR guidelines, according to The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

Marine Microalgae as a Nutritive Tool to Mitigate Ruminal Greenhouse Gas Production: In Vitro Fermentation Characteristics of Fresh and Ensiled Maize (Zea mays L.) Forage.

The aim of the present study was to evaluate the effects of marine microalgae (Dunaliella salina) as a food additive on biogas (BG), methane (CH4), carbon monoxide (CO), and hydrogen sulfide (H2S) production kinetics, as well as in in vitro rumen fermentation and the CH4 conversion efficiency of different genotypes of maize (Zea mays L.) and states of forage. The treatments were characterized by the forage of five maize genotypes (Amarillo, Montesa, Olotillo, Tampiqueño, and Tuxpeño), two states of forage (fresh and ensiled), and the addition of 3% (on DM basis) of microalgae (with and without). The parameters (b = asymptotic production, c = production rate, and Lag = delay phase before gas production) of the production of BG, CH4, CO, and H2S showed an effect (p < 0.05) of the genotype, the state of the forage, the addition of the microalgae, or some of its interactions, except for the time in the CO delay phase (p > 0.05). Moreover, the addition of microalgae decreased (p < 0.05) the production of BG, CH4, and H2S in most of the genotypes and stages of the forage, but the production of CO increased (p < 0.05). In the case of fermentation characteristics, the microalgae increased (p < 0.05) the pH, DMD, SCFA, and ME in most genotypes and forage states. With the addition of the microalgae, the fresh forage from Olotillo obtained the highest pH (p < 0.05), and the ensiled from Amarillo, the highest (p < 0.05) DMD, SCFA, and ME. However, the ensiled forage produced more (p < 0.05) CH4 per unit of SFCA, ME, and OM, and the microalgae increased it (p < 0.05) even more, and the fresh forage from Amarillo presented the highest (p < 0.05) quantity of CH4 per unit of product. In conclusion, the D. salina microalga showed a potential to reduce the production of BG, CH4, and H2S in maize forage, but its effect depended on the chemical composition of the genotype and the state of the forage. Despite the above, the energy value of the forage (fresh and ensiled) improved, the DMD increased, and in some cases, SCFA and ME also increased, all without compromising CH4 conversion efficiency.

The enduring enigma of sporadic chorea: A single center case series.

Chorea can have a wide variety of causes including neurodegenerative, pharmacological, structural, metabolic, infectious, immunologic and paraneoplastic processes. We reviewed the clinical records of patients with apparently sporadic choreic movements and no relevant family history, who presented to our neurology department (Hospital Fundación Jimenez Diaz) between 1991 and 2022. We detected 38 cases of apparent sporadic chorea (ASC); Our analysis revealed 5 cases of genetic chorea (including 3 cases with Huntington's disease) while 6 cases were autoimmune/hematological; 6 drug-related chorea, 5 metabolic-vascular, 5 due to miscellaneous conditions and 4 were of mixed etiology. No clear etiology was identified in 8 cases. The differential diagnosis of ASC is extensive and challenging. Highlights: Chorea can have a wide variety of genetic and sporadic causesWe reviewed the clinical records of patients with apparently sporadic chorea (ASC), who presented to our neurology department over the last 30 yearsWe detected 38 cases of apparent ASC; Our analysis revealed a wide array of different sporadic conditions and 5 cases of genetic choreaThe differential diagnosis of ASC is extensive and challenging.

Homocysteine, vitamin B metabolites, dopamine-substituting compounds, and symptomatology in Parkinson's disease: clinical and therapeutic considerations.

Emerging studies suggest a correlation between elevated plasma homocysteine (hcy) levels and the risk of atherosclerosis, vascular disorders, and neurodegenerative diseases, including Parkinson's disease (PD). This narrative review delves into the intricate relationships between Hcy, vitamin B metabolites, dopamine-substituting compounds, and various symptoms of PD. Patients undergoing a long-term L-dopa/dopa-decarboxylase inhibitor (DDI) regimen, especially without a concurrent catechol-O-methyl transferase (COMT) inhibitor or methyl group-donating vitamin supplementation, such as vitamins B6 and B12, exhibit an elevation in Hcy and a decline in vitamin B metabolites. These altered concentrations appear to be associated with heightened risks of developing non-motor symptoms, including peripheral neuropathy and cognitive disturbances. The review underscores the impact of levodopa metabolism via COMT on homocysteine levels. In light of these findings, we advocate for the supplementation of methyl group-donating vitamins, notably B6 and B12, in patients undergoing a high-dose L-dopa/DDI regimen, particularly those treated with L-dopa/carbidopa intestinal gel (LCIG) infusion.

The polygenic basis of relapse after a first episode of schizophrenia.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

An Easy and Effective Method for Avoiding Intraoperative Pedicle Vessels Kinking.

Vascular pedicle twisting during a microsurgical anastomosis procedure can jeopardize the viability of the flap. Although the literature describes many maneuvers to prevent vascular pedicle twisting, we present an easy and effective method that can be used when performing microsurgical anastomosis in the operating room.

Analysis and Evaluation of Dental Caries in a Mexican Population: A Descriptive Transversal Study.

Oral diseases are an important public health problem owing to their high prevalence and strong impact on people, particularly in disadvantaged populations. There is a strong relationship between the socioeconomic situation and the prevalence and severity of these diseases. Mexico is among the countries with a higher frequency range in oral diseases, highlighting dental caries, which affect more than 90% of the Mexican population. MATERIALS AND METHOD: A cross-sectional, descriptive, and observational study was carried out in 552 individuals who underwent a complete cariogenic clinical examination in different populations of the state of Yucatan. All individuals were evaluated after providing informed consent and with the consent of their legal guardians for those under legal age. We used the caries measurement methods described by the World Health Organization (WHO). Prevalence of caries, DMFT, and dft indexes were measured. Other aspects were also studied, such as oral habits and the use of public or private dental services. RESULTS: The prevalence of caries in permanent dentition was 84%. Moreover, it was found to be statistically related to the following variables: place of residence, socioeconomic level, gender, and level of education (p < 0.05). For primary teeth, the prevalence was 64% and there was no statistical relation with any of the variables studied (p > 0.05). Regarding the other aspects studied, more than 50% of the sample used private dental services. CONCLUSIONS: There is a high need for dental treatment in the population studied. It is necessary to develop prevention and treatment strategies considering the particularities of each population, driving collaborative projects to promote better oral health conditions in disadvantaged populations.

Perampanel: Medical Alternative for Essential Tremor?

OBJECTIVES: The aim of this study was to assess the safety and efficacy of perampanel in patients with refractory essential tremor (ET). METHODS: We recruited patients from our movement disorders clinic with the diagnosis of severe refractory ET, and perampanel 4 mg at night was initiated.Assessments were conducted at baseline and after 1 month of treatment with perampanel 4 mg/d. Details about tolerance and effectiveness were collected. Clinical evaluation was conducted with the Fahn-Tolosa-Marín scale, and statistical analysis was carried out with Wilcoxon matched pairs signed rank test. RESULTS: This study included 18 patients with severe ET (11 females, 7 males; mean age: 75.1 ± 12.03 years; mean duration of ET: 17.4 ± 17.03 years). Perampanel significantly improved patients' average score with refractory ET ( P ≤ 0.0001). This improvement has been occasionally quite relevant. However, a proportion of patients did not tolerate perampanel because of several adverse effects including dizziness, ataxia, irritability, and instability. CONCLUSIONS: Perampanel had a markedly positive antitremor effect in patients with ET and could be an alternative treatment. However, this drug is not devoid of adverse effects.