Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.

BACKGROUND AND AIMS: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. APPROACH AND RESULTS: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. CONCLUSIONS: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.

Analysis of DNA methylation markers for tissue identification in individuals with different clinical phenotypes.

Deoxyribonucleic acid (DNA) methylation patterns can be used to identify the type of tissue or body fluid found at a crime scene. However, tissue-related methylation levels have not been analyzed in individuals with different illnesses and medical conditions in forensic-specific studies. The primary goal of this study was to investigate if certain clinical phenotypes can alter the methylation levels of CpG sites in genes involved in tissue typing. Four studies with focus on DNA methylation analysis on individuals with different clinical conditions were selected from the Gene Expression Omnibus database. Then, a list of 137 CpG sites was compiled for further investigation. Statistical tests were performed to compare the beta-values results obtained for the control groups and the individuals affected by medical conditions. For each study, CpG sites that presented significant statistical differences between patients and control group were identified and it was possible to notice that DNA methylation levels can be affected in sites with potential forensic use. Although the observed DNA methylation variation (less than 10% difference) in this study would likely not cause any issues in body fluid identification, the results are important to show that this type of analysis should be taken into consideration when investigating and further validating body fluid markers. The CpG sites identified in this study should be further investigated by future studies on body fluids identification, and due to the significant difference in methylation levels in samples from affected individuals, caution must be taken before including these sites in tissue identification investigations.

Sex Differences in Influenza: The Challenge Study Experience.

BACKGROUND: Preclinical animal studies and retrospective human studies suggest that adult females have worse outcomes from influenza than males. Prospective studies in humans are missing. METHODS: Data from 164 healthy volunteers who underwent influenza A/California/04/2009/H1N1 challenge were compiled to compare differences between sexes. Baseline characteristics, including hormone levels, hemagglutination inhibition (HAI) titers, neuraminidase inhibition (NAI) titers, and outcomes after challenge were compared. Linear and logistic regression models were built to determine significant predictor variables with respect to outcomes of interest. RESULTS: HAI titers were similar between the sexes, but NAI titers were higher in males than females at 4 weeks and 8 weeks postchallenge. Females were more likely to have symptoms (mean, 0.96 vs 0.80; P = .003) and to have a higher number of symptoms (median, 3 vs 4; P = .011) than males. Linear and logistic regression models showed that prechallenge NAI titers, but not HAI titers or sex hormone levels, were predictive of all shedding and symptom outcomes of interest. CONCLUSIONS: Females in our cohorts were more likely to be symptomatic and to have a higher number of symptoms than males. NAI titers predicted all outcomes of interest and may explain differential outcomes between the sexes.

RXam2, a NLR from cassava (Manihot esculenta) contributes partially to the quantitative resistance to Xanthomonas phaseoli pv. manihotis.

KEY MESSAGE: The overexpression of RXam2, a cassava NLR (nucleotide-binding leucine-rich repeat) gene, by stable transformation and gene expression induction mediated by dTALEs, reduce cassava bacterial blight symptoms. Cassava (Manihot esculenta) is a tropical root crop affected by different pathogens including Xanthomonas phaseoli pv. manihotis (Xpm), the causal agent of cassava bacterial blight (CBB). Previous studies have reported resistance to CBB as a quantitative and polygenic character. This study sought to validate the functional role of a NLR (nucleotide-binding leucine-rich repeat) associated with a QTL to Xpm strain CIO151 called RXam2. Transgenic cassava plants overexpressing RXam2 were generated and analyzed. Plants overexpressing RXam2 showed a reduction in bacterial growth to Xpm strains CIO151, 232 and 226. In addition, designer TALEs (dTALEs) were developed to specifically bind to the RXam2 promoter region. The Xpm strain transformed with dTALEs allowed the induction of the RXam2 gene expression after inoculation in cassava plants and was associated with a diminution in CBB symptoms. These findings suggest that RXam2 contributes to the understanding of the molecular basis of quantitative disease resistance.

K-means cluster analysis of cooperative effects of CO, NO2, O3, PM2.5, PM10, and SO2 on incidence of type 2 diabetes mellitus in the US.

Air pollution (AP) has been shown to increase the risk of type 2 diabetes mellitus, as well as other cardiometabolic diseases. AP is characterized by a complex mixture of components for which the composition depends on sources and metrological factors. The US Environmental Protection Agency (EPA) monitors and regulates certain components of air pollution known to have negative consequences for human health. Research assessing the health effects of these components of AP often uses traditional regression models, which might not capture more complex and interdependent relationships. Machine learning has the capability to simultaneously assess multiple components and find complex, non-linear patterns that may not be apparent and could not be modeled by other techniques. Here we use k-means clustering to assess the patterns associating PM2.5, PM10, CO, NO2, O3, and SO2 measurements and changes in annual diabetes incidence at a US county level. The average age adjusted annual decrease in diabetes incidence for the entire US populations is -0.25 per 1000 but the change shows a significant geographic variation (range: -17.2 to 5.30 per 1000). In this paper these variations were compared with the local daily AP concentrations of the pollutants listed above from 2005 to 2015, which were matched to the annual change in diabetes incidence for the following year. A total of 134,925 daily air quality observations were included in the cluster analysis, representing 125 US counties and the District of Columbia. K-means successfully clustered AP components and indicated an association between exposure to certain AP mixtures with lower decreases on T2D incidence.

Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model.

BACKGROUND: It is imperative to identify new targets for improved vaccines and therapeutics against influenza. One such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein. METHODS: We conducted a randomized, double-blind, phase 2, placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. A single 50 mg/kg dose of CR6261 was infused 24 hours after challenge. The primary efficacy outcome was area under the curve (AUC) of viral RNA detection over time. RESULTS: Ninety-one healthy volunteers were randomized and underwent influenza challenge; 49 received CR6261 and 42 received placebo. CR6261 had no statistically significant effect on AUC (AUC, 48.56 log [copies/mL] × days, interquartile range [IQR], 202 vs AUC, 25.53 log [copies/mL] × days, IQR, 155; P = .315) and no clinically significant effect on influenza disease measures including number of symptoms, duration of symptoms, or inFLUenza Patient-Reported Outcome (FLU-PRO) scores. Preexisting anti-NA antibody titers were most predictive of reduced influenza disease. CR6261 reached a mean peak serum concentration of 1 × 106 ng/mL 15 minutes after infusion and a mean peak of 5.97 × 102 ng/mL in the nasal mucosa 2-3 days after infusion. CONCLUSIONS: The results of this study suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may be limited in efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multifaceted strategy rather than as a stand-alone therapeutic. CLINICAL TRIALS REGISTRATION: NCT02371668.

Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomised, placebo-controlled, double-blind, phase 1 trial.

BACKGROUND: In animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans. METHODS: In this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18-50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual. FINDINGS: Between Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log10-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log10 ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [-0·072 to 0·116]; p=0·63). INTERPRETATION: AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease. FUNDING: Office of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Influenza A Reinfection in Sequential Human Challenge: Implications for Protective Immunity and "Universal" Vaccine Development.

BACKGROUND: Identification of correlates of protection against human influenza A virus infection is important in development of broadly protective ("universal") influenza vaccines. Certain assumptions underlie current vaccine developmental strategies, including that infection with a particular influenza A virus should offer long-term or lifelong protection against that strain, preventing reinfection. In this study we report observations made when 7 volunteers participated in sequential influenza challenge studies where they were challenged intranasally using the identical influenza A(H1N1)pdm09 virus approximately 1 year apart. We evaluate and describe the outcomes of these 7 rechallenge participants and discuss what these results may suggest about correlates of protection and development of more broadly protective influenza vaccines. METHODS: Seven participants were enrolled in 2 viral challenge studies at 7.5- to 18.5-month intervals. Both challenge studies used the identical lot of influenza A (H1N1)pdm09 virus administered intranasally. We evaluated pre- and postchallenge hemagglutination inhibition, neuraminidase inhibition, and stalk antibody titers; peripheral blood leukocyte host gene expression response profiles; daily viral detection via nasal wash; and clinical signs and symptoms. RESULTS: At least 3 of 7 participants demonstrated confirmed laboratory evidence of sequential infection, with 5 of 7 demonstrating clinical evidence. CONCLUSIONS: The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted. CLINICAL TRIALS REGISTRATION: NCT01646138; NCT01971255.

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.

BACKGROUND: The development of vaccines and therapeutics has relied on healthy volunteer influenza challenge studies. A validated human infection model with wild-type A(H1N1)pdm09 was reported previously. Our objective was to characterize a wild-type influenza A/Bethesda/MM1/H3N2 challenge virus in healthy volunteers. METHODS: Participants received a single dose of a cell-based, reverse-genetics, Good Manufacturing Practices-produced wild-type influenza A(H3N2)2011 virus intranasally and were isolated at the National Institutes of Health Clinical Center for ≥9 days. Dose escalation was performed from 104 to 107 TCID50 (50% tissue culture infectious dose). Viral shedding and clinical disease were evaluated daily. RESULTS: Of 37 participants challenged, 16 (43%) had viral shedding and 27 (73%) developed symptoms, with 12 (32%) participants experiencing mild to moderate influenza disease (MMID), defined as shedding and symptoms. Only participants receiving 106 and 107 TCID50 experienced MMID at 44% and 40%, respectively. Symptom severity peaked on day 3, whereas most viral shedding occurred 1-2 days after challenge. Only 10 (29%) participants had a ≥4-fold rise in hemagglutination inhibition antibody titer after challenge. CONCLUSIONS: The A/Bethesda/MM1/H3N2 challenge virus safely induced MMID in healthy volunteers, but caused less MMID than the A(H1N1)pdm09 challenge virus even at the highest dose. There was less detection of shedding though the incidence of symptoms was similar to A(H1N1)pdm09. Fewer serum anti-hemagglutinin (HA) antibody responses with less MMID indicate that preexisting immunity factors other than anti-HA antibody may limit shedding in healthy volunteers. This A/Bethesda/MM1/H3N2 challenge virus can be utilized in future studies to further explore pathogenesis and immunity and to evaluate vaccine candidates. CLINICAL TRIALS REGISTRATION: NCT02594189.

[Associated factors to non-operative management failure of hepatic and splenic lesions secondary to blunt abdominal trauma in children]. / Factores asociados a falla en el manejo no operatorio de lesiones hepáticas o esplénicas secundarias a trauma abdominal cerrado en niños.

INTRODUCTION: The non operative management (NOM) is the standard management of splenic and liver blunt trauma in pediatric patients.Hemodynamic instability and massive transfusions have been identified as management failures. Few studies evaluate whether there exist factors allowing anticipation of these events. The objective was to identify factors associated with the failure of NOM in splenic and liver injuries for blunt abdominal trauma. PATIENTS AND METHOD: Retrospective analysis between 2007-2015 of patients admitted to the pediatric surgery at University Hospital Saint Vincent Foundation with liver trauma and/or closed Spleen. RESULTS: 70 patients were admitted with blunt abdominal trauma, 3 were excluded for immediate surgery (2 hemodynamic instability, 1 peritoneal irritation). Of 67 patients who received NOM, 58 were successful and 9 showed failure (8 hemodynamic instability, 1 hollow viscera injury). We found 3 factors associated with failure NOM: blood pressure (BP) < 90 mmHg at admission (p = 0.0126; RR = 5.19), drop in hemoglobin (Hb) > 2 g/dl in the first 24 hours (p = 0.0009; RR = 15.3), and transfusion of 3 or more units of red blood cells (RBC) (0.00001; RR = 17.1). Mechanism and severity of trauma and Pediatric Trauma Index were not associated with failure NOM. CONCLUSIONS: Children with blunted hepatic or splenic trauma respond to NOM. Factors such as BP < 90 mmHg at admission, an Hb fall > 2 g/dl in the first 24 hours and transfusion of 3 or more units of RBC were associated with the failure in NOM.

Navigating the Complexity of a Bipolar Pregnant Patient With Multiple Comorbidities.

Bipolar disorder I (BDI) is a psychiatric disorder characterized by the occurrence of at least one manic episode. Within the scope of neurological disorders, epilepsy and psychogenic nonepileptic seizures (PNES) share clinical features and can be differentiated using electroencephalogram (EEG). Substance use disorder is a condition defined by impaired control, risky use, social impairment, and addictive behaviors. We present the case of a 20-year-old pregnant woman with BDI associated with a history of epilepsy, PNES, and polyvalent substance use. The patient presented to the emergency department via the Baker Act involuntary hold multiple times throughout her pregnancy. Recognizing that the welfare of the mother and child was at risk, the court ordered a two-month commitment of inpatient psychiatric treatment at 30 weeks' gestation to ensure safe delivery. Comprehensive inpatient treatment, including risperidone, levetiracetam, lacosamide, haloperidol, diphenhydramine, lorazepam, and later clozapine, and a discharge plan for both the mother and the child are described in detail. Our goal is to contribute to the growing body of knowledge on the management of complex pregnant patients with psychiatric conditions in order to optimize outcomes for maternal and fetal health.

A novel deep intronic variant in the DMD gene causes Duchenne muscular dystrophy by pseudoexon activation encoding a nonsense codon.

Dystrophinopathies are a group of neuromuscular disorders, inherited in an X-linked recessive manner, caused by pathogenic variants in the DMD gene. Copy number variation detection and next generation sequencing allow the detection of around 99 % of the pathogenic variants. However, some patients require mRNA studies from muscle biopsies to identify deep intronic pathogenic variants. Here, we report a child suspected of having Duchenne muscular dystrophy, with a muscle biopsy showing dystrophin deficiency, and negative molecular testing for deletions, duplications, and small variants. mRNA analysis from muscle biopsy revealed a pseudoexon activation that introduce a premature stop codon into the reading frame. gDNA sequencing allowed to identified a novel variant, c.832-186 T>G, which creates a cryptic donor splice site, recognizing the underlying mechanism causing the pseudoexon insertion. This case highlights the usefulness of the mRNA analysis from muscle biopsy when routine genetic testing is negative and clinical suspicion of dystrophinopathies remains the main clinical diagnosis suspicion.

Use of Recombinant Human Bone Morphogenetic Protein-2 After Anterior Cervical Corpectomy and Fusion for the Treatment of Vertebral Osteomyelitis.

OBJECTIVE: To report the operative outcomes after treating vertebral osteomyelitis patients with an anterior cervical corpectomy and fusion procedure using recombinant human bone morphogenetic protein-2 (rhBMP-2) as graft material. METHODS: A retrospective review of electronic medical records of 26 adult patients who underwent an anterior cervical corpectomy and fusion procedure for cervical osteomyelitis using rhBMP-2 at the University of Puerto Rico University District Hospital was performed. Indication, preoperative laboratory results, levels of corpectomy, preoperative American Spinal Injury Association Impairment Scale (ASIA) score, complications, fusion evaluation at 12 months, and ASIA score at 12 months were reviewed. RESULTS: For the cohort of patients, mean age was 47 ± 13 years and 65% were male. Spinal instability was present in 54%. The levels of corpectomy were: 1 level in 2 cases, 2 levels in 15 cases, 3 levels in 8 cases, and 5 levels in 1 case. Four patients had complications and, of these, 2 experienced dysphagia. The fusion rate was 100% and no reoperations were performed. An improvement in ASIA score was seen for 54% patients at 12-month follow-up. CONCLUSIONS: This study demonstrates a fusion rate of 100% with no reoperations reported. Recombinant human bone morphogenetic protein-2 could be considered and further researched as grafting material for anterior cervical corpectomy and fusion procedures in cervical osteomyelitis patients.

Mucosal correlates of protection after influenza viral challenge of vaccinated and unvaccinated healthy volunteers.

The induction of systemic antibody titers against hemagglutinin has long been the main focus of influenza vaccination strategies, but mucosal immunity has also been shown to play a key role in the protection against respiratory viruses. By vaccinating and challenging healthy volunteers, we demonstrated that inactivated influenza vaccine (IIV) modestly reduced the rate of influenza while predominantly boosting serum antibody titers against hemagglutinin (HA) and HA stalk, a consequence of the low neuraminidase (NA) content of IIV and the intramuscular route of administration. The viral challenge induced nasal and serum responses against both HA and NA. Correlations between mucosal IgA and serum IgG against specific antigens were low, whether before or after challenge, suggesting a compartmentalization of immune responses. Even so, volunteers who developed viral shedding for multiple days had lower baseline titers across both systemic and mucosal compartments as compared to those with no shedding or a single day of shedding. Regression analysis showed that pre-challenge HA inhibition titers were the most consistent correlate of protection across clinical outcomes combining shedding and symptoms, with NA inhibition titers and HA IgG levels only predicting the duration of shedding. Despite the inclusion of data from multiple binding and functional antibody assays against HA and NA performed on both serum and nasal samples, multivariate models were unable to account for the variability in outcomes, emphasizing our imperfect understanding of immune correlates in influenza and the importance of refining models with assessments of innate and cellular immune responses.IMPORTANCEThe devastating potential of influenza has been well known for over 100 years. Despite the development of vaccines since the middle of the 20th century, influenza continues to be responsible for substantial global morbidity and mortality. To develop next-generation vaccines with enhanced effectiveness, we must synthesize our understanding of the complex immune mechanisms culminating in protection. Our study outlines the differences in immune responses to influenza vaccine and influenza infection, identifying potential gaps in vaccine-induced immunity, particularly at the level of the nasal mucosa. Furthermore, this research underscores the need to refine our imperfect models while recognizing potential pitfalls in past and future attempts to identify and measure correlates of protection.

[COVID-19 and the predominant groups of preventive behaviors and associated factors: semi-urban area]. / La COVID-19 y los grupos predominantes de conductas preventivas y factores asociados: zona semiurbana.

Background: Non-pharmacological interventions (NFI) or preventive actions (PA) are the best alternatives to control future pandemics, especially in vulnerable populations, such as semi-urban areas. Objective: To describe the predominant health behavior groups (HBG) and associated factors during the third wave of COVID-19 in a semi-urban area. Material and methods: A survey which included characteristics, factors related to COVID-19, perceptions of health behavior and PA was applied in a probabilistic sample in a first-level hospital in the State of Mexico. People of both sexes over 18 years of age were included. Using a hierarchical cluster analysis, HBGs were obtained and characterized with a descriptive and multivariate statistical analysis. Results: In a probabilistic sample (n = 260), 4 HBGs were identified: 2 of high-risk (HRG) and 2 of low-risk (LRG), and the proportions were 43.5% y 56.5%, respectively. The sociodemographic characteristics of both groups were similar. Perceptions of severity and COVID-19-related barriers significantly influenced health behaviors in LRG. In HRG, low security played a significant role, highlighting the importance of comorbidities as a clinical factor. Conclusions: In a semi-urban area, 2 crucial health behaviors were identified: one associated with low risk and the other with high risk. In the HRG, the perception of insecurity was particularly relevant, emphasizing the importance of comorbidities as a clinical factor.

Introducción: las intervenciones no farmacológicas (INF) o acciones preventivas (AP) contra enfermedades son la mejor alternativa para controlar futuras pandemias, en especial en poblaciones vulnerables, como las zonas semiurbanas. Objetivo: describir los grupos predominantes de conductas de salud (GCS) y los factores asociados durante la tercera ola de la COVID-19 en una zona semiurbana. Material y métodos: se aplicó una encuesta que incluyó las características, los factores relacionados con COVID-19, las percepciones de conductas de salud y las AP, en una muestra probabilística en un hospital de primer nivel del Estado de México. Se incluyeron personas de ambos sexos, mayores de 18 años. Mediante un análisis de conglomerados se caracterizaron los GCS con un análisis estadístico descriptivo y multivariado. Resultados: en una muestra probabilistica (n = 260), se identificaron cuatro GCS: 2 de riesgo alto de contagio por la COVID-19 (GRA) y 2 de riesgo bajo (GRB) y las proporciones fueron 43.5% y 56.5%, respectivamente. Las características sociodemográficas de los grupos fueron similares. Para los GRB los factores significativos fueron las percepciones sobre la severidad y las barreras relacionadas con la COVID-19. En los GRA fue la seguridad baja y destacó la importancia de la comorbilidad como factor clínico. Conclusiones: en una zona semiurbana se identificaron 2 conductas de salud de importancia: una de bajo riesgo y otra de alto riesgo. En el GRA, la percepción de seguridad baja fue especialmente relevante, lo cual resalta la importancia de las comorbilidades como factor clínico.

TransOrbital NeuroEndoscopic Surgery for Biopsy of the Left Cavernous Sinus: A Literature Review, Case Report, and Cadaveric Proof of Concept.

The aim of this report is to describe TransOrbital NeuroEndoscopic Surgery (TONES) as a safe alternative for obtaining a cavernous sinus (CS) biopsy. We describe this technique in a patient with a diffuse large B cell lymphoma mimicking Tolosa-Hunt's syndrome. Articles were gathered querying PubMed, Embase, and Scopus databases with terms related to a "transorbital neuroendoscopic approach." The literature search was performed by two independent authors (N.L.F. and J.R.), with inconsistencies resolved by the senior author (M.M.D.V.). After screening abstracts for relevance, full-length articles were reviewed for pertinent variables. A comparison was conducted with the illustrative case of a 69-year-old woman who presented to the emergency department with vertigo, ophthalmoplegia, and diplopia for 2 months. A brain magnetic resonance imaging revealed an infiltrative lesion at the left CS. A presumptive diagnosis of Tolosa-Hunt syndrome was made, but a confirmatory biopsy was performed using TONES. Based on our cadaveric study, literature review, and case report, the TONES approach was safe, effective for tissue diagnosis, and associated with minor morbidity and reduced hospital stay. Additional prospective studies are required to study its viability and safety in a larger group of patients.

Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia.

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Dynamics of SARS-CoV-2 Seroprevalence in a Large US population Over a Period of 12 Months.

Due to a combination of asymptomatic or undiagnosed infections, the proportion of the United States population infected with SARS-CoV-2 was unclear from the beginning of the pandemic. We previously established a platform to screen for SARS-CoV-2 positivity across a representative proportion of the US population, from which we reported that almost 17 million Americans were estimated to have had undocumented infections in the Spring of 2020. Since then, vaccine rollout and prevalence of different SARS-CoV-2 variants have further altered seropositivity trends within the United States population. To explore the longitudinal impacts of the pandemic and vaccine responses on seropositivity, we re-enrolled participants from our baseline study in a 6- and 12- month follow-up study to develop a longitudinal antibody profile capable of representing seropositivity within the United States during a critical period just prior to and during the initiation of vaccine rollout. Initial measurements showed that, since July 2020, seropositivity elevated within this population from 4.8% at baseline to 36.2% and 89.3% at 6 and 12 months, respectively. We also evaluated nucleocapsid seropositivity and compared to spike seropositivity to identify trends in infection versus vaccination relative to baseline. These data serve as a window into a critical timeframe within the COVID-19 pandemic response and serve as a resource that could be used in subsequent respiratory illness outbreaks.

Metabolic engineering of cassava to improve carotenoids.

Cassava is a staple food used in many countries around the world, despite deficiencies in micronutrients such as provitamin A carotenoids. Unfortunately, improvement of the cassava nutritional content by use of conventional breeding is slow and difficult. Therefore, there is an urgent need to develop and standardize protocols using biotechnological tools to improve cassava. The Alliance of Biodiversity International and the International Center for Tropical Agriculture (CIAT) have worked on cassava genetic transformation over the last 30 years. Here, we describe, step by step, the procedures used for genetic transformation of cassava variety TMS60444, to improve carotenoids and other traits. This protocol includes stock setup, reagents, media preparation, materials, and equipment, for the genetic transformation of embryogenic tissues. The main expected output in publishing this protocol is to provide the basis for a reproducible and reliable method to genetically modify and/or gene edit Latin American and Asian cassava varieties.