2021 World Health Organization guideline on pharmacological treatment of hypertension: Policy implications for the region of the Americas. Campbell NRC, Paccot Burnens M, Whelton PK, Angell SY, Jaffe MG, Cohn J, et al. Lancet Reg Health Am. 2022 May;9:None. https://doi.org/10.1016/j.lana.2022.100219  

Cardiovascular disease (CVD) is the leading cause of death in the Americas and raised blood pressure accounts for over 50% of CVD. In the Americas over a quarter of adult women and four in ten adult men have hypertension and the diagnosis, treatment and control are suboptimal. In 2021, the World Health Organization (WHO) released an updated guideline for the pharmacological treatment of hypertension in adults. This policy paper highlights the facilitating role of the WHO Global HEARTS initiative and the HEARTS in the Americas initiative to catalyze the implementation of this guideline, provides specific policy advice for implementation, and emphasizes that an overarching strategic approach for hypertension control is needed. The authors urge health advocates and policymakers to prioritize the prevention and control of hypertension to improve the health and wellbeing of their populations and to reduce CVD health disparities within and between populations of the Americas.

An engineered SARS-CoV-2 receptor-binding domain produced in Pichia pastoris as a candidate vaccine antigen. Limonta-Fernández M, Chinea-Santiago G, Martín-Dunn AM, González-Roche D, Bequet-Romero M, Márquez-Perera G, et al. N Biotechnol. 2022 Aug 8;S1871-6784(22)00046-2. https://doi.org/10.1016/j.nbt.2022.08.002. Online ahead of print.

Developing affordable and easily manufactured SARS-CoV-2 vaccines will be essential to achieve worldwide vaccine coverage and long-term control of the COVID-19 pandemic. Here the development is reported of a vaccine based on the SARS-CoV-2 receptor-binding domain (RBD), produced in the yeast Pichia pastoris. The RBD was modified by adding flexible N- and C-terminal amino acid extensions that modulate protein/protein interactions and facilitate protein purification. A fed-batch methanol fermentation with a yeast extract-based culture medium in a 50L fermenter and an immobilized metal ion affinity chromatography-based downstream purification process yielded 30-40mg/L of RBD. Correct folding of the purified protein was demonstrated by mass spectrometry, circular dichroism, and determinations of binding affinity to the angiotensin-converting enzyme 2 (ACE2) receptor. The RBD antigen also exhibited high reactivity with sera from convalescent individuals and Pfizer-BioNTech or Sputnik V vaccinees. Immunization of mice and non-human primates with 50µg of the recombinant RBD adjuvanted with alum induced high levels of binding antibodies as assessed by ELISA with RBD produced in HEK293T cells, and which inhibited RBD binding to ACE2 and neutralized infection of VeroE6 cells by SARS-CoV-2. Additionally, the RBD protein stimulated IFNγ, IL-2, IL-6, IL-4 and TNFα secretion in splenocytes and lung CD3⁺-enriched cells of immunized mice. The data suggest that the RBD recombinant protein produced in yeast P. pastoris is suitable as a vaccine candidate against COVID-19.

A New Model of Hemoglobin Oxygenation. Lavrinenko IA, Vashanov GA, Hernández Cáceres JL, Buchelnikov AS, Nechipurenko YD. Entropy (Basel). 2022 Aug 30;24(9):1214. https://doi.org/10.3390/e24091214
The study of hemoglobin oxygenation, starting from the classical works of Hill, has laid the foundation for molecular biophysics. The cooperative nature of oxygen binding to hemoglobin has been variously described in different models. In the Adair model, which better fits the experimental data, the constants of oxygen binding at various stages differ. However, the physical meaning of the parameters in this model remains unclear. In this work, we applied Hill’s approach, extending its interpretation; we obtained a good agreement between the theory and the experiment. The equation in which the Hill coefficient is modulated by the Lorentz distribution for oxygen partial pressure approximates the experimental data better than not only the classical Hill equation, but also the Adair equation.

A Retrospective Study of Risk Factors, Mortality, and Treatment Outcomes for Infections with Carbapenemase-Producing Enterobacterales in a Tertiary Hospital in Havana, Cuba. Yu H, Hernández González A, Estévez Torres G, González Molina MK, Hart Casares M, Han X, et al. Antibiotics (Basel). 2022 Jul;11(7):942. https://doi.org/10.3390/antibiotics11070942. Published online 2022 Jul 14.

Background The spread of carbapenem-resistant Enterobacterales in hospitals constitutes an important epidemiological and therapeutic problem that especially affects vulnerable patients such as perioperative patients. Methods We conducted a descriptive, observational, retrospective case-control study of patients infected with carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) and carbapenem-susceptible Enterobacterales during the perioperative period in a tertiary hospital. Results Metallo-β-lactamase was detected in all 124 CRE isolates, with NDM-type carbapenemase being dominant, while 3 isolates coproduced KPC-type enzyme and showed high resistance rates against all antibiotics except colistin (25.2%). By analyzing the risk factors for infection, steroid use (OR: 3.22, p < 0.01), prior use of two or more antibiotics (OR: 4.04, p = 0.01), prior use of broad-spectrum cephalosporins (OR: 2.40, p = 0.04), and prior use of carbapenem (OR: 4.77, p = 0.03) were found to be independent risk factors for CP-CRE infection. In addition, in this study, we observed that the clinical outcomes of bloodstream infections and pneumonia associated with CP-CRE posed higher mortality risks. However, by analyzing the associations between treatment options and mortality, it was found that, in bloodstream infections caused by CP-CRE, colistin-based regimens showed a significant advantage (PR = 0.40, p = 0.03). (4) Conclusions High mortality is associated with nosocomial infections in the perioperative period caused by carbapenemase-producing Enterobacterales, the dissemination of which in health care settings in Cuba remains a public health challenge.

A Review of Computational Approaches Targeting SARS-CoV-2 Main Protease to the Discovery of New Potential Antiviral Compounds. Castillo-Garit JA, Cañizares-Carmenate Y, Pham-The H, Virginia Pérez-Doñate V, Torrens F, Pérez-Giménez F. Curr Top Med Chem. 2022 Apr 26. https://doi.org/10.2174/2667387816666220426133555. Online ahead of print.

The new pandemic produced by coronavirus (SARS-CoV-2) has becomes the biggest challenge that the world is facing today. It has been creating a devastating global crisis, causing countless deaths and great panic. The search for an effective treatment remains a global challenge owing to controversies on available vaccines. A huge research effort (clinical, experimental, and computational) has emerged in response to this pandemic, and more than 125000 research reports have been published in relation with COVID-19. The majority of them focused on the discovery of novel drug candidates or repurposing of existing drugs through computational approaches that significantly speed up drug discovery. Among the different used targets, the SARS-CoV-2 main protease (Mpro), which plays an essential role in coronavirus replication, has become the preferred target for computational studies. In this review, we examine a representative set of computational studies that uses the Mpro as target for the discovery of COVID-19 small molecules. They will be divided into two main groups, structure-based, and ligand-based methods, and each one will be subdivided according to the strategies used in the research. From our point of view, the use of combined strategies could enhance the possibilities of success in the future, permitting to develop more rigorous computational studies in future efforts to combat current and future pandemics.

Assessment of changes immune status linked to COVID-19 convalescent and its clinical severity in patients and uninfected exposed relatives. Torres Rives B, Zúñiga Rosales Y, Mataran Valdés M, Roblejo Balbuena H, Martínez Téllez G, Rodríguez Pérez J, et al. Immunobiology. 2022 May 12;227(3):152216. https://doi.org/10.1016/j.imbio.2022.152216

Introduction The immune response during and after SARS-CoV-2 infection can be complex and heterogeneous, and it can be affected by the severity of the disease. It can also contribute to an unfavorable evolution and bring about short and long term effects. The aim of this study was to characterize the lymphocyte composition according to the severity of COVID-19, as well as its degree of relationship to the specific humoral response to SARS-CoV-2 in convalescents up to 106 days after the infection and in their exposed relatives. Methods An applied research was carried out with a cross-section analytical design, from March 11 to June 11, 2020 in Cuba. The sample consisted of 251 convalescents from COVID-19 over 18 years of age and 88 exposed controls who did not become ill. The B and T cell subpopulations, including memory T cells, as well as the relationship with the humoral immune response against SARS-CoV-2, were identified by flow cytometry and enzyme immunoassay. Results Convalescent patients, who evolved with severe forms, showed a decrease in frequency and a greater proportion of individuals with values ​​lower than the minimum normal range of B cells, CD3 + CD4 + cells and the CD4 + / CD8 + ratio, as well as a higher frequency and a greater proportion of individuals with values ​​above the normal maximum range of CD3 + CD8 + and NK cells. Convalescent patients with severe forms of COVID-19 that exhibited IgG / RBD titers ≥ 1/200 had a lower frequency of TEMRA CD8 + cells (p = 0.0128) and TEMRA CD4 + (p = 0.0068). IgG / RBD titers were positively correlated with the relative frequency of CD4 + CM T memory cells (r = 0.4352, p = 0.0018). Conclusions The identified alterations of B and T lymphocytes suggest that convalescent patients with the severe disease could be vulnerable to infectious, autoimmune or autoinflammatory processes; therefore, these individuals need medical follow-up after recovering from the acute disease. Furthermore, the role of T cells CD4 + CM in the production of antibodies against SARS-CoV-2 is confirmed, and it is noted that the defect of memory T cells CD8 + TEMRA could contribute to the development of severe forms of COVID-19.

Association among Terminally Differentiated T Cells, Frailty, and Dependency in a Group of Cuban Centenarians. Añé-Kourí AL, Ledón N, Ramos MB, González A, Pereira K, Rodríguez M, et al. Gerontology. 2022 Jun 21;1–10. https://doi.org./10.1159/000525062. Online ahead of print.

Introduction Centenarians are considered a model of successful aging. Cuba exhibits one of the oldest populations in Latin America with more than two thousand centenarians. Methods This study aimed to evaluate the immune phenotype of forty-three Cuban centenarians, their clinical characteristics such as comorbidities, frailty, body mass index, and some hemochemical parameters. Results Centenarians had normal body mass indexes, relatively good health status, and 21.95% of them had no comorbidities; 53.6% were classified as frail, and 7% were classified as robust. In addition, 17% of centenarians were independent, and 41.46% were moderately dependent. The seroprevalence against cytomegalovirus was 100%. Concerning pro-inflammatory markers, the majority of them had very low cytokine levels and serum C-reactive protein around the normal limit. We also found the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells. Terminally differentiated CD8+CD28- T cells were higher in frail centenarians than in pre-frail, while CD8+CD57+ and CD8+EMRA T cells were higher in moderately and severely dependent individuals than in independent individuals. Severely dependent centenarians had a lower CD4+/CD8+ ratio. Conclusion This study describes for the first time the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells, as well as its relation to frailty and/or dependency in a group of Cuban centenarians. Further studies are needed to continue understanding the natural biological aging mechanism and the relationship between terminally differentiated lymphocytes and inflammaging in the context of extreme longevity.

Assortative mate preferences for height across short-term and long-term relationship contexts in a cross-cultural sample. Pisanski K, Fernández-Alonso M, Díaz-SimónN, Oleszkiewicz A, SardinasA, Pellegrino R. Front Psychol. 2022 Aug 25;13:937146. https://doi.org/10.3389/fpsyg.2022.937146. eCollection 2022.

Height preferences reflecting positive assortative mating for height-wherein an individual’s own height positively predicts the preferred height of their mate-have been observed in several distinct human populations and are thought to increase reproductive fitness. However, the extent to which assortative preferences for height differ strategically for short-term versus long-term relationship partners, as they do for numerous other indices of mate quality, remains unclear. We explore this possibility in a large representative sample of over 500 men and women aged 15-77 from Canada, Cuba, Norway and the United States. Participants’ own heights were measured, and they indicated their height preferences for a long-term and short-term mate using graphic stimuli containing metric indices. Replicating the “male-taller norm,” participants on average preferred taller-than-average male mates, and shorter-than-average female mates. Positive assortative preferences for height were observed across sexes and samples, however the strength of these height preferences varied with relationship context for men, and not for women. Taller men preferred relatively shorter women for short-term relationships than for long-term relationships, indicating stronger assortative preferences for height in a long-term context. These results provide preliminary evidence that, in addition to mate preferences for other physical traits related to mate quality such as masculinity in the body, face, and voice, assortative preferences for height do vary as a function of expected relationship length, but this was surprisingly only observed in preferences for female height.

Augmenting antibody response to EGF-depleting immunotherapy: Findings from a phase I trial of CIMAvax-EGF in combination with nivolumab in advanced stage NSCLC. Evans R, Lee K, Wallace PK, Reid M, Muhitch J, Dozier A, et al. Front Oncol. 2022 Aug 3;12:958043. https://doi.org/10.3389/fonc.2022.958043. eCollection 2022.

Background CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a “3+3” dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.

BDNF, proBDNF and IGF-1 serum levels in naïve and medicated subjects with autism. Robinson-Agramonte MA, Michalski B, Vidal-Martinez B, Ramos Hernández L, Whilby Santiesteban M, Margaret Fahnestock M. Sci Rep. 2022 Aug 12;12(1):13768. https://doi.org/10.1038/s41598-022-17503-6  

Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) promote the development and maintenance of neural circuits. Alterations in these factors might contribute to autism spectrum disorder (ASD). We asked whether serum BDNF, proBDNF, and IGF-1 levels are altered in an ASD population compared to controls. We measured serum BDNF, proBDNF, and IGF-1 immunoreactive protein in boys and girls aged 5-15 years old with mild to moderate ASD and non-autistic controls by ELISA. IGF-1 was increased in ASD serum compared to controls and was correlated with age and with CARS scores. Serum BDNF levels did not differ between groups, however, proBDNF serum levels were decreased in subjects with ASD compared to non-autistic controls. Medicated, but not unmedicated, ASD subjects exhibited lower serum proBDNF levels compared to controls, while neither IGF-1 nor BDNF levels differed between treatment groups. These data support the involvement of proBDNF and IGF-1 in the pathogenesis and treatment of autism.

Beneficial and harmful effects of monoclonal antibodies for the treatment and prophylaxis of COVID-19: a systematic review and meta-analysis of randomized controlled trials. Hernández AV, Piscoya A, Pasupuleti V, Phan MT, Julakanti S, Khen P, et al. Am J Med. 2022 Jul 22. https://doi.org/10.1016/j.amjmed.2022.06.019

Background We systematically assessed beneficial and harmful effects of monoclonal antibodies for COVID-19 treatment, and prophylaxis in exposed to SARS-CoV-2. Methods We searched five engines and three registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs. control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19 related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. GRADE methodology was used to assess certainty of evidence. Results Twenty-seven randomized controlled trials were included: 20 in hospitalized (n=8253), five in non-hospitalized (n=2922), and two in prophylaxis (n=2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74, 95%CI 0.60-0.9, I²=20%, low certainty of evidence) and bacteremia (RR 0.77, 95%CI 0.64-0.92, I²=7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31, 95%CI 1.02-1.67, I²=77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30, 95%CI 0.17-0.53, I²=0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47, 95%CI 0.22-1.01, I²=33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (Mean difference [MD] -0.8 log₁₀, 95%CI -1.21 to -0.39, moderate certainty of evidence). There were no effects on other outcomes. Conclusions Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data is needed to determine their efficacy and safety.

Causal effects of cingulate morphology on executive functions in healthy young adults. Razzaq FA, Bringas Vega ML, Ontiveiro-Ortega M, Riaz U, Pedro A Valdés-SosaPA. Hum Brain Mapp. 2022 Jun 6. https://doi.org/10.1002/hbm.25960. Online ahead of print

In this study, we want to explore evidence for the causal relationship between the anatomical descriptors of the cingulate cortex (surface area, mean curvature-corrected thickness, and volume) and the performance of cognitive tasks such as Card Sort, Flanker, List Sort used as instruments to measure the executive functions of flexibility, inhibitory control, and working memory. We have performed this analysis in a cross-sectional sample of 899 healthy young subjects of the Human Connectome Project. To the best of our knowledge, this is the first study using causal inference to explain the relationship between cingulate morphology and the performance of executive tasks in healthy subjects. We have tested the causal model under a counterfactual framework using stabilized inverse probability of treatment weighting and marginal structural models. The results showed that the posterior cingulate surface area has a positive causal effect on inhibition (Flanker task) and cognitive flexibility (Card Sort). A unit increase (+1 mm²) in the posterior cingulate surface area will cause a 0.008% and 0.009% increase from the National Institute of Health (NIH) normative mean in Flankers (p-value <0.001), and Card Sort (p-value 0.005), respectively. Furthermore, a unit increase (+1 mm² ) in the anterior cingulate surface area will cause a 0.004% (p-value <0.001) and 0.005% (p-value 0.001) increase from the NIH normative mean in Flankers and Card Sort. In contrast, the curvature-corrected-mean thickness only showed an association for anterior cingulate with List Sort (p = 0.034) but no causal effect.

Chemical Conjugation in Drug Delivery Systems. Eras A, Castillo D, Suárez M, Santiago Vispo N, Albericio F, Rodríguez H. Front Chem. 2022 May 26;10:889083. https://doi.org/10.3389/fchem.2022.889083. eCollection 2022.

Cancer is one of the diseases with the highest mortality rate. Treatments to mitigate cancer are usually so intense and invasive that they weaken the patient to cure as dangerous as the own disease. From some time ago until today, to reduce resistance generated by the constant administration of the drug and improve its pharmacokinetics, scientists have been developing drug delivery system (DDS) technology. DDS platforms aim to maximize the drugs’ effectiveness by directing them to reach the affected area by the disease and, therefore, reduce the potential side effects. Erythrocytes, antibodies, and nanoparticles have been used as carriers. Eleven antibody-drug conjugates (ADCs) involving covalent linkage has been commercialized as a promising cancer treatment in the last years. This review describes the general features and applications of DDS focused on the covalent conjugation system that binds the antibody carrier to the cytotoxic drug.

Chronic Oral Anticoagulation Therapy and Prognosis of Patients Admitted to Hospital for COVID-19: Insights from the HOPE COVID-19 Registry. Rivera-Caravaca JM, Núñez-Gil IJ, Lip GYH, Uribarri A, Viana-Llamas MC, González A, et al. Int J Clin Pract. 2022 May 26;2022:7325060. https://doi.org/10.1155/2022/7325060. eCollection 2022.

Background Most evidence regarding anticoagulation and COVID-19 refers to the hospitalization setting, but the role of oral anticoagulation (OAC) before hospital admission has not been well explored. We compared clinical outcomes and short-term prognosis between patients with and without prior OAC therapy who were hospitalized for COVID-19. Methods Analysis of the whole cohort of the HOPE COVID-19 Registry which included patients discharged (deceased or alive) after hospital admission for COVID-19 in 9 countries. All-cause mortality was the primary endpoint. Study outcomes were compared after adjusting variables using propensity score matching (PSM) analyses. Results 7698 patients were suitable for the present analysis (675 (8.8%) on OAC at admission: 427 (5.6%) on VKAs and 248 (3.2%) on DOACs). After PSM, 1276 patients were analyzed (638 with OAC; 638 without OAC), without significant differences regarding the risk of thromboembolic events (OR 1.11, 95% CI 0.59-2.08). The risk of clinically relevant bleeding (OR 3.04, 95% CI 1.92-4.83), as well as the risk of mortality (HR 1.22, 95% CI 1.01-1.47; log-rank p value = 0.041), was significantly increased in previous OAC users. Amongst patients on prior OAC only, there were no differences in the risk of clinically relevant bleeding, thromboembolic events, or mortality when comparing previous VKA or DOAC users, after PSM. Conclusion Hospitalized COVID-19 patients on prior OAC therapy had a higher risk of mortality and worse clinical outcomes compared to patients without prior OAC therapy, even after adjusting for comorbidities using a PSM. There were no differences in clinical outcomes in patients previously taking VKAs or DOACs. This trial is registered with NCT04334291/EUPAS34399.

CIGB-300 Peptide Targets the CK2 Phospho-Acceptor Domain on Human Papillomavirus E7 and Disrupts the Retinoblastoma (RB) Complex in Cervical Cancer Cells.Ramón AC, Basukala O, Massimi P, Thomas M, Perera Y, Banks L, et al. Viruses. 2022 Jul 30;14(8):1681. https://doi.org/10.3390/v14081681

CIGB-300 is a clinical-grade anti-Protein Kinase CK2 peptide, binding both its substrate’s phospho-acceptor site and the CK2α catalytic subunit. The cyclic p15 inhibitory domain of CIGB-300 was initially selected in a phage display library screen for its ability to bind the CK2 phospho-acceptor domain ofHPV-16 E7. However, the actual role of this targeting in CIGB-300 antitumoral mechanism remains unexplored. Here, we investigated the physical interaction of CIGB-300 with HPV-E7 and its impact on CK2-mediated phosphorylation. Hence, we studied the relevance of targeting E7 phosphorylation for the cytotoxic effect induced by CIGB-300. Finally, co-immunoprecipitation experiments followed by western blotting were performed to study the impact of the peptide on the E7-pRB interaction. Interestingly, we found a clear binding of CIGB-300 to the N terminal region of E7 proteins of the HPV-16 type. Accordingly, the in vivo physical interaction of the peptide with HPV-16 E7 reduced CK2-mediated phosphorylation of E7, as well as its binding to the tumor suppressor pRB. However, the targeting of E7 phosphorylation by CIGB-300 seemed to be dispensable for the induction of cell death in HPV-18 cervical cancer-derived C4-1 cells. These findings unveil novel molecular clues to the means by which CIGB-300 triggers cell death in cervical cancer cells.

Clinical Phenotypes and Mortality Biomarkers: A Study Focused on COVID-19 Patients with Neurological Diseases in Intensive Care Units. Morales Chacón LM, Galán García L, Cruz Hernández TM, Pavón Fuentes N, Maragoto Rizo C, Morales Suárez I, et al. Behav Sci (Basel). 2022 Jul;12(7):234. https://doi.org/10.3390/bs12070234. Published online 2022 Jul 15

Purpose To identify clinical phenotypes and biomarkers for best mortality prediction considering age, symptoms and comorbidities in COVID-19 patients with chronic neurological diseases in intensive care units (ICUs). Subjects and Methods Data included 1252 COVID-19 patients admitted to ICUs in Cuba between January and August 2021. A k-means algorithm based on unsupervised learning was used to identify clinical patterns related to symptoms, comorbidities and age. The Stable Sparse Classifiers procedure (SSC) was employed for predicting mortality. The classification performance was assessed using the area under the receiver operating curve (AUC). Results Six phenotypes using a modified v-fold cross validation for the k-means algorithm were identified: phenotype class 1, mean age 72.3 years (ys)—hypertension and coronary artery disease, alongside typical COVID-19 symptoms; class 2, mean age 63 ys—asthma, cough and fever; class 3, mean age 74.5 ys—hypertension, diabetes and cough; class 4, mean age 67.8 ys—hypertension and no symptoms; class 5, mean age 53 ys—cough and no comorbidities; class 6, mean age 60 ys—without symptoms or comorbidities. The chronic neurological disease (CND) percentage was distributed in the six phenotypes, predominantly in phenotypes of classes 3 (24.72%) and 4 (35,39%); χ² (5) 11.0129 p = 0.051134. The cerebrovascular disease was concentrated in classes 3 and 4; χ² (5) = 36.63, p = 0.000001. The mortality rate totaled 325 (25.79%), of which 56 (17.23%) had chronic neurological diseases. The highest in-hospital mortality rates were found in phenotypes 1 (37.22%) and 3 (33.98%). The SSC revealed that a neurological symptom (ageusia), together with two neurological diseases (cerebrovascular disease and Parkinson’s disease), and in addition to ICU days, age and specific symptoms (fever, cough, dyspnea and chilliness) as well as particular comorbidities (hypertension, diabetes and asthma) indicated the best prediction performance (AUC = 0.67). Conclusions The identification of clinical phenotypes and mortality biomarkers using practical variables and robust statistical methodologies make several noteworthy contributions to basic and experimental investigations for distinguishing the COVID-19 clinical spectrum and predicting mortality.

Common ictal and interictal perfusion patterns. A window into the epileptogenic network and SUDEP mechanism in Drug Resistant Focal Epilepsy Morales Chacón LM, Galán García L, García-Ramón KB, Báez Martin MM, Bosch Bayard J, Alfonso Alfonso M, et al. Curr Pharm Des. 2022 Jun 3. https://doi.org/10.2174/1381612828666220603125328. Online ahead of print.

Background Focal epilepsies have been described as network disease. Noninvasive investigative techniques have been used to characterize epileptogenic networks. Objetive To describe ictal and interictal cortical and subcortical perfusion patterns using single photon emission computed tomography (SPECT), in patients with drug-resistant epilepsy (DRE). Methods Thirty-five interictal- ictal SPECT scans were obtained from 15 patients with DRE. A methodology was developed to get a relative perfusion index (PI) of 74 cortical and sub-cortical brain structures. K-means algorithm together with a modified v-fold cross-validation were used to identify the two regions of interest (ROI’s) that represent hypoperfused and hyperperfused areas. Results In common with the individual analysis, the statistical analysis evidenced that the hyperperfusion ROIs resulting from group analysis during interictal, and ictal involved mainly the cingulate gyrus, cuneus, the lingual gyrus, gyrus rectus as well as the putamen. ROIs hypoperfused included the red nucleus, the substantia nigra, and the medulla. The medians of the group analysis of the hypoperfusion and hyperperfusion ROIs were 0.601-0.565 and 1,133 – 1,119 for the ictal and interictal states, correspondingly. A group of mostly cortical structures involved in the hyperperfused ROIs in both interictal and ictal states showed no change or negative change in the transition from interictal to ictal state (mean change of -0.002). On the other hand, the brain stem, basal ganglia, red nucleus, and thalamus revealed a mean global change of 0.19, indicating a mild increase in the PI. However, some of these structures (red nucleus, substantia nigra, and medulla oblongata) remained hypoperfused during the interictal to ictal transition. Conclusion The methodology employed made it possible to identify common cortical and subcortical perfusion patterns not directly linked to epileptogenicity, but open a window for the epileptogenic network and sudden unexpected death (SUDEP) mechanism in DRE .

Control of allergic rhinitis in four latin american countries: Rinola study. Silva DL, de Barayazarra S, Valero A, García E, Uriarte S, Peñaranda A, et al. Front Allergy. 2022 Aug 24;3:980515. https://doi.org/10.3389/falgy.2022.980515. eCollection 2022.

Background Allergic rhinitis (AR) affects up to 40% of the general population, there are large-scale multicenter studies that have described its characteristics and few studies have focused on studying patients with AR in Latin America (LA). Methodology A cross-sectional, descriptive, multicenter study was carried out in four LA countries (Colombia, Argentina, Cuba and Peru). Patients diagnosed with AR between November 2017 and June 2020 were included. Sociodemographic and clinical data, sensitization profile and current treatment were collected in the Electronic Data Collection (BDClinic). Patients also filled out this questionnaires: Rhinitis Control Assessment Test (RCAT), Reflexive Total Nasal Symptom Score (rTNSS), Modified ARIA Criteria for AR Severity (mARIA) and ESPRINT-15. Risk of bias was examined by applying the STROBE checklist. Results The study included 412 patients. Median age was 25 years (15-39). Two hundred and twenty four (54.3%) were women. Nasal obstruction was present in 303 (73.5%). Three hundred and thirty four (81%) had a persistent AR. One hundred and twenty one (31.3%) had associated asthma. The most frequently positive skin tests were: Dermatophagoides pteronyssinus in 365 (88.6%) and Dermatophagoides farinae in 331 (81.3%). Four hundred and eleven patients (99%) reported that AR affected their quality of life. The median score of ESPRINT-15 was 1.87 (0.93-2.93), The mean values of RCAT and rTNSS were 19.01 (±4.59) and 5.4 (±2.97) respectively. Two hundred and fifty (60%) were receiving only oral antihistamines. Physicians decided to start nasal corticosteroids in 296 (71.8%). Only seventy patients (16.9%) were receiving immunotherapy. Conclusion These findings confirm that most of patients with AR in LA have a persistent disease with a negative impact on quality of life. Dust mites are the main sensitizers. These findings will allow to know the true impact of AR and can lead to a better disease management.

Dexamethasone: Insights into Pharmacological Aspects, Therapeutic Mechanisms, and Delivery Systems. Sagar Madamsetty V, Mohammadinejad R, Uzieliene I, Nabavi N, Dehshahri A, García-Couce J, et al. ACS Biomater Sci Eng. 2022 Apr 19;acsbiomaterials.2c00026. https://doi.org//10.1021/acsbiomaterials.2c00026. Online ahead of print.

Dexamethasone (DEX) has been widely used to treat a variety of diseases, including autoimmune diseases, allergies, ocular disorders, cancer, and, more recently, COVID-19. However, DEX usage is often restricted in the clinic due to its poor water solubility. When administered through a systemic route, it can elicit severe side effects, such as hypertension, peptic ulcers, hyperglycemia, and hydro-electrolytic disorders. There is currently much interest in developing efficient DEX-loaded nanoformulations that ameliorate adverse disease effects inhibiting advancements in scientific research. Various nanoparticles have been developed to selectively deliver drugs without destroying healthy cells or organs in recent years. In the present review, we have summarized some of the most attractive applications of DEX-loaded delivery systems, including liposomes, polymers, hydrogels, nanofibers, silica, calcium phosphate, and hydroxyapatite. This review provides our readers with a broad spectrum of nanomedicine approaches to deliver DEX safely.

Domain-level epitope mapping of polyclonal antibodies against HER-1 and HER-2 receptors using phage display technology. Pérez-Martínez D, Cabrera Infante Y, Sánchez Ramírez B, Rojas G. Sci Rep. 2022;12:12268. https://doi.org/10.1038/s41598-022-16411-z. Published online 2022 Jul 18

HER-1 and HER-2 are tumor-associated antigens overexpressed in several epithelial tumors, and successfully targeted by therapeutic approaches against cancer. Vaccination with their recombinant extracellular domains has had encouraging results in the pre-clinical setting. As complex humoral responses targeting multiple epitopes within each antigen are the ultimate goal of such active immunotherapy strategies, molecular dissection of the mixture of antibody specificities is required. The current work exploits phage display of antigenic versions of HER-1 and HER-2 domains to accomplish domain-level epitope mapping. Recognition of domains I, III and IV of both antigens by antibodies of immunized mice was shown, indicating diverse responses covering a broad range of antigenic regions. The combination of phage display and site-directed mutagenesis allowed mutational screening of antigen surface, showing polyclonal antibodies’ recognition of mutated receptor escape variants known to arise in patients under the selective pressure of the anti-HER-1 antibody cetuximab. Phage-displayed HER domains have thus the potential to contribute to fine specificity characterization of humoral responses during future development of anti-cancer vaccines.

Drivers and scorecards to improve hypertension control in primary care practice: Recommendations from the HEARTS in the Americas Innovation Group. Brettler JW, Giraldo Arcila GP, Aumala T, Best A, Campbell NR, Cyr S, et al. Lancet Reg Health Am. 2022 May;9:None. https://doi.org/10.1016/j.lana.2022.100223

Background Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Americas, and hypertension is the most significant modifiable risk factor. However, hypertension control rates remain low, and CVD mortality is stagnant or rising after decades of continuing reduction. In 2016, the World Health Organization (WHO) launched the HEARTS technical package to improve hypertension control. The Pan American Health Organization (PAHO) designed the HEARTS in the Americas Initiative to improve CVD risk management, emphasizing hypertension control, to date implemented in 21 countries. Methods To advance implementation, an interdisciplinary group of practitioners was engaged to select the key evidence-based drivers of hypertension control and to design a comprehensive scorecard to monitor their implementation at primary care health facilities (PHC). The group studied high-performing health systems that achieve high hypertension control through quality improvement programs focusing on specific process measures, with regular feedback to providers at health facilities. Findings The final selected eight drivers were categorized into five main domains: (1) diagnosis (blood pressure measurement accuracy and CVD risk evaluation); (2) treatment (standardized treatment protocol and treatment intensification); (3) continuity of care and follow-up; (4) delivery system (team-based care, medication refill), and (5) system for performance evaluation. The drivers and recommendations were then translated into process measures, resulting in two interconnected scorecards integrated into the HEARTS in the Americas monitoring and evaluation system. Interpretation Focus on these key hypertension drivers and resulting scorecards, will guide the quality improvement process to achieve population control goals at the participating health centers in HEARTS implementing countries.

Educational needs in patients with knee osteoarthritis using the SpENAT questionnaire. Martínez-Gonzáles PL, Chico Capote A, Estévez Del Toro M, Hidalgo Costa T. Reumatol Clin (Engl Ed). 2022 Apr 25;S2173-5743(22)00064-8. https://doi.org//10.1016/j.reumae.2021.09.005 Online ahead of print.

Introduction Knee osteoarthritis (KOA) is a major public health issue because it causes pain and functional limitation in patients. Engagement with self-management may, however, minimize the impact of KOA on the health of patients suffering this illness. To be fully engaged with self-management activities, knowledge about KOA is a prerequisite. There is data on people’s understanding of KOA and their needs for information about KOA. The Educational Needs Assessment Tool-Spanish version (SpENAT) is a self-reported questionnaire that assesses educational needs (Ned) in order to provide information adapted and focused on patients with knee KOA. It comprises 39 questions grouped into seven domains: Pain, Movement, Feelings, Osteoarthritis, Medical treatment, Non-medical treatment, Help. Objectives To estimate the Ned in patients with knee KOA using the SpENAT. Material and method An observational, descriptive, and cross-sectional study was carried out in 215 patients with a diagnosis of knee KOA according to the criteria of the American College of Rheumatology who attended the service’s protocolized consultation of knee conditions of rheumatology at the “Hermanos Ameijeiras” Surgical Clinical Hospital during the study period between January 2017 and August 2020. Demographic data, educational level and characteristics of the disease were recorded. All patients completed the SpENAT and were questioned about the sources they turn to obtain information on their disease. Results Women over 50 years of age and overweight with a diagnosis of OA predominated. Major Ned were observed in the domains of movement, help, pain, feeling, KOA. Patients over 50 years of age, female, normal weight, and active workers showed greater interest in the movement domain. The most used source of information was the rheumatologist (91.60%). Conclusion The Ned in patients with knee KOA are high, and are higher in the domains of movement, pain, help and feeling. The rheumatologist is the main source of information for patients with KOA, it seems wise to design a targeted strategy to educate people about KOA to provide, support and prepare them for self-management.

Effect of Exercise on Inflammation in Hemodialysis Patients: A Systematic Review. Meléndez Oliva E, Villafañe JH, Alonso Pérez JL, Alonso Sal A, Molinero Carlier G, Quevedo García A, et al. J Pers Med. 2022 Jul;12(7):1188. https://doi.org/10.3390/jpm12071188 Published online 2022 Jul 21.

Background In recent years, physical exercise has been investigated for its potential as a therapeutic tool in patients with end-stage renal disease (ESRD) undergoing hemodialysis maintenance treatment (HD). It has been shown that regular practice of moderate-intensity exercise can improve certain aspects of immune function and exert anti-inflammatory effects, having been associated with low levels of pro-inflammatory cytokines and high levels of anti-inflammatory cytokines. Purpose The aim of this review is to examine the studies carried out in this population that analyzed the effect of intradialytic exercise on the inflammatory state and evaluate which exercise modality is most effective. Methods The search was carried out in the MEDLINE, CINAHL Web of Science and Cochrane Central Register of Controlled Trials databases from inception to June 2022. The PEDro scale was used to assess methodological quality, and the Cochrane Risk of Bias Tool and MINORS were used to evaluate the risk of bias. The quality of evidence was assessed with GRADE scale. The outcome measures were systemic inflammation biomarkers. Results Mixed results were found in terms of improving inflammation biomarkers, such as CRP, IL-6 or TNFα, after exercise. Aerobic exercise seems to improve systemic inflammation when performed at medium intensity while resistance training produced better outcomes when performed at high intensity. However, some studies reported no differences after exercise and these results should be taken with caution. Conclusions The low quality of the evidence suggests that aerobic and resistance exercise during HD treatment improves systemic inflammation biomarkers in patients with ESRD. In any case, interventions that increase physical activity in patients with ESRD are of vital importance as sedentary behaviors are associated with mortality. More studies are needed to affirm solid conclusions and to make intervention parameters, such as modality, dose, intensity or duration, sufficiently clear

Efficacy and harms of tocilizumab for the treatment of COVID-19 patients: A systematic review and meta-analysis. Piscoya A, Parra Del Riego A, Cerna-Viacava R, Rocco J, Roman YM, Escobedo AA, et al. PLoS One . 2022 Jun 3;17(6):e0269368. https://doi.org/10.1371/journal.pone.0269368. eCollection 2022.

Introduction We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients. Methods Five electronic databases and two preprint webpages were searched until March 4, 2021. Randomized controlled trials (RCTs) and inverse probability treatment weighting (IPTW) cohorts assessing TCZ effects in hospitalized, COVID-19 adult patients were included. Primary outcomes were all-cause mortality, clinical worsening, clinical improvement, need for mechanical ventilation, and adverse events (AE). Inverse variance random-effects meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. Results Nine RCTs (n = 7,021) and nine IPTW cohorts (n = 7,796) were included. TCZ significantly reduced all-cause mortality in RCTs (RR 0.89, 95%CI 0.81-0.98, p = 0.03; moderate QoE) and non-significantly in cohorts (RR 0.67, 95%CI 0.44-1.02, p = 0.08; very low QoE) vs. control (standard of care [SOC] or placebo). TCZ significantly reduced the need for mechanical ventilation (RR 0.80, 95%CI 0.71-0.90, p = 0.001; moderate QoE) and length of stay (MD -1.92 days, 95%CI -3.46 to -0.38, p = 0.01; low QoE) vs. control in RCTs. There was no significant difference in clinical improvement or worsening between treatments. AEs, severe AEs, bleeding and thrombotic events were similar between arms in RCTs, but there was higher neutropenia risk with TCZ (very low QoE). Subgroup analyses by disease severity or risk of bias (RoB) were consistent with main analyses. Quality of evidence was moderate to very low in both RCTs and cohorts. Conclusions In comparison to SOC or placebo, TCZ reduced all-cause mortality in all studies and reduced mechanical ventilation and length of stay in RCTs in hospitalized COVID-19 patients. Other clinical outcomes were not significantly impacted. TCZ did not have effect on AEs, except a significant increased neutropenia risk in RCTs. TCZ has a potential role in the treatment of hospitalized COVID-19 patients.

Emerging Computational Approaches for Antimicrobial Peptide Discovery. Agüero-Chapin G, Galpert-Cañizares D, Domínguez-Pérez D, Marrero-Ponce Y,  Pérez-Machado G, Teijeira M, et al. Antibiotics (Basel). 2022 Jul;11(7):936. https://doi.org/10.3390/antibiotics11070936. Published online 2022 Jul 13.

In the last two decades many reports have addressed the application of artificial intelligence (AI) in the search and design of antimicrobial peptides (AMPs). AI has been represented by machine learning (ML) algorithms that use sequence-based features for the discovery of new peptidic scaffolds with promising biological activity. From AI perspective, evolutionary algorithms have been also applied to the rational generation of peptide libraries aimed at the optimization/design of AMPs. However, the literature has scarcely dedicated to other emerging non-conventional in silico approaches for the search/design of such bioactive peptides. Thus, the first motivation here is to bring up some non-standard peptide features that have been used to build classical ML predictive models. Secondly, it is valuable to highlight emerging ML algorithms and alternative computational tools to predict/design AMPs as well as to explore their chemical space. Another point worthy of mention is the recent application of evolutionary algorithms that actually simulate sequence evolution to both the generation of diversity-oriented peptide libraries and the optimization of hit peptides. Last but not least, included here some new considerations in proteogenomic analyses currently incorporated into the computational workflow for unravelling AMPs in natural sources.

Hepatitis E virus in Cuba: A cross-sectional serological and virological study in pigs and people occupationally exposed to pigs. Montalvo Villalba MC, Snoeck CJ, LLA Rodríguez Lay, Sausy A, Hernández López D, Bello Corredor M, et al. Zoonoses Public Health. 2022 Sep 16. https://doi.org/10.1111/zph.13000. Online ahead of print.

Surveillance of hepatitis E virus (HEV) in risk groups is an important strategy to monitor its circulation pattern and to timely detect changes thereof. The aims of this cross-sectional study were to estimate the prevalence of HEV infections in pigs and humans from different regions of the country, to identify risk factors for increasing anti-HEV IgG prevalence and to characterize HEV strains. The presence of anti-HEV antibodies was assessed by commercial ELISA in serum samples from the general population, farm and slaughterhouse employees, as well as pigs sampled in the three regions of Cuba from February to September 2016. Overall, individuals with occupational exposure to swine or swine products (70/248, 28.2%) were 4 times more likely to be seropositive compared to the general population (25/285, 8.7%; OR: 4.18; p < .001). Within the risk group, risk factors included age, number of years working in a professional activity with direct exposure to swine, geographic region and distance between residence and closest professional swine setting, while wearing gloves had a protective effect. Prevalence of total anti-HEV antibodies in swine was 88.2% (165/187) and HEV RNA was detected by real-time RT-PCR in 9.2% (16/173) swine stools. All HEV strains sequenced clustered within genotype 3. Some strains clearly belonged to subtype 3a, while another group of strains was related with subtypes 3b and 3 k but partial HEV sequences did not allow unequivocal subtype assignment. These findings suggest that the high HEV exposure in Cuban individuals with swine-related occupations could be due to enzootic HEV in certain regions, direct contact with infectious animals or their products as well as environmental contamination.

Immune, inflammatory and prothrombotic parameters in COVID-19 patients treated with an anti EGFR antibody. Saavedra D, Añé-Kourí AL, Llanez Gregorich EM, Mena J, Lorenzo-Luaces P, Diaz Londres H, et al. Immunol Lett. 2022 Sep 26;S0165-2478(22)00130-4. https://doi.org/10.1016/j.imlet.2022.09.005. Online ahead of print.

SARS-CoV-2 infection causes a range of clinical presentations and induces changes in both innate and adaptive branches of the immune system. Furthermore, direct viral action to the cells of the lung promotes over-expression of the epidermal growth factor receptor (EGFR) which triggers pro-inflammatory response, contributes to coagulopathy and intravascular thrombi as well as lung fibrosis. Based on the role of this signaling pathway in the pathophysiology of the disease, nimotuzumab, an anti-EGFR monoclonal antibody, was used to treat patients with COVID-19. The aim of this study was to determine IL-6 and PAI-1 concentrations and lymphocyte subpopulations profiles in moderately and severely ill COVID-19 patients diagnosed during the B.1.617.2 variant wave in Cuba and included in a phase I/II trial to evaluate the safety and preliminary effect of nimotuzumab in COVID-19 disease. We observed high serum levels of IL-6, elevated plasma concentration of PAI-1, mean values of neutrophils to lymphocytes ratio (NLR) above three and CD4+ lymphopenia in both groups of patients. PAI-1 and IL-6 circulating levels decreased in patients treated with nimotuzumab. More than 95% of patients in which IL-6 decreased or increased slightly, were alive within 14 days after the monoclonal antibody administration. Patients with moderate and severe disease, were no different regarding the studied parameters, addressing the idea that several immune alterations could be present before the infection becomes clinically relevant. These findings suggest that nimotuzumab could be an attractive therapeutic option to interfere with the negative relationship between cytokines and procoagulant mediators in the inflammatory and prothrombotic phases of the disease.

Lessons from Building a Sustainable Healthcare Exchange between the Netherlands and Cuba. Jonas P, Garbey Savigne E, Koster M, Choonara I. Int J Environ Res Public Health. 2022 Sep 17;19(18):11742. https://doi.org/10.3390/ijerph191811742

Over the past ten years, seven Dutch Universities have built a sustainable exchange with seven institutes in Cuban healthcare. The exchange was initiated by the Leiden University Medical Centre and the University of Medical Sciences of Havana. Cooperation with Cuba was chosen as Cuba has excellent primary healthcare and has a strong focus on prevention and public health. These were considered important due to the major contribution of non-communicable diseases to morbidity and mortality in the Netherlands. Exchanges have occurred with Dutch health professionals and students visiting Cuban healthcare institutions and Cuban postgraduate students studying in the Netherlands. There has been an increased awareness of the importance of public health and prevention in Dutch professional organizations following the exchange. The exchange has also helped to break the scientific and economic US blockade of Cuba and resulted in joint publications. In this review we described the process, key aspects, results and lessons learned in this process. Collaboration between Cuba (a middle income) and the Netherlands (a high-income country) is possible.

Machine Learning Techniques for the Diagnosis of Schizophrenia Based on Event-Related Potentials. Santos Febles E,Ontivero Ortega M,Valdés Sosa M, Sahli H. Front Neuroinform. 2022;16:893788. https://doi.org/10.3389/fninf.2022.893788. Published online 2022 Jul 8.

Antecedent The event-related potential (ERP) components P300 and mismatch negativity (MMN) have been linked to cognitive deficits in patients with schizophrenia. The diagnosis of schizophrenia could be improved by applying machine learning procedures to these objective neurophysiological biomarkers. Several studies have attempted to achieve this goal, but no study has examined Multiple Kernel Learning (MKL) classifiers. This algorithm finds optimally a combination of kernel functions, integrating them in a meaningful manner, and thus could improve diagnosis. Objective This study aimed to examine the efficacy of the MKL classifier and the Boruta feature selection method for schizophrenia patients (SZ) and healthy controls (HC) single-subject classification. Methods A cohort of 54 SZ and 54 HC participants were studied. Three sets of features related to ERP signals were calculated as follows: peak related features, peak to peak related features, and signal related features. The Boruta algorithm was used to evaluate the impact of feature selection on classification performance. An MKL algorithm was applied to address schizophrenia detection. Results A classification accuracy of 83% using the whole dataset, and 86% after applying Boruta feature selection was obtained. The variables that contributed most to the classification were mainly related to the latency and amplitude of the auditory P300 paradigm. Conclusion This study showed that MKL can be useful in distinguishing between schizophrenic patients and controls when using ERP measures. Moreover, the use of the Boruta algorithm provides an improvement in classification accuracy and computational cost.

Mirror neurons and empathy-related regions in psychopathy: systematic review, meta-analysis, and a working model. Penagos-Corzo JC, Cosio van-Hasselt M, Escobar D, Vázquez-Roque RA, Flores G. Soc Neurosci. 2022 Sep 24. https://doi.org/10.1080/17470919.2022.2128868. Online ahead of print.

Mirror neurons have been associated with empathy. People with psychopathic traits present low levels of empathy. To analyze this, a systematic review of fMRI studies of people with psychopathic traits during an emotional facial expression processing task was performed. The regions of interest were structures associated with the mirror neuron system: ventromedial prefrontal cortex (vmPFC), inferior parietal lobe (IPL), inferior frontal gyrus and superior temporal sulcus. The analysis was also extended to structures related to affective empathy (insula, amygdala and anterior cingulate cortex) and to two more emotional processing areas (orbitofrontal cortex and fusiform gyrus). Hypoactivation was more frequently observed in regions of the mirror neuron system from people with high psychopathic traits, as well as in the emotional processing structures, and those associated with affective empathy, except for the insula, where it presented higher activity. Differences were observed for all types of emotions. The results suggest that the mirror neuron system is altered in psychopathy and their relationship with affective empathy deficits is discussed.

Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator. Oliver L, Álvarez R, Díaz R, Valdés A, Colligan SH, Nemeth MJ, et al. J Immunother Cancer. 2022 Sep;10(9):e004710. https://doi.org/10.1136/jitc-2022-00471

Background Immune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function. We previously showed that a novel immune modulator, termed ‘very small size particle’ (VSSP), attenuates MDSC function in tumor-bearing mice, which was accompanied by an increase in dendritic cells (DCs) suggesting that VSSP exhibits myeloid differentiating properties. Therefore, here, we addressed two unresolved aspects of the mechanism of action of this unique immunomodulatory agent: (1) does VSSP alter myelopoiesis in the bone marrow to redirect MDSC differentiation toward a monocyte/macrophage or DC fate? and (2) does VSSP mitigate the frequency and suppressive function of human tumor-induced MDSCs? Methods To address the first question, we first used a murine model of granulocyte-colony stimulating factor-driven emergency myelopoiesis following chemotherapy-induced myeloablation, which skews myeloid output toward MDSCs, especially the polymorphonuclear (PMN)-MDSC subset. Following VSSP treatment, progenitors and their myeloid progeny were analyzed by immunophenotyping and MDSC function was evaluated by suppression assays. To strengthen rigor, we validated our findings in tumor-bearing mouse models. To address the second question, we conducted a clinical trial in patients with metastatic renal cell carcinoma, wherein 15 patients were treated with VSSP. Endpoints in this study included safety and impact on PMN-MDSC frequency and function. Results We demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and DCs with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1. This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive. Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs, and their suppressive function. Conclusions Altogether, these data revealed VSSP as a novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression.

Monitoring and evaluation platform for HEARTS in the Americas: improving population-based hypertension control programs in primary health care. Prado P, Angelo Gamarra A, Rodriguez L, Brettler J, Farrell M, Girola ME, et al. Rev Panam Salud Publica. 2022 Sep 16;46:e161. https://doi.org/10.26633/RPSP.2022.161. eCollection 2022.

HEARTS in the Americas is the Pan American Health Organization flagship program to accelerate the reduction of the cardiovascular disease (CVD) burden by improving hypertension control and CVD secondary prevention in primary health care. A monitoring and evaluation (M&E) platform is needed for program implementation, benchmarking, and informing policy-makers. This paper describes the conceptual bases of the HEARTS M&E platform including software design principles, contextualization of data collection modules, data structure, reporting, and visualization. The District Health Information Software 2 (DHIS2) web-based platform was chosen to implement aggregate data entry of CVD outcome, process, and structural risk factor indicators. In addition, PowerBI was chosen for data visualization and dashboarding for the analysis of performance and trends above the health care facility level. The development of this new information platform was focused on primary health care facility data entry, timely data reporting, visualizations, and ultimately active use of data to drive decision-making for equitable program implementation and improved quality of care. Additionally, lessons learnt and programmatic considerations were assessed through the experience of the M&E software development. Building political will and support is essential to developing and deploying a flexible platform in multiple countries which is contextually specific to the needs of various stakeholders and levels of the health care system. The HEARTS M&E platform supports program implementation and reveals structural and managerial limitations and care gaps. The HEARTS M&E platform will be central to monitoring and driving further population-level improvements in CVD and other noncommunicable disease-related health.

Multicenter Study of Carbapenemase-Producing Enterobacterales in Havana, Cuba, 2016-2021. Yu H, González Molina MK, Carmona Cartaya Y, Hart Casares M, Soe Aung M, Kobayashi N. Antibiotics (Basel). 2022 Apr 12;11(4):514. https://doi.org/10.3390/antibiotics11040514

Surveillance of carbapenem resistance is particularly important for Enterobacterales, mainly in countries with limited healthcare resources. We conducted a cross-sectional study to detect carbapenem-resistant Enterobacterales at 10 sentinel hospitals in Havana, Cuba for a six year-period (2016-2021) by the National Reference Laboratory for Health Care-Associated Infections in the Pedro Kourí Institute. A total of 152 isolates were collected with phenotypic production of metallo-β-lactamase. NDM-type carbapenemase was detected in all the 152 isolates, and KPC-type enzyme gene was simultaneously identified in four NDM-positive isolates. The most abundant carbapenemase-producing Enterobacterales (CPE) species was Klebsiella pneumoniae (69.7%), followed by Enterobacter cloacae complex (13.2%), and Escherichia coli (5.9%). Over the study period, among CPE, prevalence of K. pneumoniae was almost constant, while Enterobacter spp. showed slightly increasing tendency. The urinary tract (36.2%) was the most prevalent source of infection with CPE, followed by bloodstream (26.3%) and surgical wound (17.1%), being frequently derived from Intensive Care Units (35.5%) and urology wards (21.7%). This study revealed the present situation of CPE in hospitals in Havana, Cuba, showing the emergence and dissemination of Enterobacterales producing NDM-type carbapenemase, mainly K. pneumoniae.

Network analysis of the relationships between conspiracy beliefs towards COVID-19 vaccine and symptoms of fear of COVID-19 in a sample of Latin American countries. Caycho-Rodríguez T, Ventura-León J, Valencia PD, Vilca LW, Carbajal-León C, Reyes-Bossio M, et al. Curr Psychol. 2022 Sep 7;1-16. https://doi.org/10.1007/s12144-022-03622-w. Online ahead of print.

The present study examined how conspiracy beliefs about COVID-19 vaccines specifically relate to symptoms of fear of COVID-19 in a sample of four South American countries. A total of 1785 people from Bolivia, Colombia, Ecuador, and Peru participated, responding to a sociodemographic survey, the Fear of COVID-19 scale (FCV-19 S) and the Vaccine Conspiracy Beliefs Scale-COVID-19 (VCBS-COVID-19). Network analysis identified the most important symptoms of fear and conspiracy beliefs about COVID-19 vaccines (nodes) and the associations between them (edges). In addition, the robustness of the network of these indicators of centrality and the possible differences in the structure and connectivity of the networks between the four countries were evaluated. The results suggest that the nodes with the highest centrality were items 2 and 5 of the FCV-19 S and item 2 of the VCBS-COVID-19. Likewise, item 6 is the belief that most predicts conspiracy beliefs about vaccines against COVID-19; while item 6 was the symptom that most predicts fear of COVID-19. The findings strongly support cross-cultural similarities in the networks across the four countries rather than differences. Although it was expected that a higher presence of symptoms of fear of COVID-19 may lead people to compensate for their fear by believing in conspiratorial ideas about vaccines and, consequently, rejecting the COVID-19 vaccine, the results do not clearly show this relationship. This could lead other researchers to generate evidence to explain the differences between Latin American countries and countries in other contexts in terms of vaccination rates. This evidence could be useful to develop policies favoring vaccination against COVID-19 that are more contextualized to the Latin American region, characterized by social instability and economic recession during the pandemic.

Nimotuzumab in the Treatment of Inoperable Esophageal Tumors of Epithelial Origin. González Fernández S, Amador García Y, Boris Porras LG, Mojena Martínez L, Soler Porro LL, Pish Martí G, et al. J Oncol. 2022 Sep 1;2022:4128946. https://doi.org/10.1155/2022/4128946. eCollection 2022.

Background Nimotuzumab is a humanized monoclonal antibody that targets the epidermal growth factor receptor. It was approved in Cuba for the indication of inoperable malignant tumors of the esophagus of epithelial origin. The purpose of this study was to evaluate the safety, overall and progression-free survival, clinical response, and quality of life, in adult patients with inoperable esophageal tumors of epithelial origin treated with nimotuzumab in a practical context. Material and Methods The number of patients who developed adverse events was determined, and the frequency, seriousness, causality, and severity of these adverse events were determined. It also determined the median of survival and progression-free survival and rates at 12 and 24 months and the quality of life. Results A total of 111 patients were included. The proportion of serious and related AE with the use of nimotuzumab was 1.3%. Most of the related AEs were mild and moderate, and the most frequent AEs were diarrhea, chills, and tremors. New diagnosed patients who received nimotuzumab concurrent with chemotherapy and radiotherapy reached a median OS of 12.2 months (95% CI, 6.9-17.5) and 12- and 24-month survival rates of 51.0% and 17.0%, respectively. Median PFS was 7.8 months (95% CI, 6.2-9.5), and 12- and 24-month PFS rates were 39.3% and 11.2%, respectively. A favorable evolution of the general state of health (p=0.03) was obtained from the beginning of treatment until month 12, with a significant reduction in the appearance of nausea (p=0.009), insomnia (p=0.04), constipation (p=0.04), eating difficulties (p=0.0006), and choking when swallowing (p=0.0001), but increased in dysphagia (p=0.02). Conclusions The administration of nimotuzumab was safe in the real-world setting. New diagnosed patients that received nimotuzumab concurrent with chemotherapy and radiotherapy reached a higher overall and progression-free survival and better quality of life than the rest of the patients.

Photodynamic Therapy in Combination with the Hepatitis B Core Virus-like Particles (HBc VLPs) to Prime Anticancer Immunity for Colorectal Cancer Treatment. Hao Y, Gu Z, Yu Z, Schomann T, Sayedipour S, Aguilar JC, et al. Cancers (Basel). 2022 May 31;14911):2724. https://doi.org/10.3390/cancers14112724

Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8⁺ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy.

Pisonia Alba Assisted Synthesis of Nanosilver for Wound Healing Activity. Kannaiyan S, Easwaramoorthi D, Kannan K, Gopal A, Lakshmipathy R, Katubi KM, et al. Bioinorg Chem Appl. 2022 Sep 12;2022:1775198. https://doi.org/10.1155/2022/1775198. eCollection 2022.

Wound infection is a major clinical challenge, impacting patient morbidity and mortality, with significant economic implications. Our research focused on how Pisonia Alba (PA) leaves, which are used to treat wounds, are used to synthesize silver nanoparticles and study their wound healing property. UV-visible spectroscopy, X-ray diffraction analysis, and s electron microscope (SEM) analysis were employed to evaluate the synthesized silver nanoparticles. Using DLS and Zeta potential analysis, the size and stability of the Pisonia Alba capped silver nanoparticle were investigated. The results showed that Pisonia Alba extract stabilized silver nanoparticles are 63.88 nm in size and have a spherical shape. Antibacterial and antibiofilm potential of synthesized silver nanoparticles against pathogenic organisms Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria were investigated. The in vitro cell scratch wounding assay is used to investigate the wound healing properties of synthesized nanoparticles. Pisonia Alba stabilized silver nanoparticles (PA@AgNPs), in comparison to Pisonia Alba (PA) extract, show effective wound healing characteristics by inducing the formation of collagen and serving as a capable wound healing agent.

Potential anti neuro-inflammatory effect of BioCen-128 in animal models of dementia. Esquivel N, García Y, Menéndez R, García TE, Morales AR, Rodríguez C. Animal Model Exp Med. 2022 Aug 15. https://doi.org/10.1002/ame2.12267. Online ahead of print.

Background BioCen-128 is a new active pharmaceutical ingredient composed of a specific bovine thymic fraction of a polypeptide nature. Positive results of similar thymus extracts have been shown to be effective in delaying the processes associated with aging, immunosenescence and Alzheimer’s disease (AD), where the inflammation plays an important role. Because of the anti-inflammatory potential of BioCen-128, the aim of this study was to evaluate the granuloma model induced by a cotton wool implantation and the model induced by intracerebroventricular (ICV) administration of streptozotocin (STZ). Method The experiment was carried out using male OF-1_cenp mice weighing 20 ± 2 g. Results Mice administered BioCen-128 in via the IP route at 5, 10 and 20 mg/kg of corporal weigh showed a decrease in the wet and dry weights of the granuloma, providing evidence of a systemic anti-inflammatory effect. In the ICV model of STZ, the administration of BioCen-128 improved cognitive function. Conclusion These responses suggested an anti-neuroinflammatory effect explainable by the action of thymosin β4 and thymosin alfa proteins. The results suggested that BioCen-128 could be used in the prevention and treatment of some diseases, for example AD, where neuroinflammation is one of the biological events that take place.

Retained Primitive Reflexes and Potential for Intervention in Autistic Spectrum Disorders. Melillo R,Leisman G,Machado C, Machado-Ferrer Y, Chinchilla-Acosta M,Kamgang S, et al. Front Neurol. 2022 Jul 7;13:922322. https://10.3389/fneur.2022.922322. Published online 2022 Jul 7.

We provide evidence to support the contention that many aspects of Autistic Spectrum Disorder (ASD) are related to interregional brain functional dysconnectivity associated with maturational delays in the development of brain networks. We think a delay in brain maturation in some networks may result in an increase in cortical maturation and development in other networks, leading to a developmental asynchrony and an unevenness of functional skills and symptoms. The paper supports the close relationship between retained primitive reflexes and cognitive and motor function in general and in ASD in particular provided to indicate that the inhibition of RPRs can effect positive change in ASD.

Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults. Toledo-Romani ME, García-Carmenate M, Verdecia-Sánchez L, Pérez-Rodríguez S, Rodríguez-González M, Valenzuela-Silva C, et al. Med (N Y). 2022 Aug 8;S2666-6340(22)00320-8. https://doi.org/10.1016/j.medj.2022.08.001. Online ahead of print.

Background SOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults. Method Phase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial. Subjects (n = 810) aged 19-80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredients of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD immunoglobulin G (IgG) concentration. Secondary outcomes were safety, reactogenicity, and neutralizing antibodies. Findings Seroconversion rate in vaccinees was 76.3% after two doses and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and variants of concern (VOCs) Alpha, Beta, Delta, and Omicron. Specific, functional antibodies were detected 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE. Conclusions Two doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose. Trial registry https://rpcec.sld.cu/trials/RPCEC00000347 FUNDING: This work was supported by Finlay Vaccine Institute, BioCubaFarma, and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

Segmentation of Medical Image Using Novel Dilated Ghost Deep Learning Model. Zambrano-Vizuete M, Botto-Tobar M, Huerta-Suárez C, Paredes-Parada W, Patiño Pérez D, Ahamed Ahanger T, et al. Comput Intell Neurosci. 2022 Aug 12;2022:6872045. https://doi.org/10.1155/2022/6872045. eCollection 2022.

Image segmentation and computer vision are becoming more important in computer-aided design. A computer algorithm extracts image borders, colours, and textures. It also depletes resources. Technical knowledge is required to extract information about distinctive features. There is currently no medical picture segmentation or recognition software available. The proposed model has 13 layers and uses dilated convolution and max-pooling to extract small features. Ghost model deletes the duplicated features, makes the process easier, and reduces the complexity. The Convolution Neural Network (CNN) generates a feature vector map and improves the accuracy of area or bounding box proposals. Restructuring is required for healing. As a result, convolutional neural networks segment medical images. It is possible to acquire the beginning region of a segmented medical image. The proposed model gives better results as compared to the traditional models, it gives an accuracy of 96.05, Precision 98.2, and recall 95.78. The first findings are improved by thickening and categorising the image’s pixels. Morphological techniques may be used to segment medical images. Experiments demonstrate that the recommended segmentation strategy is effective. This study rethinks medical image segmentation methods

Sequential Semiology of Seizures and Brain Perfusion Patterns in Patients with Drug-Resistant Focal Epilepsies: A Perspective from Neural Networks. Arocha Pérez JL, Morales Chacón LM, Batista García Ramo K, Galán García L. Behav Sci (Basel). 2022 Apr 14;12(4):107. https://doi.org/10.3390/bs12040107

Ictal semiology and brain single-photon emission computed tomography have been performed in approaching the epileptogenic zone in drug-resistant focal epilepsies. The authors aim to describe the brain structures involved in the ictal and interictal epileptogenic network from sequential semiology and brain perfusion quantitative patterns analysis. A sequential representation of seizures was performed (n = 15). A two-level analysis (individual and global) was carried out for the analysis of brain perfusion quantification and estimating network structures from the perfusion indexes. Most of the subjects started with focal seizures without impaired consciousness, followed by staring, automatisms, language impairments and evolution to a bilateral tonic-clonic seizure (temporal lobe and posterior quadrant epilepsy). Frontal lobe epilepsy seizures continued with upper limb clonus and evolution to bilateral tonic-clonic. The perfusion index of the epileptogenic zone ranged between 0.439-1.362 (mesial and lateral structures), 0.826-1.266 in dorsolateral frontal structures and 0.678-1.507 in the occipital gyrus. The interictal epileptogenic network proposed involved the brainstem and other subcortical structures. For the ictal state, it included the rectus gyrus, putamen and cuneus. The proposed methodology provides information about the brain structures in the neural networks in patients with drug-resistant focal epilepsies.

Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial. Ochoa-Azze R, Chang-Monteagudo A, Climent-Ruiz Y, Macías-Abraham C, Valenzuela-Silva C, García-García MA, et al. Lancet Respir Med . 2022 Jun 9;S2213-2600(22)00100-X. https://doi.org/10.1016/S2213-2600(22)00100-X. Online ahead of print.

Background A phase 1, clinical trial to evaluate FINLAY-FR-1A vaccine in COVID-19 convalescent individuals was completed. Here, we report results of the phase 2, clinical trial. Methods We studied 450 convalescent participants with a history of asymptomatic, mild, or moderate COVID-19 at the National Institute of Haematology and Immunology and the National Centre for Sexual Education in Havana, Cuba. The study included adults aged 19-78 years who had recovered from COVID-19 and had had a negative PCR test at least 2 months before the initiation of the study. Phase 2 was done sequentially in two stages. The first stage to assess safety comprised an open, non-controlled phase 2a study in participants aged 60-78 years who received a single dose of the FINLAY-FR-1A vaccine (50 μg of recombinant dimeric receptor binding domain [RBD]). The second stage comprised the placebo-controlled, double-blind, phase 2b trial in participants aged 19-78 years, where participants were randomly assigned (4:1) into two groups: an experimental group vaccinated with a single dose of the FINLAY-FR-1A vaccine, and a control (placebo) group injected with vaccine excipient. The primary outcomes were safety, evaluated 28 days after vaccination by the occurrence of serious adverse events in all participants, and successful immune response, assessed by neutralising antibody ELISA, and defined as half-maximal surrogate virus neutralisation titres of 250 or more. Secondary endpoints included vaccine immunogenicity assessed by ELISA anti-RBD and live-virus neutralisation test. All randomly assigned participants were included in the safety analysis (safety population), and immunogenicity was evaluated in participants without study interruptions (per-protocol population). The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000366-En and WHO-ICTRP and is complete. Findings From April 9, 2021, to April 17, 2021, 663 COVID-19 convalescent participants were enrolled in the study; 213 participants did not meet the selection criteria and 450 volunteers were recruited. 20 participants aged 60-78 years were included in the open, single-group, phase 2a study and 430 participants were randomly assigned to the experimental (n=344) or control groups (n=86) in the phase 2b study of participants aged 19-78 years. 19 (95%) of 20 phase 2a volunteers achieved a successful immune response after vaccination. No vaccine-associated serious adverse events were reported in the whole study population. Minor adverse events were found, the most common being pain at the injection site (105 [29%] of 364 in the intervention group; 13 [15%] of 86 in the placebo group). A successful immune response was found in 289 (81%) of 358 participants 28 days after vaccination. The vaccine elicited a greater than 31-times increase in anti-RBD-IgG antibodies compared with prevaccination rates, and the seroconversion rate was 302 (84%) of 358 on day 28 after vaccination; the geometric mean titres of live-virus neutralisation test increased from 15·4 (95% CI 10·3-23·2) to 400·3 (272·4-588·1) and high response was found against alpha, beta, and delta variants of concern. Interpretation A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 strengthened the pre-existing natural immunity, with excellent safety profile.

Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike RBD protein vaccine: A randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study). Hernández-Bernal F, Ricardo-Cobas MC, Martín-Bauta Y, Navarro-Rodríguez Z, Piñera-Martínez M, Quintana-Guerra J, et al. EClinicalMedicine. 2022 Apr;46:101383. https://doi.org/10.1016/j.eclinm.2022.101383. Epub 2022 Apr 9.

Background Multiple vaccine candidates against COVID-19 are currently being evaluated. We evaluate the safety and immunogenicity protein of a novel SARS-CoV-2 virus receptor-binding domain (RBD) vaccine. Methods A phase 1-2, randomised, double-blind, placebo-controlled trial was carried out in “Saturnino Lora” Hospital, Santiago de Cuba, Cuba. Subjects (healthy or those with controlled chronic diseases) aged between 19 and 80 years, who gave written informed consent were eligible. Subjects were randomly assigned (1:1:1, in blocks) to three groups: placebo, 25 µg and 50 µg RBD vaccine (Abdala). The product was administered intramuscularly, 0·5 mL in the deltoid region. During the first phase, two immunization schedules were studied: 0-14-28 days (short) and 0-28-56 days (long). In phase 2, only the short schedule was evaluated. The organoleptic characteristics and presentations of vaccine and placebo were identical. All participants (subjects, clinical researchers, statisticians, laboratory technicians, and monitors) remained masked during the study period. The main endpoints were safety and the proportion of subjects with seroconversion of anti-RBD IgG antibodies, analysed by intention to treat and per protocol, respectively. The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000346. Findings Between Dec 7, 2020, and Feb 9, 2021, 792 subjects were included; 132 (66 in each vaccination schedule, divided into 22 for each group) in phase 1, and 660 (220 in each group plus 66 from the short scheme of phase 1) in phase 2. The product was well tolerated. No severe adverse events were reported. During phase 1, the incidence of adverse events in the 25 µg, 50 µg, and placebo arms for the short schedule were 6/22 (27·3%), 6/22 (27·3%), 3/22 (13·6%), respectively, and for the long schedule were 8/22 (36·4%), 9/22 (40·9%), 4/22 (18·2%), respectively. In phase 2, adverse reactions were reported by 53/242 (21·9%), 75/242 (31·0%) and 41/242 (16·9%) participants in the 25 µg, 50 µg, and placebo group, respectively. Adverse reactions were minimal, mostly mild, and from the injection site, which resolved in the first 24-48 hours. In phase 1, seroconversion at day 56 was seen in 95·2% of the participants (20/21) in the 50 μg group, 81% (17/21) in the 25 μg group, and none in the placebo group (0/22). For the long schedule, seroconversion at day 70 was seen in 100% of the participants (21/21) in the 50 μg group, 94·7% (18/19) in the 25 μg group, and none in the placebo group (0/22). In phase 2, seroconversion of anti-RBD IgG antibodies at day 56 was seen in 89·2% of the participants in the 50 μg group (214/240; 95% CI 84·5-92·82), 77·7% in the 25 μg group (185/238; 72·0-82·9) and 4·6% in the placebo group (11/239; 2·3-8·1). Compared with the placebo arm, the differences in the proportion of participants with seroconversion were 73·1% (95% CI 66·8-79·5) and 84·6% (79·4-89·7) in the 25 μg and 50 μg groups, respectively. The seroconversion rate in the 50 μg group was significantly higher than in the 25 μg group (p=0·0012). Interpretation The Abdala vaccine was safe, well tolerated, and induced humoral immune responses against SARS-CoV-2. These results, in the context of the emergency COVID-19 pandemic, support the 50 μg dose, applied in a 0-14-28 days schedule, for further clinical trials to confirm vaccine efficacy.

Synthesis of Four Steroidal Carbamates with Antitumor Activity against Mouse Colon Carcinoma CT26WT Cells: In Vitro and In Silico Evidence. Fernández Pacheco D, Alonso D, González Ceballos L, Zaldo Castro A, Brown Roldán S, García Díaz M, et al. Int J Mol Sci. 2022 Aug 7;23(15):8775. https://doi.org/10.3390/ijms23158775

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by ¹H and ¹³C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.

The shared mother-child epigenetic signature of neglect is related to maternal adverse events. León I, Herrero Roldán S, Rodrigo MJ, López Rodríguez M, Fisher J, Mitchell C, et al. Front Physiol. 2022 Aug 24;13:966740. https://doi.org/10.3389/fphys.2022.966740. eCollection 2022.

Studies of DNA methylation have revealed the biological mechanisms by which life adversity confers risk for later physical and mental health problems. What remains unknown is the “biologically embedding” of maternal adverse experiences resulting in maladaptive parenting and whether these epigenetic effects are transmitted to the next generation. This study focuses on neglectful mothering indexed by a severe disregard for the basic and psychological needs of the child. Using the Illumina Human Methylation EPIC BeadChip in saliva samples, we identified genes with differentially methylated regions (DMRs) in those mothers with (n = 51), versus those without (n = 87), neglectful behavior that present similar DMRs patterns in their children being neglected versus non-neglected (n = 40 vs. 75). Mothers reported the emotional intensity of adverse life events. After covariate adjustment and multiple testing corrections, we identified 69 DMRs in the mother epigenome and 42 DMRs in the child epigenome that were simultaneously above the α = 0.01 threshold. The common set of nine DMRs contained genes related to childhood adversity, neonatal and infant diabetes, child neurobehavioral development and other health problems such as obesity, hypertension, cancer, posttraumatic stress, and the Alzheimer’s disease; four of the genes were associated with maternal life adversity. Identifying a shared epigenetic signature of neglect linked to maternal life adversity is an essential step in breaking the intergenerational transmission of one of the most common forms of childhood maltreatment.

Type 1 neurodegeneration with brain iron accumulation: a case report. Labrada-Aguilera PE, Guach-Hevia DA, Almira-Gómez CR, González-Lago DA. J Med Case Rep. 2022 Jun 3;16(1):217. https://doi.org/10.1186/s13256-022-03430-7

Background Type 1 neurodegeneration with brain iron accumulation is a rare neurological disorder with estimated prevalence of one to two per million persons worldwide, characterized by progressive degeneration of basal ganglia, globus pallidus, and reticular part of substantia nigra, produced by brain iron accumulation due to a defect in the gene producing pantothenate kinase 2. Clinical presentations include dystonia, dysarthria, dysphagia, dementia, severe mental retardation, and severe movement disability at later stages. The characteristic pattern on brain magnetic resonance imaging shows the “eye of the tiger” sign. Treatment in late stages is mainly symptomatic. We report the case of a Cuban boy with high-severity brain iron accumulation, with positive clinical and imaging findings diagnosed in a late stage of the illness. This degree of severity has never been reported in Cuba and is rarely reported worldwide. Case presentation We present the case of a 19-year-old male white Cuban boy who presented to our department with features of spasticity, dystonia, gait difficulty, dysarthria, dysphagia, aggressiveness, and sleep disorders. He was diagnosed with pantothenate kinase-associated neurodegeneration on the basis of clinical findings and typical “eye of the tiger” pattern on brain magnetic resonance imaging. Detailed evaluation was carried out, and symptomatic treatment and physiotherapy were started with trihexyphenidyl, cabergoline, baclofen, and intramuscular botulinum neurotoxin as well as daily home sessions of passive stretching, weight bearing, and muscle massaging. At 3 months reevaluation, the patient showed a great improvement of motor function, with a decrease of dystonic symptoms, although language, cognition, and functional independence showed no improvement. The prognosis of the patient remains reserved. Conclusion The diagnosis can be made based on the presence of clinical and imaging features. The presence of “eye-of-the-tiger” sign on magnetic resonance imaging must be considered a nearly pathognomonic sign of neurodegeneration with brain iron accumulation presence. Treatment after high-severity presentation remains directed toward symptomatic findings. Both dopamine agonists and anticholinergic agents are useful to treat motor symptoms, but there is not yet an effective treatment to stop the underlying degeneration. New therapeutic approaches are needed to counteract late stages of the disease and improve prognosis.

Wellens syndrome as an independent predictor of in-hospital cardiovascular complications. de la Torre Fonseca LM, Alarcón Cedeño R, Jiménez Díaz VA, Wang L, Loor Cedeño FI, Juan-Salvadores P.Acta Cardiol. 2022 Aug 15;1–7. https://doi.org/10.1080/00015385.2022.2093797. Online ahead of print

Introduction Wellens Syndrome was described for the first time in the eighties, as an equivalent pattern of a critical lesion of the anterior descending artery. Different risk factors have been associated with a worse prognosis during hospitalisation in patients with non-ST segment elevation acute coronary syndrome. However, it is unknown whether the presence of Wellens Syndrome alone contributes to an increase in in-hospital cardiovascular complications. Material and method Analytical prospective cohort study in 141 patients with the diagnosis of acute coronary syndrome without ST segment elevation who underwent coronary angiography between 2016 and 2020. Results Wellens syndrome was diagnosed in 64 patients with a mean age of 66.31 ± 12.54, of which 21 patients had a cardiac event during hospitalisation: hemodynamic complication 14 (21.9%), refractory or recurrent angina 4 (6.3%) and Acute myocardial infarction 3 (4.7%) confirming a relative risk (RR): 4.88 (95% confidence interval (CI) 1.92-12.45) p = 0.001. Conclusions The presence of Wellens Syndrome is independently associated with the appearance of cardiac complications during hospitalisation. Key points SW is now known to be a relatively frequent presentation of ACS, not addressed in depth in clinical practice guidelines for NSTEACS. This syndrome is generally caused by a severe ADA occlusion that, if not adequately treated, could evolve into a large infarction. According to the results of the different series published, the incidence of cardiovascular risk factors in SW is similar to other forms of presentation of ischaemic heart disease.At present, the exact relationship between the main cardiovascular risk factors and SW is unknown; in addition to the possible associations of this syndrome with in-hospital cardiovascular complications and its value as a predictor of the occurrence of cardiac complications, elements that are included in the results of the present study.

Whole genome sequences of Treponema pallidum subsp. endemicum isolated from Cuban patients: The non-clonal character of isolates suggests a persistent human infection rather than a single outbreak. Vrbová E, Noda AA, Grillová L, Rodríguez I, Forsyth A, Oppelt J, et al. PLoS Negl Trop Dis . 2022 Jun 10;16(6):e0009900. https://doi.org/10.1371/journal.pntd.0009900. Online ahead of print.

Bejel (endemic syphilis) is a neglected non-venereal disease caused by Treponema pallidum subsp. endemicum (TEN). Although it is mostly present in hot, dry climates, a few cases have been found outside of these areas. The aim of this work was the sequencing and analysis of TEN isolates obtained from “syphilis patients” in Cuba, which is not considered an endemic area for bejel. Genomes were obtained by pool segment genome sequencing or direct sequencing methods, and the bioinformatics analysis was performed according to an established pipeline. We obtained four genomes with 100%, 81.7%, 52.6%, and 21.1% breadth of coverage, respectively. The sequenced genomes revealed a non-clonal character, with nucleotide variability ranging between 0.2-10.3 nucleotide substitutions per 100 kbp among the TEN isolates. Nucleotide changes affected 27 genes, and the analysis of the completely sequenced genome also showed a recombination event between tprC and tprI, in TP0488 as well as in the intergenic region between TP0127-TP0129. Despite limitations in the quality of samples affecting breadth of sequencing coverage, the determined non-clonal character of the isolates suggests a persistent infection in the Cuban population rather than a single outbreak caused by imported case.