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Constantine E Kosmas,1,2 Maria D Bousvarou,3 Andreas Sourlas,3 Evangelia J Papakonstantinou,4 Edilberto Peña Genao,2 Rogers Echavarria Uceta,2 Eliscer Guzman1,2 1Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA; 2Cardiology Clinic, Cardiology Unlimited, PC, New York, NY, USA; 3School of Medicine, University of Crete, Heraklion, Greece; 4General Directorate of Public Health and Social Welfare, Athens, Attica Region, GreeceCorrespondence: Constantine E Kosmas, Email cekosmas1@gmail.comAbstract: Cardiovascular disease (CVD) is the most common cause of death in a global scale and significantly depends on the elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and the subsequent formation of atherosclerotic plaques. While physicians have several LDL-C-lowering agents with diverse mechanisms of action, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran, angiopoietin-like protein 3 (ANGPTL3) inhibitors have recently emerged as a powerful addition in the armamentarium of lipid-lowering strategies, especially for patients with refractory hypercholesterolemia, as in the case of patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 protein is a glycoprotein secreted by liver cells that is implicated in the metabolism of lipids along with other ANGPTL proteins. These proteins inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C, and triglyceride (TG) levels. Evinacumab is a monoclonal antibody that targets, binds to, and pharmacologically inhibits ANGPTL3, which was recently approved by the United States Food and Drug Administration (FDA) as a complementary agent to other LDL-C lowering regimens for patients aged 12 or older with HoFH, based on clinical trial evidence that confirmed its safety and efficacy in those patients. Antisense oligonucleotides (ASOs) also represent an interesting class of agents that target and inhibit the mRNA derived from the transcription of ANGPTL3 gene. This review aims to present and discuss the current clinical and scientific data pertaining to the role of ANGPTL3 inhibitors, a novel lipid-modifying class of agents capable of reducing LDL-C levels via a mechanism independent of LDL receptors.Keywords: cardiovascular disease, ANGPTL3 inhibitors, evinacumab, refractory hypercholesterolemia, familial hypercholesterolemia, LDL-cholesterol, LDL receptors

Alonso Soto,1,2 Dante M Quiñones-Laveriano,1 Faviola Valdivia,3 Eduardo Juscamayta-López,3 Johan Azañero-Haro,2 Liliana Chambi,2 Helen Horna,3 Gladys Patiño,4 Elizabet Guzman,4 Jhony A De la Cruz-Vargas1 1Instituto de Investigaciones en Ciencias Biomédicas, Universidad Ricardo Palma, Lima, Perú; 2Department of Medicine, Hospital Nacional Hipólito Unanue, Lima, Peru; 3Department of Public Health, Instituto Nacional de Salud, Lima, Peru; 4Department of Clinical Pathology, Hospital Nacional Hipólito Unanue, Lima, PeruCorrespondence: Alonso SotoInstituto de Investigaciones en Ciencias Biomédicas, Universidad Ricardo Palma, Av. Alfredo Benavides 5440, Santiago de Surco, Lima, 15039, Per&#x00FATel +051 996128953Email alonso.soto@urp.edu.pePurpose: The purpose of this study is to evaluate the frequency of viral and bacterial respiratory pathogens detected by molecular methods in sputum samples of patients hospitalized for COVID-19 and to evaluate its impact on mortality and unfavorable outcomes (in-hospital death or mechanical ventilation).Patients and Methods: The prospective cohort included patients with diagnosis of COVID-19 hospitalized at Hospital Nacional Hipólito Unanue. Sociodemographic and clinical data were collected from clinical records. Sputum samples were analyzed with the Biofire Filmarray Pneumonia plus® respiratory panel. Crude and adjusted associations with unfavorable outcomes were evaluated using logistic regression models.Results: Ninety-three patients who were able to collect sputum samples were recruited between September 8 and December 28, 2020. The median age was 61.7 years (IQR 52.3– 69-8) and 66 (71%) were male. The most frequent symptoms were dyspnea, cough, fever, and general malaise found in 80 (86%), 76 (82%), 45 (48%), and 34 (37%) patients, respectively. Fifty-three percent of patients had comorbidities. Seventy-six (82%) patients received antibiotics prior to admission and 29 (31%) developed unfavorable outcome. Coinfection was evidenced in 38 (40.86%) cases. The most frequently found bacteria were Staphylococcus aureus, Streptococcus agalactiae, Haemophilus influenzae and Klebsiella pneumoniae in 11 (11.83%), 10 (10.75%), 10 (10.75%), and 8 (8.6%) cases, respectively. Streptococcus pneumoniae was found in one case (1.08%). We neither identify atypical bacteria nor influenza virus. No association was found between the presence of viral or bacterial microorganisms and development of unfavorable outcomes (OR 1.63; 95% CI 0.45– 5.82).Conclusion: A high frequency of respiratory pathogens was detected by molecular methods in patients with COVID-19 pneumonia but were not associated with unfavorable outcomes. No atypical agents or influenza virus were found. The high use antibiotics before admission is a concern. Our data suggest that the use of drug therapy against atypical bacteria and viruses would not be justified in patients hospitalized for COVID-19.Keywords: SARS-CoV-2, coinfection, molecular biology, mortality, COVID-19

ObjectivesTo determine the effectiveness of the Contra Caries Oral Health Education Program (CCOHEP) for improving low-income, Spanish-speaking parents' oral health knowledge and behaviors for their young children. Mexican American children in the United States suffer disproportionately high prevalence and severity of early childhood caries, yet few evaluated, theory-based behavioral interventions exist for this population. CCOHEP is a theory-based curriculum consisting of four 2-h interactive classes designed for and by Spanish speakers and led by designated community health educators (promotoras). Topics included children's oral hygiene, caries etiology, dental procedures, nutrition, child behavior management, and parent skill-building activities.MethodsLow-income Spanish-speaking parents/caregivers of children aged 0-5 years were recruited through community services in an agricultural city in California. Survey questions from the Oral Health Basic Research Facts Questionnaire measuring oral health-related behaviors and knowledge were verbally administered before, immediately after, and 3 months after attendance at CCOHEP. Five questions measured aspects of parental toothbrushing for their children (frequency, using fluoridated toothpaste, brushing before bed, not drinking or eating after nighttime brushing, adult assistance), three questions measured other oral health behaviors, and 16 questions measured oral health-related knowledge. Analyses of within-person changes between pre- and post-tests and again between post-test and 3-month follow-up consisted of McNemar's test for binary outcomes and sign tests for ordinal outcomes.ResultsOverall, 105 caregivers participated in CCOHEP (n = 105 pretest, n = 95 post-test, n = 79 second post-test). At baseline, all parents self-reported doing at least one aspect of toothbrushing correctly, but only 13% reported performing all five aspects according to professional guidelines. At post-test, 44% of parents reported completing all aspects of toothbrushing according to professional guidelines (P < .001). Statistically significant improvements were seen in 4 aspects of toothbrushing (P ≤ .008) between pretest and post-test (all but adult assistance). The second post-test showed 3 of these improvements were maintained, while adult assistance and the other reported behaviors improved (P ≤ .008). Between pretest and post-test, checking child's teeth monthly and frequency of sweet drinks consumption improved (P ≤ .008), while frequency of eating sweet foods did not change. Knowledge was high at baseline (mean 12.8 of 16), but 6 knowledge items improved significantly between pretest and post-test. Improvements were maintained at second post-test.ConclusionsContra Caries Oral Health Education Program improved low-income Spanish-speaking parents' oral hygiene knowledge and self-reported behaviors for their young children, and change was sustained 3 months after the end of the intervention. Future, more rigorous evaluation of the intervention is recommended.

Constantine E Kosmas,1 Andreas Skavdis,2 Andreas Sourlas,3 Evangelia J Papakonstantinou,4 Edilberto Peña Genao,5 Rogers Echavarria Uceta,5 Eliscer Guzman1 1Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA; 2School of Medicine, University of Athens, Athens, Greece; 3School of Medicine, University of Crete, Heraklion, Greece; 4General Directorate of Public Health and Social Welfare, Attica Region, Athens, Greece; 5Cardiology Clinic, Cardiology Unlimited, PC, New York, NY, USACorrespondence: Constantine E Kosmas 168-24 Powells Cove Blvd., Beechhurst, NY 11357, USATel +1-646-734-7969Email cekosmas1@gmail.comAbstract: The current era of preventive cardiology continues to emphasize on low-density lipoprotein cholesterol (LDL-C) reduction to alleviate the burden of atherosclerotic cardiovascular disease (ASCVD). In this regard, the pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme via monoclonal antibodies has emerged as a novel lipid-lowering therapy, leading to a marked reduction in circulating LDL-C levels and subsequent improvement of cardiovascular outcomes. As these agents are increasingly used in current clinical practice, mounting scientific and clinical evidence supports that PCSK9 inhibitors offer an excellent safety and tolerability profile with a low incidence of adverse events. Notably, the most frequently reported side effects are injection-site reactions. In contrast to statins, PCSK9 inhibitors do not appear to exert a detrimental effect on glycemic control or to increase the incidence of new-onset diabetes mellitus. Accumulating evidence also indicates that PCSK9 inhibitors are a safe, well-tolerated and effective therapeutic strategy for patients with statin intolerance. On the other hand, as PCSK9 inhibitors reduce LDL-C to unprecedented low levels, a large body of current research has examined the effects of their long-term administration on neurocognition and on levels of vitamin E and other fat-soluble vitamins, providing encouraging results. This review aims to present and discuss the current clinical and scientific evidence pertaining to the safety and tolerability of PCSK9 inhibitors.Keywords: hypercholesterolemia, cardiovascular disease, CVD, PCSK9 inhibitors, safety, tolerability

Constantine E Kosmas,1 Alba Muñoz Estrella,2 Andreas Skavdis,3 Edilberto Peña Genao,4 Ian Martinez,5 Eliscer Guzman1 1Department of Medicine, Division of Cardiology, Montefiore Medical Center, Bronx, NY, USA; 2Department of Medicine, Mount Sinai St. Luke’s-West Hospital, New York, NY, USA; 3School of Medicine, University of Athens, Athens, Greece; 4Cardiology Clinic, Cardiology Unlimited, PC, New York, NY, USA; 5Department of Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USACorrespondence: Constantine E Kosmas Tel +1-646-734-7969Email cekosmas1@gmail.comAbstract: Proprotein convertase subtilisin kexin 9 (PCSK-9)-targeting therapy has arisen as a new line for the treatment of hyperlipidemia. Inclisiran is a double-stranded small RNA molecule that works by blocking the transcription of PCSK-9, leading to a reduction of PCSK9 levels in the hepatocytes, resulting in an increased expression of low-density lipoprotein (LDL) receptors in the hepatocyte membrane and, as a consequence, it reduces the circulating levels of LDL cholesterol (LDL-C). Compared to the other LDL-C-lowering medications, such as statins, ezetimibe and PCSK-9 inhibitors, inclisiran proposes an infrequent dosing of twice a year, while simultaneously providing a significant reduction of LDL-C. Its prolonged effect offers an advantage against medication non-compliance, which is one of the main causes for not achieving LDL-C goals with standard therapy. Inclisiran has also proven to have a relatively safe profile with adverse effects occurring in similar frequency as with placebo. This review aims to present and discuss the current clinical and scientific data pertaining to the role of inclisiran in the management of hypercholesterolemia and treatment of cardiovascular disease (CVD).Keywords: proprotein convertase subtilisin kexin 9, PCSK-9, inclisiran, hypercholesterolemia, cardiovascular disease, CVD

School recess, though beneficial to students in many ways, can be a problematic setting due to inadequate supervision, structure, and safety. A peer praise note (PPN) intervention was implemented on the recess playground to address these concerns at a Title I elementary school. Researchers used a single-subject reversal design across all students to evaluate intervention effectiveness. Results included overall improvements in the level, trend, and variability of office discipline referrals (ODRs), especially from reversal to reinstatement of the intervention, and an effect size (percentage of data points exceeding the median; PEM) suggesting that PPNs effectively decreased ODRs. Results from social validity surveys completed by recess aides and students indicated participants' perceptions that PPNs helped improve student behavior and peer relations, communicate playground rules, extend supervision responsibilities, and offer structured activity to peer praisers. Limitations, future research, and implications are addressed.

Constantine E Kosmas,1 Delia Silverio,2 Julio Ovalle,2 Peter D Montan,2 Eliscer Guzman3 1Division of Cardiology, Department of Medicine, Mount Sinai Hospital, New York, NY, USA; 2Cardiology Clinic, Cardiology Unlimited, PC, New York, NY, USA; 3Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA Abstract: Evolocumab is a PCSK9 inhibitor which is administered subcutaneously, and when added to statin therapy it has been shown to cause a significant incremental LDL-C reduction, leading to a reduction of cardiovascular risk. Evolocumab has a favorable side effect profile, and its self-administration at home appears to be safe and effective with the appropriate training and instructions from a health care provider. Current studies are showing encouraging results regarding adherence to evolocumab in real-life settings, and adherence rates to evolocumab appear to be better than those to statins. However, further larger studies are needed for a more definitive assessment of the short- and long-term patient adherence rates to evolocumab. In addition, reductions in the price of evolocumab may also be necessary to improve cost-effectiveness of the drug. Keywords: evolocumab, adherence, hypercholesterolemia, cardiovascular risk

Shambhu Aryal,1 Enrique Diaz-Guzman,2 David M Mannino3 1Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, NC, 2Division of Pulmonary, Allergy and Critical Care, University of Alabama, Birmingham, AL, 3Department of Preventive Medicine and Environmental Health, University of Kentucky, Lexington, KY, USA Abstract: Chronic obstructive pulmonary disease (COPD), one of the most common chronic diseases and a leading cause of death, has historically been considered a disease of men. However, there has been a rapid increase in the prevalence, morbidity, and mortality of COPD in women over the last two decades. This has largely been attributed to historical increases in tobacco consumption among women. But the influence of sex on COPD is complex and involves several other factors, including differential susceptibility to the effects of tobacco, anatomic, hormonal, and behavioral differences, and differential response to therapy. Interestingly, nonsmokers with COPD are more likely to be women. In addition, women with COPD are more likely to have a chronic bronchitis phenotype, suffer from less cardiovascular comorbidity, have more concomitant depression and osteoporosis, and have a better outcome with acute exacerbations. Women historically have had lower mortality with COPD, but this is changing as well. There are also differences in how men and women respond to different therapies. Despite the changing face of COPD, care providers continue to harbor a sex bias, leading to underdiagnosis and delayed diagnosis of COPD in women. In this review, we present the current knowledge on the influence of sex on COPD risk factors, epidemiology, diagnosis, comorbidities, treatment, and outcomes, and how this knowledge may be applied to improve clinical practices and advance research. Keywords: chronic obstructive lung disease, sex, smoking, comorbidity, sex bias

This paper argues the need for broader criteria than are customarily used, for measuring pupil achievement, school effectiveness and impact on educational policy in the plural and highly unequal societies of Mexico and Central America. We proceed by first presenting the context of highly centralized mainstream educational provision, concentrated in urban areas contrasting with the extremely limited services available in rural communities. Second, we describe grass-roots educational solutions to this latter condition. Finally, we will situate these solutions within the framework of international scholarship on assessment, evaluation and impact measurement in order to permit the achievements of these experiences to be credited and lessons to be drawn from them. We conclude that comprehensive, contest-sensitive evaluation establishes a two way communication between the educational system and local school experience.