Philippine pediatric COVID-19 living clinical practice guidelines as of March 2022

Executive Summary@#The Coronavirus disease 2019 (COVID-19) pandemic has triggered a global crisis and has affected millions of people worldwide. With the evolution of the different variants of concern, the incidence of COVID- 19 in the pediatric population has risen. The Surveillance and Analysis of COVID-19 in Children Nationwide (SALVACION) Registry, developed by the Pediatric Infectious Disease Society of the Philippines (PIDSP) and the Philippine Pediatric Society (PPS), has reported 3,221 cases as of March 31, 2022, with 90.4% requiring hospitalization and 36.2% with moderate to critical disease severity. Given the magnitude of the impact of COVID-19, with most of the clinical recommendations available designed towards adult patients, there was an urgent need for clinicians, public health officials and the government to also prioritize evidence-based clinical practice guidelines for the pediatric population. Hence, the development of the Philippine Pediatric COVID-19 Living Clinical Practice Guidelines was conceptualized. This independent project, funded and supported by the PPS and PIDSP, aimed to formulate up-to-date, evidence-based recommendations on the treatment, diagnosis, infection prevention and control of COVID-19 in children. Following the standard CPG development process outlined in the DOH Manual for CPG Development and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, 15 evidence summaries and 24 recommendations were generated by 12 consensus panelists representing their specific health organizations and institutions.

Eficacia analgésica de la electroterapia y técnicas afines: revisiones sistemáticas / Analgesic efficacy of electrotherapy and similar techniques. Systematic reviews

Hacemos una revisión bibliográfica de las revisiones sistemáticas y metaanálisis publicados que hacen referencia a la eficacia analgésica de la electroterapia. Resumimos estos trabajos y discutimos sus resultados y conclusiones.Aunque existen resultados positivos, la mayor parte de estas revisiones, salvo en determinados casos, no parecen confirmar la eficacia analgésica de la electroterapia y sus posibles beneficios parecen, en general, de escasa relevancia; dado que tampoco existe una definitiva evidencia de su ineficacia, son necesarios estudios más rigurosos para obtener conclusiones definitivas.Pensamos que este trabajo puede servir de ayuda en futuros trabajos de investigación sobre electroterapia y técnicas afines, al sintetizar la amplia información existente. (AU)

Medicina basada en la evidencia y rehabilitación / Evidence based medicine and rehabilitation

La evaluación económica de las tecnologías sanitarias se está convirtiendo en una prioridad para los sistemas de salud. Es una de las razones por las que la llamada Medicina Basada en la Evidencia está en plena actualidad y tiene una importancia cada vez mayor. En este trabajo se aborda el problema del estudio de la literatura científica. La obtención de evidencias resulta en muchas ocasiones complicado debido a la ingente cantidad de ensayos clínicos, a las limitaciones de las principales bases de datos, etc., por lo que el médico recibe muchas veces resultados contradictorios. Actualmente las revisiones sistemáticas (como las realizadas por la Colaboración Internacional Cochrane) están aportando los más altos niveles de evidencias sobre la eficacia de regímenes preventivos, terapéuticos y rehabilitadores, pudiendo proporcionar al médico rehabilitador que lo desee una guía de extraordinaria utilidad. Aunque asumiendo sus imperfecciones, la Medicina Basada en la Evidencia, junto con la experiencia y conocimientos clínicos del médico, puede llevar a una mejor, más racional y estimulante práctica de la medicina aunando los intereses colectivos con los individuales. (AU)

EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion.

We have examined the mechanism and functional significance of hemidesmosome disassembly during normal epithelial cell migration and squamous carcinoma invasion. Our findings indicate that a fraction of EGF receptor (EGF-R) combines with the hemidesmosomal integrin alpha6beta4 in both normal and neoplastic keratinocytes. Activation of the EGF-R causes tyrosine phosphorylation of the beta4 cytoplasmic domain and disruption of hemidesmosomes. The Src family kinase inhibitors PP1 and PP2 prevent tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes without interfering with the activation of EGF-R. Coimmunoprecipitation experiments indicate that Fyn and, to a lesser extent, Yes combine with alpha6beta4. By contrast, Src and Lck do not associate with alpha6beta4 to a significant extent. A dominant negative form of Fyn, but not Src, prevents tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes. These observations suggest that the EGF-R causes disassembly of hemidesmosomes by activating Fyn, which in turn phosphorylates the beta4 cytoplasmic domain. Neoplastic cells expressing dominant negative Fyn display increased hemidesmosomes and migrate poorly in vitro in response to EGF. Furthermore, dominant negative Fyn decreases the ability of squamous carcinoma cells to invade through Matrigel in vitro and to form lung metastases following intravenous injection in nude mice. These results suggest that disruption of hemidesmosomes mediated by Fyn is a prerequisite for normal keratinocyte migration and squamous carcinoma invasion.

Spinal cord infarction: prognosis and recovery in a series of 36 patients.

OBJECTIVE: To study the clinical evolution and the functional outcome of patients suffering from spinal cord infarction who were treated at the Spinal Cord Injuries Unit. To try to determine the factors that could have influence in their functional outcome. SETTING: In a Spinal Cord Injuries Unit, regionally-based, and which forms part of a general hospital with a high level of specialization. METHOD: Retrospective study of the medical records of patients suffering from vascular spinal cord ischemia, as acute anterior spinal artery syndrome or associated with aortic surgery or rupture. Cases that were due to compressive, tumoral or inflammatory pathologies were excluded. Assessment of the neurological syndrome followed the ASIA/IMSOP criteria. Age, sex, history and magnetic resonance imaging (MRI) findings were analyzed. Assessment of functional outcome was made regarding ambulatory ability or wheelchair use, and bladder/sphincter control. RESULTS: Thirty-six cases were selected, the commonest group being spinal cord ischemia due to idiopathic causes (36.1%). Following these, there were cases associated with aortic surgery (25%), systemic arteriosclerosis (19.4%) and acute deficit of perfusion (11.1%). The average age of the patients was 59.3 years, with a mortality of 22.2% during the hospital stay. Regarding the functional outcomes at the moment of discharge, it must be pointed out that 57.1% of the patients were wheelchair users, 25% were ambulatory, using technical aids, and 17.9% were fully ambulatory. The group who could perform some kind of walking was significantly younger than the group of wheelchair users (48.17 vs 61.38 years). Additionally, it became evident that those patients who did not show voluntary muscle contraction at the time of admission (ASIA groups A and B) presented a higher risk of being wheelchair users. CONCLUSION: Acute spinal cord ischemia syndrome has a severe prognosis with permanent and disabling sequelae. Initial neurological assessment following ASIA/IMSOP classification proves to be the best predictor of prognosis, and the patient's advanced age constitutes a negative factor for functional recovery.

Tyrosine phosphorylation of the beta 4 integrin cytoplasmic domain mediates Shc signaling to extracellular signal-regulated kinase and antagonizes formation of hemidesmosomes.

Ligation of the alpha(6)beta(4) integrin induces tyrosine phosphorylation of the beta(4) cytoplasmic domain, followed by recruitment of the adaptor protein Shc and activation of mitogen-activated protein kinase cascades. We have used Far Western analysis and phosphopeptide competition assays to map the sites in the cytoplasmic domain of beta(4) that are required for interaction with Shc. Our results indicate that, upon phosphorylation, Tyr(1440), or secondarily Tyr(1422), interacts with the SH2 domain of Shc, whereas Tyr(1526), or secondarily Tyr(1642), interacts with its phosphotyrosine binding (PTB) domain. An inactivating mutation in the PTB domain of Shc, but not one in its SH2 domain, suppresses the activation of Shc by alpha(6)beta(4). In addition, mutation of beta(4) Tyr(1526), which binds to the PTB domain of Shc, but not of Tyr(1422) and Tyr(1440), which interact with its SH2 domain, abolishes the activation of ERK by alpha(6)beta(4). Phenylalanine substitution of the beta(4) tyrosines able to interact with the SH2 or PTB domain of Shc does not affect incorporation of alpha(6)beta(4) in the hemidesmosomes of 804G cells. Exposure to the tyrosine phosphatase inhibitor orthovanadate increases tyrosine phosphorylation of beta4 and disrupts the hemidesmosomes of 804G cells expressing recombinant wild type beta(4). This treatment, however, exerts a decreasing degree of inhibition on the hemidesmosomes of cells expressing versions of beta(4) containing phenylalanine substitutions at Tyr(1422) and Tyr(1440), at Tyr(1526) and Tyr(1642), or at all four tyrosine phosphorylation sites. These results suggest that beta(4) Tyr(1526) interacts in a phosphorylation-dependent manner with the PTB domain of Shc. This event is required for subsequent tyrosine phosphorylation of Shc and signaling to ERK but not formation of hemidesmosomes.

The autoantibodies to alpha 6 beta 4 integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of human beta 4.

This study was undertaken to characterize the antigenic determinants recognized by the autoantibodies of patients with ocular cicatricial pemphigoid (OCP). OCP is a subepithelial, blistering, autoimmune disease that mainly affects the conjunctiva and other mucous membranes. We previously demonstrated that a cDNA clone, isolated from a keratinocyte expression library by using immunoaffinity-purified OCP autoantibody, encoded the cytoplasmic domain of beta 4 integrin subunit. Our subsequent studies showed that sera from all the OCP patients that were tested recognize the human beta 4 integrin subunit. To identify the prevalent epitopes of the anti-beta 4 autoantibodies of OCP, we have used cell lines transfected with vectors encoding a wild-type beta 4 subunit, a tailless beta 4 subunit, or a beta 4 subunit lacking the extracellular domain. Nontransfected cell lines were used as controls. Lysates from these cell lines were analyzed with OCP sera, IgG fractions from OCP sera, and immunoaffinity-purified OCP autoantibodies. Abs to extracellular and cytoplasmic domains of human beta 4 integrin were used as positive controls, whereas normal human sera and normal human IgG fractions were used as negative controls. The reactivity of OCP Abs was determined by using immunoblotting, immunoprecipitation, and FACS analysis. The results of this study indicate that OCP sera, OCP IgG fractions, and immunoaffinity-purified OCP autoantibodies react with the intracellular and not the extracellular domain of human beta 4 integrin subunit. In vitro cell culture experiments demonstrated that OCP autoantibody binds to the cytoplasm of the cells. The relevance of these findings to the pathogenesis of OCP is discussed.

Integrin-mediated activation of focal adhesion kinase is required for signaling to Jun NH2-terminal kinase and progression through the G1 phase of the cell cycle.

The extracellular matrix exerts a stringent control on the proliferation of normal cells, suggesting the existence of a mitogenic signaling pathway activated by integrins, but not significantly by growth factor receptors. Herein, we provide evidence that integrins cause a significant and protracted activation of Jun NH2-terminal kinase (JNK), while several growth factors cause more modest or no activation of this enzyme. Integrin-mediated stimulation of JNK required the association of focal adhesion kinase (FAK) with a Src kinase and p130(CAS), the phosphorylation of p130(CAS), and subsequently, the recruitment of Crk. Ras and PI-3K were not required. FAK-JNK signaling was necessary for proper progression through the G1 phase of the cell cycle. These findings establish a role for FAK in both the activation of JNK and the control of the cell cycle, and identify a physiological stimulus for JNK signaling that is consistent with the role of Jun in both proliferation and transformation.

Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin beta4 cytoplasmic domain.

The cytoplasmic domain of the integrin beta4 subunit mediates both association with the hemidesmosomal cytoskeleton and recruitment of the signaling adaptor protein Shc. To examine the significance of these interactions during development, we have generated mice carrying a targeted deletion of the beta4 cytoplasmic domain. Analysis of homozygous mutant mice indicates that the tail-less alpha6beta4 binds efficiently to laminin 5, but is unable to integrate with the cytoskeleton. Accordingly, these mice display extensive epidermal detachment at birth and die immmediately thereafter from a syndrome resembling the human disease junctional epidermolysis bullosa with pyloric atresia (PA-JEB). In addition, we find a significant proliferative defect. Specifically, the number of precursor cells in the intestinal epithelium, which remains adherent to the basement membrane, and in intact areas of the skin is reduced, and post-mitotic enterocytes display increased levels of the cyclin-dependent kinase inhibitor p27(Kip). These findings indicate that the interactions mediated by the beta4 tail are crucial for stable adhesion of stratified epithelia to the basement membrane and for proper cell-cycle control in the proliferative compartments of both stratified and simple epithelia.

Epithelial attachment alters the outcome of Helicobacter pylori infection.

Genetically defined in vivo models are needed to assess the importance of target cell attachment in bacterial pathogenesis. Gastric colonization by Helicobacter pylori in human populations is common and persistent, and has various outcomes including peptic ulcers and cancer. The impact of attachment on the course of infection was examined in transgenic mice expressing a human receptor for H. pylori in their gastric epithelium. Persistent infection by a clinical isolate occurred at comparable microbial densities in transgenic and nontransgenic littermates. However, microbial attachment in transgenic mice resulted in production of autoantibodies to Lewisx carbohydrate epitopes shared by bacteria and acid-secreting parietal cells, chronic gastritis, and parietal cell loss. This model should help identify bacterial and host genes that produce attachment-related pathology.

Inhibition of collagen lattice contraction by pentoxifylline and interferon-alpha, -beta, and -gamma.

The ability to control wound contraction is important in preventing disfiguring scarring in burn and trauma patients. Fibroblasts within the wound generate the mechanical forces that cause this contraction, and their interactions with various extracellular matrix components are thought to regulate this process. Because pentoxifylline and the interferons are believed to moderate fibroblast production of such matrix components, we assessed the effects of these agents on wound contraction in vitro, using a model wherein dermal fibroblasts are incorporated into a collagen lattice. Pentoxifylline and interferon-alpha, -beta, and -gamma inhibited lattice contraction in a dose-dependent manner and showed no effect on cell number or cell viability. These results suggest that pentoxifylline and the interferons may retard wound contraction in vivo and thus reduce scarring associated with severely contracted wounds. Further study is needed to determine the mechanism of action of these agents on the collagen lattice model.