Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

The RNA-binding protein AUF1 facilitates Akt phosphorylation at the membrane.

Mammalian target of rapamycin (mTOR), which is part of mTOR complex 1 (mTORC1) and mTORC2, controls cellular metabolism in response to levels of nutrients and other growth signals. A hallmark of mTORC2 activation is the phosphorylation of Akt, which becomes upregulated in cancer. How mTORC2 modulates Akt phosphorylation remains poorly understood. Here, we found that the RNA-binding protein, AUF1 (ARE/poly(U)-binding/degradation factor 1), modulates mTORC2/Akt signaling. We determined that AUF1 is required for phosphorylation of Akt at Thr308, Thr450, and Ser473 and that AUF1 also mediates phosphorylation of the mTORC2-modulated metabolic enzyme glutamine fructose-6-phosphate amidotransferase 1 at Ser243. In addition, AUF1 immunoprecipitation followed by quantitative RT-PCR revealed that the mRNAs of Akt, glutamine fructose-6-phosphate amidotransferase 1, and the mTORC2 component SIN1 associate with AUF1. Furthermore, expression of the p40 and p45, but not the p37 or p42, isoforms of AUF1 specifically mediate Akt phosphorylation. In the absence of AUF1, subcellular fractionation indicated that Akt fails to localize to the membrane. However, ectopic expression of a membrane-targeted allele of Akt is sufficient to allow Akt-Ser473 phosphorylation despite AUF1 depletion. Finally, conditions that enhance mTORC2 signaling, such as acute glutamine withdrawal, augment AUF1 phosphorylation, whereas mTOR inhibition abolishes AUF1 phosphorylation. Our findings unravel a role for AUF1 in promoting membrane localization of Akt to facilitate its phosphorylation on this cellular compartment. Targeting AUF1 could have therapeutic benefit for cancers with upregulated mTORC2/Akt signaling.

Depressive Symptoms and Overperception of Airflow Obstruction in Older Adults With Asthma.

OBJECTIVE: Older adults are at increased risk for depression and poor asthma outcomes. We examined whether depressive symptoms are associated with overperception of airflow obstruction and a pattern of worse asthma control, but not pulmonary function. METHODS: We recruited a cohort of adults with asthma 60 years and older in East Harlem and the Bronx, New York. Baseline measures included the Geriatric Depression Scale, Asthma Control Questionnaire, and Mini Asthma Quality of Life Questionnaire. Spirometry was conducted at baseline to assess pulmonary function. Perception of airflow obstruction was assessed for 6 weeks following baseline by participants entering estimates of peak expiratory flow (PEF) into a programmable peak flow meter followed by PEF blows. Participants were blinded to actual PEF values. The percentage of time that participants were in the overperception zone was calculated as an average. RESULTS: Among the 334 participants (51% Hispanic, 25% Black), depressive symptoms were associated with overperception of airflow obstruction (ß = 0.14, p = .029), worse self-reported asthma control (ß = 0.17, p = .003), and lower asthma-related quality of life (ß = -0.33, p < .001), but not with lung function (ß = -0.01, p = .82). Overperception was also associated with worse self-reported asthma control (ß = 0.14, p = .021), but not lung function (ß = -0.05, p = .41). CONCLUSIONS: Depressive symptoms were associated with greater perceived impairment from asthma, but not pulmonary function. Overperception of asthma symptoms may play a key role in the relationship between depression and asthma outcomes in older adults.

Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes.

Patients affected by diabetes show an increased risk of developing Alzheimer disease (AD). Similarly, patients with AD show impaired insulin function and glucose metabolism. However, the underlying molecular mechanisms connecting these two disorders are still not well understood. Herein, we investigated the microtubule-associated protein tau as a new link between AD and diabetes. To determine whether diabetes causes cognitive decline by a tau-dependent mechanism, we treated non-transgenic (Ntg) and tau-knockout mice with streptozotocin, causing type 1 diabetes-like disease (T1D). Interestingly, although induction of T1D in Ntg mice led to cellular and behavioral deficits, it did not do so in tau-knockout mice. Thus, data suggest that tau is a fundamental mediator of the induction of cognitive impairments in T1D. Tau dysregulation, which causes a reduction in synaptic protein levels, may be responsible for the cognitive decline observed in Ntg streptozotocin-treated mice. Concomitantly, we demonstrate the novel finding that depletion of endogenous tau mitigates behavioral impairment and synaptic deficits induced in T1D-like mice. Overall, our data reveal that tau is a key molecular factor responsible for the induction of cognitive deficits observed in T1D and represents a potential therapeutic target for diabetes and patients with AD.

MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: The treatment of choice for locally advanced rectal cancer is preoperative chemoradiotherapy. Despite half of patients do not respond and suffer unnecessary toxicities and surgery delays, there are no biomarkers to guide preoperative CRT outcome. MicroRNA-21 has been related to acquisition of 5-fluorouracil resistance; however, its potential predictive value of response to preoperative chemoradiotherapy in locally advanced rectal cancer remains unknown. METHODS: Nighty-two patients diagnosed with locally advanced rectal cancer who were preoperatively treated with chemoradiotherapy were selected for this study. Moreover, microRNA-21 expression was quantified in formalin-fixed paraffin-embedded biopsies from this cohort, and the results obtained were correlated with clinical and molecular characteristics, pathological response, and outcome. RESULTS: MicroRNA-21 was found overexpressed in 77.6% cases, and significantly correlated with tumor grade after preoperative chemoradiotherapy (P = 0.013) and with pathological response (P = 0.013). The odds ratio of having miR-21 overexpression and not getting a respond to chemoradiotherapy resulted in 9.75 CI 2.24 to 42. Sensitivity, specificity, negative predictive values, and positive predictive value were 86.6, 60, 42.8, and 92%, respectively. Multivariate analysis confirmed the clinical significance of miR-21 determining preoperative chemoradiotherapy response. CONCLUSIONS: MicroRNA-21 expression efficiently predicts preoperative chemoradiotherapy pathological response in locally advanced rectal cancer.

[Screening for bipolar disorder in primary care patients with psychological symptoms]. / Cribado para el trastorno bipolar en pacientes de atención primaria que presentan síntomas psicológicos.

OBJECTIVE: To estimate the proportion of positive results in the screening of bipolar disorder (BD) among primary care patients presenting with psychological symptoms, and to analyze their characteristics. DESIGN: Multicenter cross-sectional study. SETTINGS: Nineteen Primary Care clinics in different Spanish regions. PATIENTS: A total of 360 consecutive primary care patients aged 18 to 70, presenting with psychological symptoms. MEASUREMENTS: Screening for BP was performed by means of the Mood Disorders Questionnaire. Data on quality of life (EuroQol-5D) and functional impairment (Sheehan Disability Inventory) were obtained. Data on psychiatric comorbidity and data on the use of psychotropic medication were acquired by review of medical records. RESULTS: Of the patients screened, 11.9% were positive (95%CI: 8.8%-15.7%). Only two patients had a diagnosis of BP in their clinical records and, although more than half received treatment with antidepressants, only two received treatment with mood stabilizers. Positive screening is associated with work, social and family dysfunction, greater perceived stress and poor quality of life. CONCLUSIONS: BD screening in primary care patients with psychological problems leads to a striking proportion of positive results, indicating that there may be a significant prevalence of BP patients, most of them undiagnosed and untreated. Further research is needed to determine the role that Primary Care can or should assume in the screening, diagnosis and management of this disorder.

Endogenous murine tau promotes neurofibrillary tangles in 3xTg-AD mice without affecting cognition.

Recent studies on tauopathy animal models suggest that the concomitant expression of the endogenous murine tau delays the pathological accumulation of human tau, and interferes with the disease progression. To elucidate the role of endogenous murine tau in a model with both plaques and tangles, we developed a novel transgenic mouse model by crossing 3xTg-AD with mtauKO mice (referred to as 3xTg-AD/mtauKO mice). Therefore, this new model allows us to determine the pathological consequences of the murine tau. Here, we show that 3xTg-AD/mtauKO mice have lower tau loads in both soluble and insoluble fractions, and lower tau hyperphosphorylation level in the soluble fraction relative to 3xTg-AD mice. In the 3xTg-AD model endogenous mouse tau is hyperphosphorylated and significantly co-aggregates with human tau. Despite the deletion of the endogenous tau gene in 3xTg-AD/mtauKO mice, cognitive dysfunction was equivalent to 3xTg-AD mice, as there was no additional impairment on a spatial memory task, and thus despite increased tau phosphorylation, accumulation and NFTs in 3xTg-AD mice no further effects on cognition are seen. These findings provide better understanding about the role of endogenous tau to Alzheimer's disease (AD) pathology and for developing new AD models.

Impact of a Moderate CYP3A4 Inducer (Bosentan) on Lurbinectedin Pharmacokinetics and Safety in Patients with Advanced Solid Tumors: An Open-Label, Two-Way, Crossover, Phase Ib Drug-Drug Interaction Study.

This open-label, two-way, crossover, phase Ib drug-drug interaction study investigated whether the pharmacokinetics (PKs) and safety profile of lurbinectedin (LRB) are affected by co-administration of a moderate CYP3A4 inducer (bosentan, BOS) in adult patients with advanced solid tumors. Eleven patients were randomly assigned to Sequence 1 (LRB + BOS in Cycle 1 [C1] and LRB alone in Cycle 2 [C2]) or Sequence 2 (LRB alone in C1 and LRB + BOS in C2), and finally, eight patients (four per sequence) were considered evaluable for PK assessment. LRB (3.2 mg/m2, 1 h [h], intravenous) was administered alone or combined with multiple BOS administration (125 mg/12 h oral; 5.5 days). Co-administration with BOS decreased the systemic total exposure (area under the curve, AUC) of LRB by 21% for AUC0-t and 20% for AUC0-∞ and increased clearance by 25%. Co-administration with BOS did not significantly modify the unbound plasma LRB PK parameters. BOS increased the conversion of LRB to its metabolite M1, with no changes on its metabolite M4. The LRB safety profile was consistent with the toxicities previously described for this drug. No differences in terms of toxicity were found between LRB with and without BOS. In summary, the magnitude of the observed changes precludes a clinically relevant effect of BOS co-administration on LRB exposure and its safety profile.

MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

PURPOSE: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. PATIENTS AND METHODS: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. RESULTS: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. CONCLUSIONS: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

A first-in-human study of the fibroblast activation protein-targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors.

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8+ and Ki67+CD8+ T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.

Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline.

Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ß-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M(1) receptors (M(1)Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M(1)Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M(1)R(-/-) mice. Our data show that M(1)R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M(1)R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar Aß in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M(1)R were attributed to changes in the glycogen synthase kinase 3ß and protein kinase C activities. Finally, deleting the M(1)R increased the astrocytic and microglial response associated with Aß plaques. Our data highlight the significant role that disrupting the M(1)R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M(1)R agonists for treating AD.

Anti-drug antibodies in the current management of cancer.

Monoclonal antibodies (mAbs) have become one of the main therapeutic weapons in modern oncology, mainly as targeted therapies, and immune checkpoint inhibitors. The generation of anti-drug antibodies (ADAs) after their administration can alter their pharmacokinetic, pharmacodynamic, efficacy and safety profile causing infusion-related reactions. Several risk factors have been associated with ADAs development, notably host genetics and immune status, comorbidity, concomitant medications, mAbs molecular structure, dose and route of administration. ADAs are not usually tested on daily clinical practice, being their analysis generally placed in early stages of drug development. ELISA-type assay the most common method. ADAs detection can involve important implications for treatment strategies of cancer patients, guiding therapeutic adjustment. In oncology, some studies about ADAs synthesis related to targeted therapies and immune checkpoint inhibitors have been recently published. Several strategies are proposed to reduce mAbs immunogenicity, such as different schedules, routes of administration or even the use of immunosuppressants. Another question that arises in relation to ADAs generation is the need to measure the concentration levels of active drug to guide the administration schedule. In this review, we will discuss all the aspects that are currently under discussion in relation with ADAs in oncology.

Adoptive cell therapy for solid tumors: Chimeric antigen receptor T cells and beyond.

Adoptive cell therapy with chimeric antigen receptor T cells has caused a significant revolution in the treatment of hematological malignancies. Unfortunately, for solid tumors, this treatment modality has been proven insufficient to achieve significant antitumor activity. The use of modified T cell receptors towards tumor-associated antigens (NY-ESO, MAGE-A4) has recently shown antitumor activity in synovial sarcoma. Also, treatment with tumor-infiltrating lymphocytes shows clinical activity in metastatic cervical cancer and melanoma resistant to checkpoint inhibitors. Strategies to improve results and broaden the applicability of therapeutic lymphocytes for solid tumors include local delivery, fourth generation chimeric antigen receptor T cells, off-the-shelf T lymphocytes and private neoantigen-directed cells, among others. In this review, we summarize the status of adoptive cell therapy using T cells for solid tumors and the investigational strategies being tested in this field.

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study.

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086-2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110-2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531-13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

Tunable Whispering Gallery Mode Photonic Device Based on Microstructured Optical Fiber with Internal Electrodes.

We propose and experimentally demonstrate the first tunable whispering gallery mode (WGM) photonic device based on side-hole microstructured optical fiber (SH-MOF) with internal electrodes, in which the WGM quality factors do not decrease significantly during the tuning process. The resonant modes are redshifted simply by increasing the temperature. A description of the thermal tuning properties of the WGMs in SH-MOF with internal electrodes is performed by using a two-stage computational methodology, where the effects of metal filling process are considered. SH-MOF devices with internal electrodes are tested and the experimental results show excellent agreement with the theory. A linear relationship between the shift rate of the WGM modes and temperature is observed. The tunable SH-MOF microresonator with internal electrodes is anticipated to find potential applications in optical filtering, optical switching, and highly integrated tunable photonic devices.

Caracterización de los determinantes sociales de la salud, en la mortalidad materna de Cundinamarca, 2016-2019 / Characterization of social determinants of health in maternal mortality in Cundinamarca, 2016-2019 / Caracterização dos determinantes sociais da saúde na mortalidade materna em Cundinamarca, 2016-2019

Introducción: la mortalidad materna es un indicador sensible del grado de desarrollo de un país. Por ello fue incluido en los objetivos de desarrollo sostenible, pues su presencia mide la importancia que un país le da a la salud materna-perinatal y a la salud pública. Objetivo: describir las variables que caracterizan la mortalidad materna en Cundinamarca durante el periodo 2016-2019 y los determinantes sociales que pudieron influenciar en la ocurrencia del evento mortalidad materna, con el fin de orientar las políticas y programas que permitan el logro de metas relacionadas con la disminución de la ocurrencia de la mortalidad materna en el departamento. Métodos: se establecieron frecuencias absolutas y relativas que caracterizaron la muerte materna entre el 2016 y 2019, basados en datos del Sistema de Vigilancia Epidemiológica de la Mortalidad Materna en la Web (SVEMMBW). Se realizó un análisis bivariado a través del cálculo de las diferencias relativas de las razones a partir de un grupo de referencia dentro de cada variable, con el fin de determinar el impacto de los determinantes sociales en salud en la mortalidad materna. Resultados: para el año 2019 la razón más alta de muerte materna, teniendo en cuenta la edad, se representa en mujeres mayores de 40 años. Se observó que en el 2016 las mujeres con nivel de educación primaria tuvieron un mayor riesgo de mortalidad materna (RR: 1,56 IC: 95 %: 1,27-1,92); así mismo, la mujer dada de alta de manera inadecuada es un indicador que está presente en casi una cuarta parte de los casos 2016-2019; sin embargo, debe ser resuelto mediante estrategias apoyadas en educación efectiva del talento humano asistencial. El indicador de muerte materna es altamente sensible a condiciones de inequidad.

Introduction: Maternal mortality is a sensitive indicator of a country's level of development. For this reason, it was included in the Sustainable Development Goals, because its presence measures the importance a country gives to maternal and perinatal health and public health. Objective: To describe the variables that characterized maternal mortality in Cundinamarca during the 2016-2019 period and the social determinants that could have influenced the occurrence of maternal mortality. This is in order to guide policies and programs that facilitate achieving goals related to reducing the occurrence of maternal mortality in the department. Methods: Absolute and relative frequencies that characterized maternal mortality between 2016 and 2019 were established, based on data from the Web-based Maternal Mortality Epidemiological Surveillance System (SVEMMBW, for the Spanish original). A bivariate analysis was carried out by calculating the relative differences of the reasons based on a reference group within each variable, in order to determine the impact of social determinants on health in maternal mortality. Results: For 2019, the most common reason for maternal mortality, taking age into account, was represented in women over the age of 40. It was observed that, in 2016, women with a lower level of primary education had a greater risk of maternal mortality (RR: 1.56 CI: 95%: 1.27-1.92). Furthermore, women inappropriately discharged from the hospital is an indicator present in almost a quarter of the cases from 2016-2019. However, this must be resolved through strategies supported by effective education for human resources in healthcare. The indicator of maternal mortality is extremely sensitive to conditions of inequality.

Introdução: a mortalidade materna é um indicador sensível do grau de desenvolvimento de um país. Por isso, foi incluída nos objetivos de desenvolvimento sustentável, pois sua presença mede a importância que um país dá à saúde materno-perinatal e à saúde pública. Objetivo: descrever as variáveis que caracterizam a mortalidade materna em Cundinamarca durante o período 2016-2019 e os determinantes sociais que podem influenciar a ocorrência do evento de mortalidade materna, a fim de orientar políticas e programas que permitam alcançar metas relacionadas à redução na ocorrência de mortalidade materna no departamento. Métodos: foram estabelecidas as frequências absolutas e relativas que caracterizaram a morte materna entre 2016 e 2019, com base nos dados do Sistema de Vigilância Epidemiológica da Mortalidade Materna na Web (SVEMMBW). Foi realizada análise bivariada por meio do cálculo das diferenças relativas das razões de um grupo de referência dentro de cada variável, a fim de determinar o impacto dos determinantes sociais da saúde na mortalidade materna. Resultados: para o ano de 2019, a maior taxa de morte materna, tendo em conta a idade, está representada nas mulheres com mais de 40 anos. Observou-se que em 2016 mulheres com ensino fundamental apresentaram maior risco de mortalidade materna (RR: 1,56 IC: 95%: 1,27-1,92); da mesma forma, a mulher que recebeu alta inadequadamente é um indicador que está presente em quase um quarto dos casos 2016-2019; no entanto, deve ser resolvido por meio de estratégias apoiadas na educação efetiva dos recursos humanos nos cuidados de saúde. O indicador de morte materna é altamente sensível a condições de iniquidade.

Intervención de foco de brote de rabia animal en el municipio de Anapoima, Cundinamarca, Colombia, 2019 / Animal rabies outbreak intervention in the municipality of Anapoima, Cundinamarca, Colombia, 2019 / Intervenção do foco de surto de raiva animal no município de Anapoima, Cundinamarca, Colômbia, 2019

Objetivo: realizar la investigación y contención de brote de rabia animal en el perímetro del foco del caso índice del municipio de Anapoima. Métodos: estudio de investigación de brote con intervención del foco de índole retrospectivo, a partir de la confirmación del caso por laboratorio el 26 de abril de 2019. El equipo de respuesta inmediata departamental (conformado por tres médicos veterinarios, dos epidemiólogos y una enfermera), fue activado y desarrolló acciones en la zona de foco definido en 5 km alrededor de la vivienda del caso índice (vereda Panamá, sector Gallinazos, finca La Esmeralda del municipio de Anapoima). Tanto la población humana como la de gatos y perros de la zona fueron caracterizadas, se determinan factores de riesgo, se controló la población animal con vacunación y gestión del riesgo. Resultados: fueron visitadas 26 veredas que correspondieron al total del foco con 3.185 viviendas y se censaron 3.489 personas, de las cuales el 47% eran de sexo femenino y el 53% de sexo masculino. La cobertura de vacunación canina para control en el foco fue de 88% y la felina del 83%. Conclusiones: se confirma rabia en su ciclo silvestre en el departamento de Cundinamarca, con transmisión de animal silvestre a animal doméstico, con alto riesgo de transmisión a los humanos.

Objective: conduct the research and containment of the animal rabies outbreak in the focus perimeter of the index case in the municipality of Anapoima. Methods: outbreak investigation study with retrospective focus intervention, starting with laboratory confirmation of the case on April 26, 2019. The departmental immediate response team (made up of three veterinarians, two epidemiologists, and a nurse) was activated and carried out actions in the focus area defined as 5 km surrounding the dwelling of the index case (Panama township, Gallinazos sector, La Esmeralda farm, municipality of Anapoima). Both the human population, cats and dogs in the area were characterized. Risk factors were determined, the animal population was controlled with vaccination and risk management. Results: 26 townships were visited which corresponded to the total of the focus point with 3,185 dwellings. 3,489 people underwent a census, of which 47% were female, and 53% were male. The canine vaccine coverage to exercise control in the focus area was 88% with 83% for feline vaccination. Conclusions: rabies was confirmed in the forest cycle in the department of Cundinamarca, with transmission from forest animals to domestic animals, with a high risk of transmission to humans.

Objetivo: realizar a pesquisa e contenção do surto de raiva animal no perímetro do foco do caso índice no município de Anapoima. Métodos: estudo retrospectivo de pesquisa de surto com intervenção focal, baseado na confirmação laboratorial do caso em 26 de abril de 2019. A equipe departamental de resposta imediata (composta por: três veterinários, dois epidemiologistas e uma enfermeira), foi acionada e realizou ações na zona foco definida em 5 km ao redor da casa do caso índice (aldeia Panamá, setor Gallinazos, fazenda La Esmeralda do município de Anapoima). População humana, gatos e cães da área foram caracterizados, determinaram-se os fatores de risco, a população animal foi controlada com vacinação e gestão de risco. Resultados: foram visitadas 26 aldeias que correspondiam ao total do foco com 3.185 domicílios e 3.489 pessoas cadastradas, sendo 47% do sexo feminino e 53% do sexo masculino. A cobertura da vacinação canina para controle no foco foi de 88% e felina 83%. Conclusão: a raiva no seu ciclo silvestre é confirmada no departamento de Cundinamarca, com transmissão de animais silvestres para animais domésticos, com alto risco de transmissão para humanos.

Autosomal dominant hyperostosis/osteosclerosis with high serum alkaline phosphatase activity.

We studied eight affected and four unaffected individuals from a Colombian family with autosomal dominant diffuse high bone density. Affected individuals have normal, proportional height and high serum alkaline phosphatase activity. Radiographically, affected members exhibit generalized, symmetrically diffuse endosteal hyperostosis of the long bones and skull with narrow medullary cavities and loss of the diploë, respectively. There is no periosteal reaction or decreased hematopoiesis. Furthermore, osteosclerosis affects vertebral bodies, ribs, pelvis, mandible, clavicles, and scapulae. Bone mineral density is 2.4-7.3 SD above the mean for age and gender in affected individuals. Affected vs. unaffected individuals' Z-scores were (mean +/- SD) 5.03 +/- 1.77 vs. 0.08 +/- 0.97, respectively, P = 0.0004). Three affected subjects older than 40 yr old lost bone mass in 6 yr. No dysmorphism, abnormal facial features, bone fractures, or cranial nerve involvement was found. The pattern of inheritance, the absence of asymmetries and malformations, the increased serum alkaline phosphatase, the peak bone mass that appears to decrease physiologically with age, and the involvement of cortical and trabecular bone suggest a new variant of hyperostosis/osteosclerosis that affects the entire skeleton.

Deformability analysis of sickle blood using ektacytometry.

Sickle cell disease (SCD) is characterized by decreased erythrocyte deformability, microvessel occlusion and severe painful infarctions of different organs. Ektacytometry of SCD red blood cells (RBC) is made difficult by the presence of rigid, poorly-deformable irreversibly sickled cells (ISC) that do not align with the fluid shear field and distort the elliptical diffraction pattern seen with normal RBC. In operation, the computer software fits an outline to the diffraction pattern, then reports an elongation index (EI) at each shear stress based on the length and width of the fitted ellipse: EI=(length-width)/(length+width). Using a commercial ektacytometer (LORCA, Mechatronics Instruments, The Netherlands) we have approached the problem of ellipse fitting in two ways: (1) altering the height of the diffraction image on a computer monitor using an aperture within the camera lens; (2) altering the light intensity level (gray level) used by the software to fit the image to an elliptical shape. Neither of these methods affected deformability results (elongation index-shear stress relations) for normal RBC but did markedly affect results for SCD erythrocytes: (1) decreasing image height by 15% and 30% increased EI at moderate to high stresses; (2) progressively increasing the light level increased EI over a wide range of stresses. Fitting data obtained at different image heights using the Lineweaver-Burke routine yielded percentage ISC results in good agreement with microscopic cell counting. We suggest that these two relatively simple approaches allow minimizing artifacts due to the presence of rigid discs or ISC and also suggest the need for additional studies to evaluate the physiological relevance of deformability data obtained via these methods.