High threshold efficacy responses in moderate-to-severe atopic dermatitis are associated with additional quality of life benefits: pooled analyses of abrocitinib monotherapy studies in adults and adolescents.

BACKGROUND: Once-daily abrocitinib treatment provided meaningful improvements in signs and symptoms of moderate-to-severe atopic dermatitis (AD) in randomized controlled studies. OBJECTIVE: To evaluate proportions of patients with responses meeting higher threshold efficacy responses than commonly used efficacy end points and to determine if these responses were associated with quality-of-life (QoL) benefits. METHODS: Data from a phase 2b (NCT02780167) and two phase 3 studies (NCT03349060/JADE MONO-1; NCT03575871/JADE MONO-2) in adult and adolescent patients (N = 942) with moderate-to-severe AD receiving once-daily abrocitinib 200 mg, abrocitinib 100 mg or placebo were pooled. Commonly used (Eczema Area and Severity Index [EASI]-75 and ≥4-point improvement in Pruritus Numerical Rating Scale [PP-NRS4]) and higher threshold efficacy end points (EASI-90 to

Care pathways in atopic dermatitis: a retrospective population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is a complex disease with variations in severity and healthcare utilization. Examining patient pathways through analyses of longitudinal patient data provides an opportunity to describe real-world clinical patient care and evaluate healthcare access and treatment. OBJECTIVE: To describe longitudinal care pathways including health care management, treatment patterns and disease progression (by proxy measures) in patients with AD. MATERIALS AND METHODS: This was a longitudinal observational study, which used linked data from national and regional healthcare registers in Sweden. Patients with AD were identified through diagnosis in primary or secondary care or by dispensed medications. Descriptive statistics for number of healthcare visits, type of dispensed drug class, rate of - and time to - referral to secondary care and treatment escalation were calculated. RESULTS: A total of 341 866 patients with AD distributed as 197 959 paediatric (age < 12), 36 133 adolescent (age ≥ 12- < 18) and 107 774 adult (age ≥ 18) patients were included in this study. Healthcare visits to primary and secondary care and dispensation of AD-indicated treatments were more common during the year in which managed AD care was initiated. Topical corticosteroids (TCSs) and emollients were the most frequently used treatments across all age cohorts while systemic treatment was uncommon in all age cohorts. Among patients who initiated treatment with TCSs, 18.2% escalated to TCSs with higher potency following the start of managed AD care. CONCLUSIONS: We found that healthcare contacts and use of AD-indicated treatments were concentrated in the year during which managed AD care was initiated and decreased significantly thereafter. Since a significant proportion of patients with AD have flares and persistent AD, our results suggest that patients with AD may be monitored infrequently and are undertreated. There is a need to inform practitioners about adequate treatment options to provide individualized care, in particular for patients with persistent severe AD.

Gastric adenocarcinoma in childhood: a case report and a literature review. / Adenocarcinoma gástrico en la infancia. Reporte de caso y revisión de la literatura.

Gastric tumors, especially gastric adenocarcinomas, are rare in childhood and adolescence, as a result of which there is limited information. Therefore, management is typically extrapolated from adult patients. We report the case of a 10-year-old girl referred to our institution with systemic symptoms and pyloric syndrome. An infiltrating antro-pyloric lesion without evidence of metastasis was found. Histopathological analysis confirmed the presence of an undifferentiated diffuse gastric adenocarcinoma with signet ring cells. Diagnostic laparoscopy was carried out, which demonstrated signs of peritoneal carcinomatosis, so palliative chemotherapy was proposed.

Los tumores gástricos, en especial el adenocarcinoma gástrico, son infrecuentes en la infancia y la adolescencia. Por ello, la información sobre esta patología es limitada, de ahí que el manejo sea extrapolado de pacientes adultos. Reportamos el caso de una niña de 10 años de edad, remitida a nuestra institución, con síndrome constitucional y síndrome pilórico, en quien se encontró una lesión infiltrativa antropilórica sin evidencia de metástasis. El reporte histopatológico confirmó un adenocarcinoma gástrico difuso indiferenciado con células en anillo de sello. Se realizó laparoscopia diagnóstica donde se encuentran signos de carcitonamatosis peritoneal, por lo que se ofreció quimioterapia con intención paliativa.

Adenocarcinoma gástrico en la infancia. Reporte de caso y revisión de la literatura / Gastric adenocarcinoma in childhood: a case report and a literature review

Los tumores gástricos, en especial el adenocarcinoma gástrico, soninfrecuentes en la infancia y la adolescencia. Por ello, la informaciónsobre esta patología es limitada, de ahí que el manejo sea extrapoladode pacientes adultos.Reportamos el caso de una niña de 10 años de edad, remitida anuestra institución, con síndrome constitucional y síndrome pilórico,en quien se encontró una lesión infiltrativa antropilórica sin eviden-cia de metástasis. El reporte histopatológico confirmó un adenocar-cinoma gástrico difuso indiferenciado con células en anillo de sello.Se realizó laparoscopia diagnóstica donde se encuentran signos decarcitonamatosis peritoneal, por lo que se ofreció quimioterapia conintención paliativa.(AU)

Gastric tumors, especially gastric adenocarcinomas, are rare inchildhood and adolescence, as a result of which there is limited infor-mation. Therefore, management is typically extrapolated from adultpatients.We report the case of a 10-year-old girl referred to our institutionwith systemic symptoms and pyloric syndrome. An infiltrating antro-py-loric lesion without evidence of metastasis was found. Histopathologicalanalysis confirmed the presence of an undifferentiated diffuse gastricadenocarcinoma with signet ring cells. Diagnostic laparoscopy wascarried out, which demonstrated signs of peritoneal carcinomatosis, sopalliative chemotherapy was proposed.(AU)

Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis.

Given the lack of head-to-head studies of systemic therapies in moderate-to-severe atopic dermatitis (AD), network meta-analyses (NMAs) can provide comparative efficacy and safety data to inform clinical decision-making. In this NMA, eligible randomized controlled trials (RCTs) published before 24 October 2019 were identified by a systematic literature review. Short-term (12-16 weeks) efficacy (Investigator's Global Assessment [IGA] and Eczema Area and Severity Index [EASI] responses), patient-reported outcomes (PROs) and safety data from each trial were abstracted and analysed separately for monotherapy and combination therapy (systemic plus topical anti-inflammatory therapy). RCTs were analysed in fixed-effects and random-effects Bayesian NMA models. Overall, 19 phase 2 and phase 3 RCTs of abrocitinib, baricitinib, dupilumab, lebrikizumab, nemolizumab, tralokinumab and upadacitinib were included. In monotherapy RCTs, upadacitinib 30 mg once daily (QD) had the numerically highest efficacy (83.6% achieved ≥50% improvement in EASI [EASI-50 response]), followed by abrocitinib 200 mg QD (74.6%), upadacitinib 15 mg QD (70.5%), dupilumab 300 mg every 2 weeks (Q2W) (63.4%) and abrocitinib 100 mg QD (56.7%). Similar trends in EASI-75 and EASI-90 response were observed. In combination therapy RCTs, abrocitinib 200 mg QD had the highest EASI-50 (86.6%), followed by dupilumab 300 mg Q2W (82.4%) and abrocitinib 100 mg QD (79.7%). Similar findings were observed for IGA response and PROs. In monotherapy and combination therapy RCTs, the probability of treatment-emergent adverse events (TEAEs) was higher among all active treatments than with placebo (except for dupilumab 300 mg Q2W [odds ratio (OR), 0.96; 95% credible interval (CrI), 0.45-2.18] and abrocitinib 100 mg QD [OR, 0.95; 95% CrI, 0.35-2.66] in combination therapy RCTs), although active treatments did not significantly differ from one another. Abrocitinib, dupilumab and upadacitinib were consistently the most effective systemic therapies in adult and adolescent patients with AD, with no significant TEAE differences in short-term RCTs.

Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats.

Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

Hormone therapy with tamoxifen reduces plasma levels of NT-B-type natriuretic peptide but does not change ventricular ejection fraction after chemotherapy in women with breast cancer

The objective of this study was to evaluate the effect of tamoxifen on the plasma concentration of NT-pro-B-type natriuretic peptide (NT-proBNP) in women undergoing chemotherapy for breast cancer and to correlate changes in NT-proBNP with the left ventricular ejection fraction (LVEF). Over a period of 12 months, we followed 60 women with a diagnosis of breast cancer. The patients were separated into a group that received only chemotherapy (n=23), a group that received chemotherapy + tamoxifen (n=21), and a group that received only tamoxifen (n=16). Plasma levels of NT-proBNP were assessed at 0 (T0), 6 (T6), and 12 (T12) months of treatment, and echocardiography data were assessed at T0 and T12. Plasma NT-proBNP levels were increased in the chemotherapy-only group at T6 and T12, whereas elevated NT-proBNP levels were only found at T6 in the chemotherapy + tamoxifen group. At T12, the chemotherapy + tamoxifen group exhibited a significant reduction in the peptide to levels similar to the group that received tamoxifen alone. The chemotherapy-only group exhibited a significant decrease in LVEF at T12, whereas the chemotherapy + tamoxifen and tamoxifen-only groups maintained levels similar to those at the beginning of treatment. Treatment with tamoxifen for 6 months after chemotherapy significantly reduced the plasma levels of NT-proBNP and did not change LVEF in women with breast cancer.

Hormone therapy with tamoxifen reduces plasma levels of NT-B-type natriuretic peptide but does not change ventricular ejection fraction after chemotherapy in women with breast cancer.

The objective of this study was to evaluate the effect of tamoxifen on the plasma concentration of NT-pro-B-type natriuretic peptide (NT-proBNP) in women undergoing chemotherapy for breast cancer and to correlate changes in NT-proBNP with the left ventricular ejection fraction (LVEF). Over a period of 12 months, we followed 60 women with a diagnosis of breast cancer. The patients were separated into a group that received only chemotherapy (n=23), a group that received chemotherapy + tamoxifen (n=21), and a group that received only tamoxifen (n=16). Plasma levels of NT-proBNP were assessed at 0 (T0), 6 (T6), and 12 (T12) months of treatment, and echocardiography data were assessed at T0 and T12. Plasma NT-proBNP levels were increased in the chemotherapy-only group at T6 and T12, whereas elevated NT-proBNP levels were only found at T6 in the chemotherapy + tamoxifen group. At T12, the chemotherapy + tamoxifen group exhibited a significant reduction in the peptide to levels similar to the group that received tamoxifen alone. The chemotherapy-only group exhibited a significant decrease in LVEF at T12, whereas the chemotherapy + tamoxifen and tamoxifen-only groups maintained levels similar to those at the beginning of treatment. Treatment with tamoxifen for 6 months after chemotherapy significantly reduced the plasma levels of NT-proBNP and did not change LVEF in women with breast cancer.

Effect of tamoxifen on the coronary vascular reactivity of spontaneously hypertensive female rats.

Tamoxifen has been associated with a reduction in the incidence of myocardial infarction. However, the effects of tamoxifen on coronary reactivity have not been fully elucidated. The objective of this study was to determine the effects of chronic treatment with tamoxifen on coronary vascular reactivity in spontaneously hypertensive rats (SHR). Female SHR were divided into four groups (N = 7 each): sham-operated (SHAM), sham-operated and treated with tamoxifen (10 mg/kg) by gavage for 90 days (TAMOX), ovariectomized (OVX), and ovariectomized and treated with tamoxifen (OVX+TAMOX). Mean arterial pressure (MAP), heart rate (HR), coronary perfusion pressure (CPP), and coronary vascular reactivity were measured. MAP and HR were reduced (9.42 and 11.67%, respectively) in the OVX+TAMOX group compared to the OVX group (P < 0.01). The coronary vascular reactivity of the OVX+TAMOX group presented smaller vasoconstrictor responses to acetylcholine (2-64 µg) when compared to the OVX group (P < 0.01) and this response was similar to that of the SHAM group. The adenosine-induced vasodilator response was greater in the TAMOX group compared to the SHAM and OVX groups (P < 0.05). Baseline CPP was higher in OVX+TAMOX and TAMOX groups (136 ± 3.6 and 130 ± 1.5 mmHg) than in OVX and SHAM groups (96 ± 2 and 119 ± 2.3 mmHg; P < 0.01). Tamoxifen, when combined with OVX, attenuated the vasoconstriction induced by acetylcholine and increased the adenosine-induced vasodilatory response, as well as reducing the MAP, suggesting beneficial effects of tamoxifen therapy on coronary vascular reactivity after menopause.

Effect of tamoxifen on the coronary vascular reactivity of spontaneously hypertensive female rats

Tamoxifen has been associated with a reduction in the incidence of myocardial infarction. However, the effects of tamoxifen on coronary reactivity have not been fully elucidated. The objective of this study was to determine the effects of chronic treatment with tamoxifen on coronary vascular reactivity in spontaneously hypertensive rats (SHR). Female SHR were divided into four groups (N = 7 each): sham-operated (SHAM), sham-operated and treated with tamoxifen (10 mg/kg) by gavage for 90 days (TAMOX), ovariectomized (OVX), and ovariectomized and treated with tamoxifen (OVX+TAMOX). Mean arterial pressure (MAP), heart rate (HR), coronary perfusion pressure (CPP), and coronary vascular reactivity were measured. MAP and HR were reduced (9.42 and 11.67 percent, respectively) in the OVX+TAMOX group compared to the OVX group (P < 0.01). The coronary vascular reactivity of the OVX+TAMOX group presented smaller vasoconstrictor responses to acetylcholine (2-64 µg) when compared to the OVX group (P < 0.01) and this response was similar to that of the SHAM group. The adenosine-induced vasodilator response was greater in the TAMOX group compared to the SHAM and OVX groups (P < 0.05). Baseline CPP was higher in OVX+TAMOX and TAMOX groups (136 ± 3.6 and 130 ± 1.5 mmHg) than in OVX and SHAM groups (96 ± 2 and 119 ± 2.3 mmHg; P < 0.01). Tamoxifen, when combined with OVX, attenuated the vasoconstriction induced by acetylcholine and increased the adenosine-induced vasodilatory response, as well as reducing the MAP, suggesting beneficial effects of tamoxifen therapy on coronary vascular reactivity after menopause.

Obesity patterns among women in a slum area in Brazil.

High-energy diet and sedentary lifestyle fail to completely explain the epidemic of obesity in developing countries. In this cross-sectional survey, the prevalence and patterns of overweight/obesity were assessed among women in a slum in Brazil. Using anthropometric measurements, shorter form of the International Physical Activity Questionnaire (IPAQ), and a 24-hour diet recall questionnaire, data were collected from 632 women aged 20-60 years. The prevalence of overweight and obesity was 29% and 17% respectively. Physical inactivity was found in 17% of the women; 12% of them had short stature, and 44% had energy intake below the recommended dietary allowance. Results of multiple logistic regression showed that overweight/obesity differed significantly (p < 0.05) in the following aspects: abdominal circumference, energy intake, and short stature. A high prevalence of overweight/obesity was found in a very poor community associated with high-energy intake and short stature.

[Hemoglobin S haplotypes: their epidemiologic, anthropologic and clinical importance]. / Haplotipos de la hemoglobina S: importancia epidemiológica, antropológica y clínica.

The link between beta s-gene haplotypes and sickle cell anemia has permitted a better understanding of the biological manifestations of this disease. The use of better laboratory methods can help rule out other hereditary factors that can camouflage the real hemoglobin genotype. The clinical heterogeneity of sickle cell disease, which is characterized by the presence of S hemoglobin, can be explained in terms of fetal hemoglobin (HbF) levels, ratio of G gamma chains to A gamma chains, 2,3-diphosphoglycerate levels, linked mutations, beta s haplotypes, coexistence of alpha-thalassemia, and environmental factors. The inheritance of Sen and Arab/Indian beta-gene cluster polymorphisms is associated with a milder clinical course, whereas the Central African Republic (CAR) or Bantu, Cameroon, and Benin haplotypes are linked with severe sickle cell disease. The CAR haplotype carries the worst prognosis of all (less than 12% HbF levels and adult-type G gamma:A gamma ratio). Once characterized, these DNA polymorphisms also assume great importance as anthropologic and genetic markers. In America, beta s haplotypes are contributing to a better understanding of Black American roots and their African ancestry. There is ample evidence of genetic variability not only between different Black populations in America, but also within the same country, as is the case in Costa Rica.

The relative levels of different types of beta-mRNA and beta-globin in BFU-E derived colonies from patients with beta chain variants; further evidence for somatic mosaicism in the Hb Costa Rica carrier [beta 77(EF1)His-->Arg].

We have identified and quantitated the different types of mRNA in single BFU-E derived colonies from Hb S and Hb Atlanta [beta 75 (E19)Leu-->Pro] heterozygotes and observed that the normal and mutated mRNAs were present in equal quantities. Similar studies for the different protein products gave less accurate data because high performance liquid chromatography methods were not sensitive enough for the analysis of a single colony, and as many as five colonies needed to be combined. The level of Hb S (approximately 40%) was the same as in red cell lysates of the Hb S heterozygote, while that of the unstable beta-Atlanta chain was lower than expected from the values observed in red cells. Similar studies for a carrier of the stable Hb Costa Rica [beta 77(EF1) His-->Arg] which was reported to be the result of a somatic cell mutation (1) gave quite different data. Dot-blot analysis with 32P-labeled probes and allele specific amplification methodology identified numerous colonies with beta A-mRNA only, while 12-15% of the colonies contained both beta A- and beta-Costa Rica-mRNA. This limited distribution of the beta-Costa Rica-mRNA was confirmed by hemoglobin analysis with anion exchange high performance liquid chromatography. These results are considered to provide additional and convincing evidence for a somatic mosaicism for the CAC-->CGC mutation at codon 77 of the beta gene which occurred during the development of the embryo and results in the presence of only some 6-8% of the abnormal Hb Costa Rica in the circulating red cells.

Hb Costa Rica or alpha 2 beta 2 77(EF1)His --> Arg: the first example of a somatic cell mutation in a globin gene.

We have identified a minor hemoglobin component (approximately 5%) in the blood of a healthy Costa Rican female, but not in her mother and two brothers (father not studied), that has an His --> Arg replacement at position beta 77 (Hb Costa Rica). No other amino acid replacements were observed and no beta- or gamma-chain-like peptides were present. Hb Costa Rica has abnormal stability. Sequence analyses of numerous polymerase chain reaction (PCR)-amplified segments of DNA that contain exon 2 of the beta gene failed to identify a CAC --> CGC (His --> Arg) mutation. The same was the case when cDNA was sequenced, indicating that a beta-Costa Rica-mRNA could not be detected with this procedure. Gene mapping of genomic DNA with Bg/II, BamHI, and HindIII gave normal fragments only and with the same intensity as observed for the fragments of a normal control. The quantities of the beta chain variants Hb J-Iran and Hb Fukuyama with related mutations at beta 77 vary between 30% and 45% in heterozygotes, whereas that of Hb F-Kennestone with the same His --> Arg mutation but in the G gamma-globin gene, is a high 40%-45% (as percentage of total G gamma) in a heterozygous newborn. These different observations exclude a heterozygosity of the A --> G mutation at codon beta 77, as well as a deletion comparable to that of Hbs Lepore or Kenya, or a beta-globin gene duplication, and point to a nontraditional inheritance of Hb Costa Rica. Allele-specific amplification of cDNA with appropriate primers identified the presence of a low level of mutated mRNA in the reticulocytes of the patient, which was confirmed by dotblot analysis of the same material with 32P-labeled probes. Comparable amplification products were not observed in genomic DNA. The A --> G mutation apparently occurred in a somatic cell at a relatively early stage in the development of the hematopoietic cell system, and Hb Costa Rica accumulated through rapid cell divisions in patchy areas in the bone marrow (somatic mosaicism). An unequal distribution of Hb Costa Rica over the red cells supports this possibility.

[Structural variants of hemoglobin in Ibero-America]. / Variantes estructurales de la hemoglobina en Iberoamérica.

Structural hemoglobin variants are reviewed for Iberoamerica; specially in Latin America, they reflect racial composition and geographic origin. Latin American genetic composition is a function of ethnic composition in each country (mainly Africans and Spaniards, and the "indians" or native peoples). For this reason the distribution of hemoglobin variants has been greatly affected by the individual and population movements, specially as a result of the 18th and 19th century African slave trade. Scientific, sanitary, social and cultural factors explain (at least for Latin America and Portugal), a quantitative and qualitative subestimation of the structural variants of hemoglobin. In Spain, which has extensive research on the subject, the Caucasian variant number is known to be high, compared with Latin America and Portugal. Concerning origin and prevalence of hemoglobin polymorphism, the only established positive selection force is malaria falciparum. In Iberoamerica, the Hb S, as the major polymorphism and the HbC, have the greatest clinical and anthropological importance. Nevertheless, most variants are rare (found in an individual person or a particular family). Other minor Iberoamerica polymorphisms are the Hb E and D-Punjab, from Asia; and the Hb Korle-Bu, G-Philadelphia and A2 from Africa.