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Purificación Martínez del Prado,1 Isabel Alvarez-López,2,3 Severina Domínguez-Fernández,4 Arrate Plazaola,5 Oliver Ibarrondo,6 Elena Galve-Calvo,1 Nerea Ancizar-Lizarraga,2,3 María Gutierrez-Toribio,4 Ainhara Lahuerta-Martínez,5 Javier Mar6,7 1Medical Oncology Service, Basurto University Hospital, Bilbao, Spain; 2Medical Oncology Service, Donostia University Hospital, Donostia-San Sebastián, Spain; 3Biodonostia Health Research Institute, Donostia-San Sebastián, Spain; 4Medical Oncology Service, Araba University Hospital, Vitoria-Gasteiz, Spain; 5Medical Oncology Service, Onkologikoa, Donostia-San Sebastián, Spain; 6AP-OSI Research Unit, Alto Deba Integrated Health Care Organization, Mondragon, Spain; 7Health Services Research on Chronic Patients Network, Kronikgune Group, Bilbao, Spain Purpose: The 21-gene recurrence score (RS) is a genomic test developed as a prognostic and predictive tool to improve the treatment decision making in cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer. This study examined the clinical and economic impact of its use in 4 Basque Country university hospitals. Methods: Taking into consideration the RS result, we recorded the recommended initial systemic adjuvant therapy (endocrine therapy with or without chemotherapy) according to standard clinicopathologic factors and the final decision about chemotherapy. Then, if the RS was high, chemotherapy was recommended; it was not recommended if the RS was low; for those with an intermediate RS, clinicopathologic factors were considered, and the initial recommendation based on those factors was maintained. In addition, the probability of switching treatment was calculated. Then, we developed an economic evaluation by measuring the treatment’s incremental short-term budget impact from both the societal perspective and that of the Basque Health System. Patients’ characteristics and chemotherapy use were analyzed using logistic regressions and receiver operating characteristic curves. Results: Without an RS, chemotherapy would have been prescribed to 56% of 401 patients, but, with RS use, that percentage decreased to 25. The overall rate of decision change was 35.4%. Test inclusion led to a reduction in chemotherapy costs of €922 per patient in the total population. Although this reduction did not entirely offset the cost of the test, the productivity loss per patient was reduced by €1,977. Conclusion: The 21-gene RS test significantly changed the indication for chemotherapy. As chemotherapy treatments with no benefit were avoided, patients’ quality of life was improved. The short-term economic impact was negative for the Basque Health Service, but savings resulted when sick-leave costs were included. Keywords: early-stage breast cancer, adjuvant chemotherapy, 21-gene assay, economic evaluation, health care costs

The quantification of phytochemicals with nutritional benefits relies on accuracy yet time-consuming, expensive and destructive methodologies. In contrast, optical indices widely employed in disciplines such as ecology can serve as fast, low-cost, and non-destructive tools for tracking pigment changes. However, their potential application in postharvest phases and commercialization (i.e., supermarkets) remains underexplored. In this context, this work aimed to investigate the feasibility of using the normalized difference vegetation index (NDVI), the chlorophyll content index (CCI) and the photochemical reflectance index (PRI) to estimate phytochemicals of nutraceutical interest (chlorophylls, carotenoids and tocopherols). A fully factorial and randomized experimental design (combining different illumination, packaging, and collecting time) was conducted in two green leafy packaged vegetables (rocket and spinach). With this design that induced differences in physiological parameters a database with variable content of isoprenoids (carotenoids, chlorophylls, and tocopherols) based on treatments was created. By establishing correlations and models between isoprenoids and optical indices, the NDVI was revealed as a valuable tool to estimate chlorophyll content in both species, while the PRI tracked both tocopherol and carotenoid (except for β-carotene) content. Taking this approach, estimation of the sum of total carotenoids and tocopherols was achieved using the PRI. This study confirms the possibility of extending the use of the NDVI and PRI to real-time nutritional monitoring in different stages of production and commercialization. A future application envisions integrating this technology into refrigerators for enhanced consumer access to nutritional information.

Dengue virus serotypes 1 to 4 (DENV1–4) and Zika virus (ZIKV) are mosquito-borne flaviviruses that induce both virus-specific and broadly reactive antibodies. A first DENV infection is thought to induce antibodies that wane over 2 years to titers that can subsequently enhance severe dengue disease. Secondary DENV infection with a different serotype is thought to induce stable, cross-serotype protective antibodies. Low dengue disease incidence after the recent Zika pandemic led to the hypothesis that ZIKV infection is also transiently cross protective. We investigated antibody kinetics in 4189 children up to 11 years after one and multiple DENV and ZIKV infections in longitudinal cohorts in Nicaragua. We used a DENV inhibition enzyme-linked immunosorbent assay (iELISA), which measures antibodies associated with protection against dengue and Zika disease and with enhancement of dengue disease severity. Unexpectedly, we found that overall DENV iELISA titers stabilized by 8 months after primary DENV infection to a half-life longer than a human life and waned, although gradually, after secondary DENV infection. Similarly, DENV iELISA titers were stable or rose after primary ZIKV infection but declined in individuals with histories of DENV and ZIKV infection. In contrast, kinetics of anti-ZIKV antibodies after ZIKV infection were similar regardless of prior DENV immunity. We observed heterogeneity in DENV iELISA titer, suggesting that individual antibody titer set point, rather than waning, is important for future dengue disease risk. Together, these findings change our understanding of anti-flavivirus antibody kinetics and have implications for measuring vaccine efficacy and for predicting future dengue and Zika outbreaks.

The Zika pandemic sparked intense interest in whether immune interactions among dengue virus serotypes 1 to 4 (DENV1 to -4) extend to the closely related Zika virus (ZIKV). We investigated prospective pediatric cohorts in Nicaragua that experienced sequential DENV1 to -3 (2004 to 2015), Zika (2016 to 2017), and DENV2 (2018 to 2020) epidemics. Risk of symptomatic DENV2 infection and severe disease was elevated by one prior ZIKV infection, one prior DENV infection, or one prior DENV infection followed by one ZIKV infection, compared with being flavivirus-naïve. By contrast, multiple prior DENV infections reduced dengue risk. Further, although high preexisting anti-DENV antibody titers protected against DENV1, DENV3, and ZIKV disease, intermediate titers induced by previous ZIKV or DENV infection enhanced future risk of DENV2 disease and severity, as well as DENV3 severity. The observation that prior ZIKV infection can modulate dengue disease severity like a DENV serotype poses challenges to development of dengue and Zika vaccines.

BackgroundPaedeatric Zika remains an understudied topic. WHO and the Pan American Health Organization (PAHO) Zika case definitions have not been assessed in children. We aimed to characterise clinical profiles and evaluate the diagnostic performance of the WHO and PAHO case definitions in a large cohort of paediatric Zika cases.MethodsFrom January, 2016 to February, 2017, encompassing the major 2016 Zika epidemic, participants in the Pediatric Dengue Cohort Study (PDCS) in Managua, Nicaragua, were encouraged to visit the study health centre at first indication of any illness. PDCS participants were aged 2-14 years, healthy at enrolment, and recruited before the initiation of the present study. Molecular and serological assays were used to test participants exhibiting any of four broad clinical profiles suspected of resulting from a symptomatic Zika virus infection. These clinical profiles were: fever and at least two of headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations, and leukopenia; fever and at least two of nausea or vomiting, rash, aches and pains, positive tourniquet test, leukopenia, and any dengue warning sign; undifferentiated fever without evident cause, with or without any other clinical finding; and afebrile rash with or without any other clinical finding. We characterised acute clinical findings (signs, symptoms, and complete blood counts) in both Zika cases and non-Zika cases.FindingsWe prospectively followed a cohort of about 3700 children, of which 1110 were deemed eligible for inclusion. Four participants with laboratory-confirmed Zika (three co-infections with dengue virus, one missing complete blood count data) and two participants who were non-Zika cases (missing complete blood count data) were excluded from analysis. We analysed 556 laboratory-confirmed Zika and 548 non-Zika cases. The WHO case definition captured 176 confirmed Zika cases, and the PAHO definition 109 confirmed Zika cases, who presented with the most clinical findings and a dengue-like clinical profile. The remaining two thirds of Zika cases, principally characterised by undifferentiated fever or afebrile rash, were missed. Among Zika cases, rash (n=440)-particularly generalised erythematous rash (n=334)-fever (n=333), leukopenia (n=217), and headache (n=203) were most common and peaked within 3 days of illness onset. The most common Zika presentation over the first week of illness was rash only (n=80). The sensitivity of Zika case definitions increased across paediatric age (from 11·3% to 56·1% for the WHO case definition and from 6·0% to 36·6% for the PAHO case definition), as the prevalence of most clinical findings (particularly arthralgia) increased with age, irrespective of previous dengue virus infection. Consequently, Zika manifested differently across paediatric age; older Zika cases presented with a dengue-like clinical profile while younger Zika cases presented with undifferentiated fever or afebrile rash.InterpretationWe provide the most thorough description of paediatric Zika to date. Most paediatric Zika cases go undetected under the WHO and PAHO case definitions, suggesting that current standards for Zika case ascertainment require revision. Zika manifests with mild but differing clinical profiles across paediatric age, presenting major challenges to diagnosis, surveillance, and efforts to control future Zika epidemics.FundingUS National Institutes of Health.

Pathological processes often change the mechanical properties of cells. Increased rigidity could be a marker of cellular malfunction. Erythrocytes are a type of cell that deforms to squeeze through tiny capillaries; changes in their rigidity can dramatically affect their functionality. Furthermore, differences in the homeostatic elasticity of the cell can be used as a tool for diagnosis and even for choosing the adequate treatment for some illnesses. More accurate types of equipment needed to study biomechanical phenomena at the single-cell level are very costly and thus out of reach for many laboratories around the world. This study presents a simple and low-cost technique to study the rigidity of red blood cells (RBCs) through the application of electric fields in a hand-made microfluidic chamber that uses a capacitor principle. As RBCs are deformed with the application of voltage, cells are observed under a light microscope. From mechanical force vs. deformation data, the elastic constant of the cells is determined. The results obtained with the capacitor-based method were compared with those obtained using optical tweezers, finding good agreement. In addition, P. falciparum-infected erythrocytes were tested with the electric field applicator. Our technique provides a simple means of testing the mechanical properties of individual cells.

Summary: Early stress detection of crops requires a thorough understanding of the signals showing the very first symptoms of the alterations in the photosynthetic light reactions. Detection of the activation of the regulated heat dissipation mechanism is crucial to complement passively induced fluorescence to resolve ambuiguities in energy partitioning.Using leaf spectroscopy, we evaluated the capability of pigment spectral unmixing to calculate the fluorescence quantum efficiency (FQE) and simultaneously retrieve fast absorption changes in a drought and nitrogen deficiency experiment with tomato. In addition, active fluorescence measurements and pigment analyses of xanthophylls, carotenes and chlorophylls were conducted.We observed notable responses in noninvasive proximal sensing‐retrieved FQE values under stress, but as expected, these alone were not enough to identify the constraints in photosynthetic efficiency. Reflectance‐based detection of the 535‐nm peak absorption change was able to complement FQE and indicate the activation of regulated heat dissipation for both stress treatments under growing light conditions. However, further complexity in the light harvesting energy regulation needs to be accounted for when considering additional light stress.Our results underscore the potential of complementary in vivo quantitative spectroscopy‐based products in the early and nondestructive stress diagnosis of plants, marking the path for further applications. [ABSTRACT FROM AUTHOR]

Background: Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease. Methods: This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the relationship of serotype and immune status with dengue severity. Dengue cases were confirmed by molecular, serological, and/or virological methods, and study participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients. Results: We enrolled a total of 15,833 participants, of whom 3,308 (21%) were positive for DENV infection. Of 2,644 cases with serotype result by RT-PCR, 559 corresponded to DENV1, 1,002 to DENV2, 760 to DENV3 and 323 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 caused a higher proportion of severe disease compared to other serotypes, whereas DENV3 caused the greatest percentage of severity according to the WHO-2009 classification. DENV2 was associated with increased odds of pleural effusion and low platelet count, while DENV3 was associated with both hypotensive and compensated shock. Conclusions: These findings demonstrate differences in dengue severity by serotype and immune status and emphasize the critical need for a dengue vaccine with balanced effectiveness against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and serostatus. Author summary: Dengue, a major public health threat, is a viral infection spread by mosquitoes that can cause a range of symptoms from mild to life-threatening. Our study analyzed 19 years of data from two pediatric studies of dengue in children 6 months to 17 years of age in Managua, Nicaragua. We aimed to understand how dengue severity varies with different serotypes of dengue virus (DENV1-4) and whether the child had experienced a previous DENV infection or not. We also used two classification schemes of dengue severity, published by the World Health Organization in 1997 and 2009. Overall, we found that DENV2 and DENV3 caused the most severe disease in children. DENV3 and DENV1 led to severe outcomes in both primary (first) infection and secondary infections with another DENV serotype, while DENV2 and DENV4 manifested severity in secondary infections. These findings highlight the importance of a balanced dengue vaccine that can protect against all four virus serotypes, as current vaccines show varying effectiveness by serotype. Our research emphasizes the need for effective prevention and treatment strategies to manage dengue, particularly in regions where the virus is widespread. [ABSTRACT FROM AUTHOR]

Background Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically subdominant region, has not been established for influenza virus A/H3N2. Methods Household transmission studies were conducted in Managua, Nicaragua, across 3 influenza seasons. Household contacts were tested for influenza virus infection using reverse-transcription polymerase chain reaction. We compared preexisting antibody levels against full-length HA, HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay, along with hemagglutination inhibition assay titers, between infected and uninfected participants. Results A total of 899 individuals participated in household activation, with 329 infections occurring. A 4-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (adjusted odds ratio [aOR], 0.82 [95% confidence interval {CI},.68–.98]; P =.04). In adults, anti-HA stalk antibodies were independently associated with protection (aOR, 0.72 [95% CI,.54–.95]; P =.02). However, in 0- to 14-year-olds, anti-NA antibodies (aOR, 0.67 [95% CI,.53–.85]; P <.01) were associated with protection against infection, but anti-HA stalk antibodies were not. Conclusions The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history. [ABSTRACT FROM AUTHOR]

In 2015, a Zika epidemic in Brazil began spreading throughout the Americas. Zika virus (ZIKV) entered Managua, Nicaragua, in January 2016 and caused an epidemic that peaked in July-September 2016. ZIKV seropositivity was estimated among participants of pediatric (n = 3,740) and household (n = 2,147) cohort studies, including an adult-only subset from the household cohort (n = 1,074), in Managua. Seropositivity was based on a highly sensitive and specific assay, the Zika NS1 blockade-of-binding ELISA, which can be used in dengue-endemic populations. Overall seropositivity for the pediatric (ages 2-14), household (ages 2-80), and adult (ages 15-80) cohorts was 36, 46, and 56%, respectively. Trend, risk factor, and contour mapping analyses demonstrated that ZIKV seroprevalence increased nonlinearly with age and that body surface area was statistically associated with increasing seroprevalence in children. ZIKV seropositivity was higher in females than in males across almost all ages, with adjusted prevalence ratios in children and adults of 1.11 (95% CI: 1.02-1.21) and 1.14 (95% CI: 1.01-1.28), respectively. No household-level risk factors were statistically significant in multivariate analyses. A spatial analysis revealed a 10-15% difference in the risk of ZIKV infections across our 3-km-wide study site, suggesting that ZIKV infection risk varies at small spatial scales. To our knowledge, this is the largest ZIKV seroprevalence study reported in the Americas, and the only one in Central America and in children to date. It reveals a high level of immunity against ZIKV in Managua as a result of the 2016 epidemic, making a second large Zika epidemic unlikely in the near future.

El síndrome de hemivagina obstruida y anomalía renal ipsilateral (OHVIRA) es producido por una alteración en el desarrollo de los conductos de Mu?ller y Wolff en la vida fetal. El síndrome es poco frecuente, se reporta una prevalencia de 1/2.000 a 1/28.000 casos. La endometriosis se presenta en un 19% de los casos complicando esta patología. El tratamiento del síndrome OHVIRA consiste en resecar el tabique vaginal drenando el hematocolpos. Hasta el momento no existe un consenso en recomendar la realización de una laparoscopia diagnóstica. El objetivo de este estudio es reportar la eventual importancia de la laparoscopia diagnóstica/terapéutica como parte del manejo del síndrome OHVIRA.

Zika virus (ZIKV) infection recently caused major epidemics in the Americas and is linked to congenital birth defects and Guillain-Barré Syndrome. A pilot study of ZIKV infection in Nicaraguan households was conducted from August 31 to October 21, 2016, in Managua, Nicaragua. We enrolled 33 laboratory-confirmed Zika index cases and their household members (109 contacts) and followed them on days 3-4, 6-7, 9-10, and 21, collecting serum/plasma, urine, and saliva specimens along with clinical, demographic, and socio-economic status information. Collected samples were processed by rRT-PCR to determine viral load (VL) and duration of detectable ZIKV RNA in human bodily fluids. At enrollment, 11 (10%) contacts were ZIKV rRT-PCR-positive and 23 (21%) were positive by IgM antibodies; 3 incident cases were detected during the study period. Twenty of 33 (61%) index households had contacts with ZIKV infection, with an average of 1.9 (range 1-6) positive contacts per household, and in 60% of these households, ≥50% of the members were positive for ZIKV infection. Analysis of clinical information allowed us to estimate the symptomatic to asymptomatic (S:A) ratio of 14:23 (1:1.6) among the contacts, finding 62% of the infections to be asymptomatic. The maximum number of days during which ZIKV RNA was detected was 7 days post-symptom onset in saliva and serum/plasma and 22 days in urine. Overall, VL levels in serum/plasma, saliva, and urine specimens were comparable, with means of 5.6, 5.3 and 4.5 log10 copies/ml respectively, with serum attaining the highest VL peak at 8.1 log10 copies/ml. Detecting ZIKV RNA in saliva over a similar time-period and level as in serum/plasma indicates that saliva could potentially serve as a more accessible diagnostic sample. Finding the majority of infections to be asymptomatic emphasizes the importance of silent ZIKV transmission and helps inform public health interventions in the region and globally.

The ability to culture normal human mammary epithelial cells (HMEC) greatly facilitates experiments that seek to understand both normal mammary cell biology and the many differences between normal and abnormal human mammary epithelia. To maximize in vivo relevance, the primary cell culture conditions should maintain cells in states that resemble in vivo as much as possible. Towards this goal, we compared the properties of HMEC strains from two different reduction mammoplasty tissues that were grown in parallel using different media and culture conditions. Epithelial organoids were initiated into three different media: two commonly used serum-free-media, MCDB 170-type (e.g. MEGM) and WIT-P, and a low stress media, M87A. Growth, lineage heterogeneity, p16 protein expression, and population doublings to senescence were measured for each culture condition. MCDB 170 caused rapid senescence and loss of heterogeneity within 2 to 3 passages, but some cultures went through the 1 to 2 month process of selection to generate clonal finite post-selection post-stasis cells. WIT-P caused impressive expansion of luminal cells in 2nd passage followed by their near complete disappearance by passage 4 and senescence shortly thereafter. M87A supported as much as twice the number of population doublings compared to either serum-free medium, and luminal and myoepithelial cells were present for as many as 8 passages. Thus, of the three media compared, WIT-P and MCDB 170 imposed rapid senescence and loss of lineage heterogeneity, phenotypes consistent with cells maintained in high-stress conditions, while M87A supported cultures that maintained multiple lineages and robust growth for up to 60 population doublings. In conjunction with previous studies examining the molecular properties of cultures grown in these media, we conclude that M87A medium is most able to support long-term culture of multiple lineages similar to in vivo conditions, thereby facilitating investigations of normal HMEC biology relevant to the mammary gland in situ.

Drought‐related die‐off events have been observed throughout Europe in Scots pine (Pinus sylvestris L.). Such events are exacerbated by carbon starvation that is, an imbalance of photosynthetic productivity and resource usage. Recent evidence suggests that optically measurable photosynthetic pigments such as chlorophylls and carotenoids respond to water stress (WS). However, there is a lack of measurements using imaging spectroscopy, and the mechanisms linking xanthophyll‐related changes in reflectance captured by the photochemical reflectance index (PRI) and chlorophyll changes in red edge position (REP) to WS are not understood. To probe this, we conducted a greenhouse experiment where 3‐year‐old Pinus sylvestris saplings were subjected to water limitation and followed using hyperspectral imaging (HSI) spectroscopy, water status and photosynthetic measurements. Carotenoids (e.g., xanthophyll cycle) and chlorophylls responded to WS, which was observed using the HSI‐derived indices PRI and REP respectively. The spatial‐temporal response in these two pigment‐reflectance groupings differed. The spatial distribution of PRI represented the light intensity around the time of the measurement, whereas REP reflected the daily averaged light intensity over the experimental course. A further difference was noted upon rewatering, where the carotenoid‐related PRI partially recovered but the chlorophyll‐related REP did not. Summary statement: Hyperspectral imaging spectroscopy was used to detect water stress‐induced changes in Scots pine reflectance. Differential carotenoid and chlorophyll‐related responses were found, probably related to the experimental light environment. [ABSTRACT FROM AUTHOR]