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Abstract As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels.

BackgroundHereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks.MethodsPatients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients F12 gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured.ResultsSeventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6–88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 vs. baseline) and D-dimer in 71% (p=0.001 vs. baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p

Background: Drug provocation tests (DPT) are considered the gold standard procedure to ascertain the diagnosis of beta-lactam (BL) allergy. Regarding route of administration, current recommendations prioritize oral challenges, considering them safer, and reserving the intravenous route for drugs for which this is the only formulation. Objective: To compare in terms of tolerance and safety two protocols of BL DPT, using an oral protocol (OR-DPT) and an intravenous protocol (IV-DPT). Methods: A descriptive, retrospective study was performed, including adult patients who underwent IV-DPT or OR-DPT for suspected immediate or delayed hypersensitivity to BL antibiotics, over a period of 4 years (between January 2018 and December 2021). Demographical data, index hypersensivity reactions’ characteristics and tolerance to DPT were reviewed. Results: A total of 1036 patients underwent DPT, mean age of 56.8 (standard deviation, SD, 17.8) years, 655 were women (63.2%). Immediate drug hypersensitivity reactions (DHR) had occurred in 564 of patients (54.4%). OR-DPT were performed in 439 (42.4%) and IV-DPT in 597 (57.6%). The frequency of reactions during DPT, regardless of the route used, was low (3.6%): only 16 (3.6%) in OR-DPT and 21 (3.5%) in IV-DPT. From IV-DPT, 16 out 21 DHR during DPT were immediate compared with 4 out of 16 in OR-DPT. Adjusted relative risk of developing a hypersensitivity reaction during IV-DPT versus OR-DPT was 1.13 (95% confidence interval (CI)0.57–2.22). Conclusion: The results suggest that OR-DPT and IV-DPT are both safe procedures when adequately performed. However, IV-DPT protocols showed a higher rate of immediate DHR during DPT probably due to the selection of basal high-risk patients to undergo IV-DPT. In conclusion, IV-DPT may be considered as an option for challenges in drug-allergy studies, entailing a precise administration.

PurposeTo determine and compare the serum levels of complement Factor H (FH), monomeric C-Reactive Protein (mCRP) and pentameric C-Reactive protein (pCRP) in patients with age-related macular degeneration (AMD) and to correlate them with clinical, structural and functional parameters.MethodsCross-sectional observational study. One hundred thirty-nine individuals (88 patients and 51 healthy controls) from two referral centers were included and classified into three groups: early or intermediate AMD (n=33), advanced AMD (n=55), and age and sex matched healthy controls (n=51). Serum levels of FH, mCRP, and pCRP were determined and correlated with clinical and imaging parameters.ResultsPatients with intermediate AMD presented FH levels significantly lower than controls [186.5 (72.1-931.8) µg/mL vs 415.2 (106.1-1962.2) µg/mL; p=0.039] and FH levels

Abstract Background We describe the first school-located influenza vaccination campaign with quadrivalent live-attenuated influenza vaccine (LAIV) among pre-school children in Italy, coupled with an innovative school-centred influenza-like illnesses (ILIs) surveillance using a self-sampling non-invasive saliva collection method. Methods The pilot study was proposed during the 2021/2022 influenza season to fifteen pre-schools in the Milan municipality. LAIV was offered directly in school to all healthy children without contraindications. ILI differential diagnosis was conducted by real-time RT-PCR for influenza A/B and SARS-CoV-2. Results Five pre-schools were involved in the pilot project and overall, 135 families (31.2%) participated in the study, adhering to both surveillance and vaccination; 59% of families had an immigrant background. No pupil experienced adverse reactions after vaccination. Nineteen saliva samples were collected from sixteen children (11.8%). Six samples (31.6%) tested positive for SARS-CoV-2; none was positive for influenza A/B. Conclusions The participation in the immunisation campaign was good, considering possible absences due to COVID-19 pandemic, and the intranasal administration was well tolerated and helped to overcome parental hesitancy. Saliva sampling represented a useful tool to reduce children’s stress and increase parents’ compliance. The high participation of families with an immigrant background suggests that school-based interventions can represent an effective strategy to overcome socioeconomic and cultural barriers.

Abstract Phenotypic plasticity is a main mechanism for organisms to cope with changing environments and broaden their ecological range. Plasticity is genetically based and can evolve under natural selection, such that populations within a species show distinct phenotypic responses to the environment if evolved under different conditions. Understanding how intraspecific variation in phenotypic plasticity arises is critical to assess potential adaptation to ongoing climate change. Theory predicts that plasticity is favored in more favorable but variable environments. Yet, many theoretical predictions about benefits, costs, and selection on plasticity remain untested. To test these predictions, we took advantage of three genetic trials in the northern Rocky Mountains, USA, which assessed 23 closely located Pinus ponderosa populations over 27 years. Mean environmental conditions and their spatial patterns of variation at the seed source populations were characterized based on six basic climate parameters. Despite the small area of origin, there was significant genetic variation in phenotypic plasticity for tree growth among populations. We found a significant negative correlation between phenotypic plasticity and the patch size of environmental heterogeneity at the seed source populations, but not with total environmental spatial variance. These results show that populations exposed to high microhabitat heterogeneity have evolved higher phenotypic plasticity and that the trigger was the grain rather than the total magnitude of spatial heterogeneity. Contrary to theoretical predictions, we also found a positive relationship between population plasticity and summer drought at the seed source, indicating that drought can act as a trigger of plasticity. Finally, we found a negative correlation between the quantitative genetic variance within populations and their phenotypic plasticity, suggesting compensatory adaptive mechanisms for the lack of genetic diversity. These results improve our understanding of the microevolutionary drivers of phenotypic plasticity, a critical process for resilience of long‐lived species under climate change, and support decision‐making in tree genetic improvement programs and seed transfer strategies.

Abstract Hereditary angioedema (HAE) is a rare autosomal dominant disease, with patients often suffering with associated symptoms for many years before receiving a correct diagnosis. The symptoms greatly impact a patient's quality of life (QoL) and include excruciating abdominal pain and angioedema of the skin and submucosa. Angioedema of the larynx represents a significant mortality risk in undiagnosed patients, and a large proportion of patients with HAE receive incorrect diagnoses and undergo unnecessary surgery. HAE‐specific treatments can control and prevent acute life‐threatening episodes, in addition to improving QoL, emphasizing the value of early diagnosis for patients. Diagnostic delay may be due to a lack of HAE awareness by healthcare professionals and the similarity of HAE symptoms with those of more common conditions, complicating differential diagnosis. The multifaceted nature of the condition may result in visits to one of many different medical settings, for example: the Emergency Room, pediatrics, general practice, otolaryngology, gastroenterology, and dermatology. Therefore, it is crucial that physicians in multiple healthcare specialties are aware of the disease to ensure that patients with HAE receive a timely diagnosis. Using patient cases from various medical specialties, this review highlights the necessity for cross‐specialty awareness of HAE and outlines the essential information for the various healthcare professionals that may encounter a patient with HAE symptoms, in order to effectively treat and/or diagnose HAE.

Coagulase-negative staphylococci (CoNS) are reportedly responsible for 50–60% of bloodstream infections in very preterm (Staphylococcus capitis is an increasingly prevalent pathogen in the neonatal setting, frequently causing central-line-associated bloodstream infections (CLABSIs) that can be difficult to eradicate. Central venous catheter (CVC) removal versus in situ treatment with CoNS CLABSIs is a controversial treatment strategy with no clear consensus. We reviewed all S. capitis CLABSIs in our NICU between 2019 and 2022, focusing on the role of catheter removal in eradication. Among the 25 patients, 17 CVCs were removed after diagnosis, leading to a 76.5% eradication rate in this group. Three infants had a persistently positive blood culture after CVC substitution. A new catheter was then inserted after a 48 h washout period, resulting in resolution of the infection. Only two of the eight patients (25%) who retained their catheter after diagnosis achieved infection eradication with antibiotic therapy alone. When feasible, catheter removal seems to be the most effective strategy for eradicating S. capitis CLABSIs, sometimes even requiring a 48 h washout period before reinsertion. Further studies on this topic are needed to better standardize the management of this type of infection.

Purpose – The study aims to explore and explain the affordances and constraints of two-mode virtual collaboration as experienced by a newly forming international research team. Design/methodology/approach – This is self-reflective and action-oriented research on the affordances and constraints of two-mode virtual collaboration. In the spirit of professional development, the authors (nine researchers at different career stages and from various counties) engaged in a joint endeavour to evaluate the affordances and constraints of virtual collaborations in light of the recent literature while also researching the authors' own virtual collaboration during this evaluative task (mid-January–April 2021). The authors used two modes: synchronous (Zoom) and asynchronous (emails) to communicate on the literature exploration and recorded reactions and emotional responses towards existing affordances and constraints through a collective journal. Findings – The results suggest both affordances in terms of communication being negotiable and evolving and constraints, particularly in forming new relations given tools that may not be equally accessible to all. Journaling during collaborations could be a valuable tool, especially for virtual collective work, because it can be used to structure the team supported negotiation and discussion processes, especially often hidden processes. It is evident that the role of a leader can contribute to an alignment in the assumptions and experiences of trust and consequently foster greater mutual understanding of the circumstances for productive team collaborations. Originality/value – The findings of this study can inform academics and practitioners on how to create and facilitate better opportunities for collaboration in virtual teams as a rapidly emerging form of technology-supported working.

Abstract Background Covid-19 pandemic became an unexpected stressor for the entire population and, particularly, for pregnant women and lactating mothers. The alarming infectious risk together with the lockdown period could affect the emotional state of mothers-to-be, as well as breastfeeding rates, mother-baby bonding, or neonatal weight gain. The aim of this study is to describe the impact of this world health emergency in mother-baby pairs right after the first wave of Sars-Cov-2 pandemic (from March to May 2020). Study design A prospective observational study was carried out in mother–child dyads from those women who gave birth between June and August 2020 in a tertiary hospital. 91 mother-baby pairs were initially enrolled and 56 of them completed the follow-up. The study design had two separate steps: i) Step one: A clinical interview plus three psychometric tests (EPDS: Edinburgh Postnatal Depression Scale, PBQ: Postpartum Bonding Questionnaire and STAI-S: State-Trait Anxiety Inventory); ii) Step two: mother–child dyads were followed using a round of three brief telephone interviews (conducted at the newborn’s 7, 14 and 28 days of age) to accurately depict the newborn’s outcome in the neonatal period. Results In terms of maternal mental health, 25% of the sample screens positively in the EPDS, requiring further evaluation to rule out depressive symptoms. STAI-state and PBQ detect no abnormalities in either anxiety levels or mother–child bonding in our sample, as 100% of the mothers score below the cut-off points in each test (34 and 26 respectively). When comparing feeding practices (breast/bottle feeding) in 2020 to those practices during pre-pandemic years (2017–2019), a significant increase in breastfeeding was found in pandemic times. All newborns in the sample showed an adequate weight gain during their first month of life. Conclusion Women and newborns in our sample did not experience an increase in adverse outcomes in the neonatal period in terms of maternal mental health, breastfeeding rates, bonding and further neonatal development.

La psicoterapia multifamiliar es un modelo complejo de terapia grupal que permite incluir en un mismo lugar a pacientes, familias y equipo terapéutico. En febrero de 2018, un Equipo de Intervención Precoz en Psicosis de la red pública de salud mental creó un Grupo Multifamiliar para jóvenes con psicosis incipiente. Para la adaptación del grupo se aplicaron los principios del Diálogo Abierto de Jaakko Seikkula (2016); los estudios de Irvin Yalom (1996) acerca de los factores grupales de cambio, en concreto, el factor Infundir Esperanza y Aprendizaje interpersonal; y la perspectiva fenomenológica de Jakob Wyrsch (1949) que considera la identidad de la persona durante las primeras fases. En el artículo se expone la necesidad de utilizar este tipo de dispositivo grupal no solo como una herramienta de tratamiento sino también como un espacio de observación clínica y prevención. Se ilustra nuestro trabajo con la presentación de casos clínicos.

Abstract Background The Icatibant Outcome Survey (IOS) is an international registry monitoring the use of icatibant, a bradykinin B2 receptor antagonist indicated for the acute treatment of hereditary angioedema (HAE) attacks. Our goal was to assess disease characteristics and icatibant treatment outcomes in patients with HAE due to C1 inhibitor deficiency (HAE type 1 or 2 (HAE-1/2)) from Spain relative to other countries participating in IOS. Methods Descriptive retrospective analyses of data are reported from 10 centers in Spain vs 51 centers in 12 other participating countries (July 2009 to January 2019). Results No meaningful differences were identified between patients in Spain (n = 119) and patients across other countries (n = 907) regarding median age at symptom onset (15.0 vs 12.0 years) or diagnosis (22.3 vs 20.5 years). Overall HAE attack rates (total attacks/total years of follow-up) were 2.66 in Spain and 1.46 across other countries. Patients in Spain reported fewer severe/very severe HAE attacks before treatment (41.0% vs 45.9%; P

Over the last decade, national and international agencies have repeatedly called for research practices aligned with the Responsible Research and Innovation (RRI), with varied effects on different disciplines and countries. The COVID-19 pandemic made this need even more critical. This study aimed to explore whether and how, from researchers’ point of view, the COVID-19 pandemic has led to changes in RRI-based research practices in the different disciplines and, more generally, society’s perception of science. 1499 researchers in the three Catalan-speaking regions of Spain responded to an online questionnaire in the first months of the pandemic. Results showed that while only half perceived an impact on RRI-based practices, this proportion was higher for Health Sciences and Social Sciences researchers in all the dimensions. Most researchers perceived a positive impact on societal actors’ views of science, although researchers in the Humanities were more sceptical than those in other disciplines. The analysis of open-ended questions revealed researchers from all disciplines were also concerned about fake news and claimed that researchers’ working conditions and research funding across all disciplines needed to be improved for future research to be capable of coping with current and future challenges. Received: 31 December 2021 Accepted: 29 September 2022

Abstract To analyze functional and anatomical response patterns to dexamethasone (DEX) implant in diabetic macular edema (DME), to describe proportion of responders and non-responders, and to propose a new DME grading system. Retrospective, multicenter, observational cohort study. Naïve and non-naïve DME patients were treated with DEX, with visual acuity (VA) ≥ 0.2 logMAR and central subfield thickness (CST) of ≥ 300 µm. Functional and anatomical responses were graded after 2 and 4 months, and categorized as early and stable improvement, early and progressive improvement, pendular response, delayed improvement, and persistent non-response. 417 eyes were included (175 treatment naïve eyes). Compared to non-naïve eyes, naïve eyes showed a very good functional response (VA gain ≥ 10 letters) more frequently after 2 and 4 months (56% and 57% [naïve] vs. 33% and 28% [non-naïve], p

Abstract Background To identify different response patterns to intravitreal dexamethasone implants (IDI) in naïve and previously treated (PT) diabetic macular edema (DME) eyes in a real-life setting. Methods 342 IDI injections (203 DME eyes) were included. Number of IDI injections, percentage (%) of eyes with 1, 2, 3 and ≥ 4 injections, time to reinjections, visual acuity (VA), intraocular pressure (IOP) and central retinal thickness (CRT) were evaluated for naïve and PT DME eyes over 24 months. Results Mean number of injections was significantly lower in naïve vs PT DME eyes (1.40 ± 0.9 vs 1.82 ± 0.9, p

School-related gender-based violence (SRGBV) is highly prevalent worldwide which calls for a range of early prevention and innovative solutions. The presence of GBV in the school context is well-documented and it highlights the importance of building competencies of teachers and other school professionals for recognizing and intervening in SRGBV cases. This paper analyses the current and future teachers' training needs, and their level of preparedness for detecting and intervening in cases of GBV in the school context, with the objective of developing a targeted training program. The participants in this study were 597 current and future teachers and other school professionals from Croatia, Finland, and Spain. An ad-hoc built questionnaire was distributed in the three participating countries. Results show that the interest in receiving training is related to the perceived importance of coping with GBV in the (future) work and that the main topics of the training should focus on addressing parties of SRGBV, guidelines for prevention and intervention in schools as well as online GBV. These findings were similar in three countries, and they provided user-generated topics and tools that served as a guideline for the development of a training program that aims to increase the knowledge about SRGBV and to develop skills for coping with GBV in the school context regarding victims, bystanders and perpetrators.

Abstract Background Diabetic retinopathy (DR) is the leading cause of blindness in type 1 Diabetes Mellitus (DM) patients, as a consequence of impaired blood flow in the retina. Optical coherence tomography angiography (OCTA) is a newly developed, non-invasive, retinal imaging technique that permits adequate delineation of the perifoveal vascular network. It allows the detection of paramacular areas of capillary non perfusion and/or enlargement of the foveal avascular zone (FAZ), representing an excellent tool for assessment of DR. The relationship of these microvascular changes with systemic factors such as metabolic control or duration of the disease still needs to be elucidated. Methods Prospective, consecutive, large-scale OCTA study. A complete ocular examination including a comprehensive series of OCTA images of different scan sizes captured with 2 OCT devices (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA, USA, and Triton Deep Range Imaging OCT, Topcon Corp, Topcon, Japan) will be obtained as part of the yearly routine follow up visits in type 1 DM patients seen in the Diabetes Unit of the Endocrinology department which give written informed consent to participate in the project. The aim of this study is to investigate the relationship between OCTA-derived parameters and systemic factors, as metabolic control (Hb1Ac, lipid profile, cholesterol, etc), and other relevant clinical factors as demographics or duration of the disease. Discussion This study is directed to investigate the relationship between the status of the perifoveal vascular network and systemic markers of the disease, and in particular to study whether these changes reflect those occurring elsewhere in the body affected by diabetic microvascular disease, as the kidneys or the brain. If these relationships were demonstrated, early detection of these microvascular changes by OCTA could lead to modifications in the pharmacological management of type 1 diabetic patients, as a way to reduce the risk of future complications in both the eye and other organs. Trial registration ClinicalTrials.gov, trial number NCT03422965.

Congenital cytomegalovirus infection (cCMV) is the most common congenital viral infection, with a consistent rate of morbidity, mortality, and long-term sequelae, especially in the case of late diagnosis. Nevertheless, a universal screening for CMV is not currently recommended, and global awareness about this infection, as well as accurate and shared indications on follow-up and treatment, are still lacking. We reviewed data about 59 suspect cCMV cases who referred to our center from 2014 to 2021. We report 41 cases of confirmed cCMV diagnosed at birth, with clinical or radiological abnormalities in 36.6% of them. Other five patients received a late diagnosis and all presented neurological impairment. Twelve patients received therapy with Valganciclovir within the first month of life, with favorable outcome in nine cases. Therapy after the first month of life was attempted in four patients, with improvement in one case. The overall awareness about cCMV infection was 32.6%. Considering our population, maternal serological screening followed by targeted testing of neonates could be an effective strategy. Some aspects of cCMV infection management should be further investigated, such as indication of treatment after the first month of life or in asymptomatic patients. Awareness about the infection should be improved to implement preventive strategies.

Conferences are ideal platforms for studying gender gaps in science because they are important cultural events that reflect barriers to women in academia. Here, we explored women’s participation in ecology conferences by analyzing female representation, behavior, and personal experience at the 1st Meeting of the Iberian Society of Ecology (SIBECOL). The conference had 722 attendees, 576 contributions, and 27 scientific sessions. The gender of attendees and presenters was balanced (48/52% women/men), yet only 29% of the contributions had a woman as last author. Moreover, men presented most of the keynote talks (67%) and convened most of the sessions. Our results also showed that only 32% of the questions were asked by women, yet the number of questions raised by women increased when the speaker or the convener was a woman. Finally, the post-conference survey revealed that attendees had a good experience and did not perceive the event as a threatening context for women. Yet, differences in the responses between genders suggest that women tended to have a worse experience than their male counterparts. Although our results showed clear gender biases, most of the participants of the conference failed to detect it. Overall, we highlight the challenge of increasing women’s scientific leadership, visibility and interaction in scientific conferences and we suggest several recommendations for creating inclusive meetings, thereby promoting equal opportunities for all participants.

The purpose of this study was to evaluate specifically the relationship between glycated haemoglobin (HbA1c) levels and retinal optical coherence tomography (OCT) and OCT angiography (OCTA) parameters in type 1 Diabetes Mellitus (DM). A total of 478 type 1 DM patients and 115 controls were included in a prospective OCTA trial (ClinicalTrials.gov NCT03422965). Subgroup analysis was performed for controls, no diabetic retinopathy (DM-no DR) and DR patients (DM-DR), and HbA1c levels. OCT and OCTA measurements were compared with HbA1c levels (current and previous 5 years). DM-no DR patients with HbA1c levels >7.5% showed lower VD than DM-DR and controls (20.16 vs. 20.22 vs. 20.71, p < 0.05), and showed a significant correlation between HbA1c levels and FAZc (p = 0.04), after adjusting for age, gender, signal strength index, axial length, and DM disease duration. DM-DR patients with HbA1c > 7.5% presented greater CRT than DM-no DR and controls (270.8 vs. 260 vs. 251.1, p < 0.05) and showed a significant correlation between HbA1c and CRT (p = 0.03). In conclusion, greater levels of HbA1c are associated with OCTA changes in DM-no DR patients, and with structural OCT changes in DM-DR patients. The combination of OCTA and OCT measurements and HbA1c levels may be helpful to identify patients at risk of progression to greater stages of the diabetic microvascular disease.

Purpose. This study aims to find out which tool, fundus autofluorescence (FAF) or spectral domain optical coherence tomography (SD-OCT), is more sensitive in detecting retinal pigment epithelium (RPE) demise overlying drusen and can, therefore, help predict geographic atrophy (GA) appearance in Age-Related Macular Degeneration (AMD). Methods. A single-site, retrospective, observational, longitudinal study was conducted. Patients with intermediate AMD (iAMD) (large (>125 μm) or intermediate (63–125 μm) drusen with hyper/hypopigmentation) with a minimum follow-up of 18 months were included. Drusen with overlying incipient RPE atrophy were identified on SD-OCT defined as choroidal hypertransmission or nascent geographic atrophy (nGA). These selected drusen were, then, traced backwards in time to determine if incipient RPE atrophy overlying drusen was observed on FAF (well-demarcated region of absence of autofluorescence) before, simultaneously, or after having detected the first signs of incipient RPE atrophy on SD-OCT. The number of drusen in which signs of incipient RPE atrophy was detected earlier using FAF or SD-OCT was compared. The time elapsed from the identification with the more sensitive method to the other was recorded and analyzed. Results. One hundred and thirty-three drusen in 22 eyes of 22 patients were included. Of these, 112 (84.2%) drusen showed choroidal hypertransmission and 21(15.8%) nGA. Early signs of atrophy overlying drusen were found simultaneously on SD-OCT and FAF in 52 cases (39.1%, 95% CI 30.8–47.9%), earliest on FAF in 51 (38.3%, 95% CI 30.0–47.2%) and first on SD-OCT in 30 (22.6%, 95% CI 15.8–30.6%; p

Objective. Congenital adrenal hyperplasia (CAH) is the most common cause of adrenal insufficiency in pediatrics. Chronic glucocorticoid replacement is the mainstay of treatment in the classic forms of CAH, and mineralocorticoid replacement therapy is mandatory in the salt-wasting form. Fasting is a mild stressor, which can expose to dehydration, hypotension, hypoglycemia, and acute adrenal crisis in patients with adrenal insufficiency. Case. We report the case of an adolescent affected by the classic form with salt-losing CAH, who observed Ramadan for 30 days, without individualized therapeutic management plan. After Ramadan, a dramatic increase of ACTH level (1081 pg/ml, n.v. 6–57), reduced cortisolemia, tendency to hypotension, and weight loss were recorded. She experienced insomnia, intense thirst, asthenia, and headache. The symptoms disappeared restarting the previous therapy schedule and increasing the total hydrocortisone daily dose with progressive restoring of hormonal control. Conclusion. Our case confirms that patients with CAH are vulnerable, especially during fasting in Ramadan, with a higher risk of acute adrenal crisis. CAH patients should reform and individualize their treatment plan and be submitted to careful monitoring.

PurposeTo evaluate the long-term cumulative probability of intraocular pressure (IOP) elevation with the intravitreal dexamethasone implant (IDI) when used to treat different indications: diabetic macular edema, uveitis, retinal vein occlusion.Methods705 IDI injections (429 eyes) were assessed and Kaplan-Meier graphs were generated to assess: the probability of different levels of IOP elevation (IOP≥21, ≥25 or ≥35 mmHg), IOP change ≥10 mmHg, initiation of IOP-lowering treatment, glaucoma surgery, IOP change with repeat injections and IOP elevation in eyes with glaucoma and ocular hypertension (OHT).ResultsThe cumulative probability of IOP ≥21, ≥25 and ≥35 mmHg was 50%-60%, 25%-30% and 6%-7% at 12-24 months, respectively. The probability of initiating IOP-lowering medication was 31%-54% at 12-24 months. Glaucoma and OHT eyes had a higher probability of mild IOP elevation (≥21 mmHg, 65.1%, 75% and 57.8%, p = 0.01), yet a similar moderate (≥25 mmHg, 22.3%, 28% and 30.2%, p = 0.91) and severe elevation of IOP (≥35 mmHg, 3.7%, 7.1% and 4%, p = 0.71) as normal eyes. Glaucoma surgery was required in only 0.9% cases (4/429). At baseline, 8.8% of the treated eyes had glaucoma, 6.7% OHT and 16.9% were already on IOP-lowering medication.ConclusionsIn the long-term (24 months), IOP elevation is common, generally mild (30% IOP, ≥25 mmHg) and well-tolerated, resolving with topical treatment (54%) and rarely requiring surgery (0.9%).

PURPOSE:To evaluate the repeatability and reproducibility of retinal and choroidal thickness measured with Swept source Optical Coherence Tomography (SS-OCT) in eyes with Diabetic Macular Edema (DME). METHODS:42 DME eyes were imaged using SS-OCT standard Macular scanning protocols. Retinal and choroidal thickness were measured in the Total macular circle (TMC) and foveal central subfield (FCS) using device-integrated specific software. The coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were determined as a measure of repeatability and relative reliability within graders. Reproducibility was assessed using Bland-Altman plots and 95% limits of agreement (LoA) were determined as a measure of interobserver variability. RESULTS:Intragrader CR of retinal and choroidal thickness were 8.37 and 12.20 microns for TMC and 22.24 and 32.40 microns for FCS, and intergrader 95% LoA were 7.37-8.69 and -27.2-27.71 microns for TMC and -34.21-41.93 and -30.46-24.84 for FCS, respectively. Retinal and choroidal thickness showed very good intraobserver reliability for both TMC and FCS (ICC 0.99, LoA 0.98-0.99 in all cases). Intraobserver and interobserver variability for retinal and choroidal thickness was not significantly different for TMC (p = 0.98 and p = 0.90, p = 0.98 and p = 0.91) or FCS (p = 0.97 and p = 0.85, p = 0.78 and p = 0.73), respectively. CONCLUSIONS:Retinal and choroidal thickness in DME eyes can be quantified with good reliability, repeatability and reproducibility using new OCT devices that incorporate swept source technology. The technical advantages of this technology may provide new insights in the understanding of the choroidal changes related with DME.

Anaphylaxis is the most severe form of allergic reaction, resulting from the effect of mediators and chemotactic substances released by activated cells. Mast cells and basophils are considered key players in IgE-mediated human anaphylaxis. Beyond IgE-mediated activation of mast cells/basophils, further mechanisms are involved in the occurrence of anaphylaxis. New insights into the potential relevance of pathways other than mast cell and basophil degranulation have been unraveled, such as the activation of the contact and the coagulation systems. Mast cell heparin released upon activation provides negatively charged surfaces for factor XII (FXII) binding and auto-activation. Activated FXII, the initiating serine protease in both the contact and the intrinsic coagulation system, activates factor XI and prekallikrein, respectively. FXII-mediated bradykinin (BK) formation has been proven in the human plasma of anaphylactic patients as well as in experimental models of anaphylaxis. Moreover, the severity of anaphylaxis is correlated with the increase in plasma heparin, BK formation and the intensity of contact system activation. FXII also activates plasminogen in the fibrinolysis system. Mast cell tryptase has been shown to participate in fibrinolysis through plasmin activation and by facilitating the degradation of fibrinogen. Some usual clinical manifestations in anaphylaxis, such as angioedema or hypotension, or other less common, such as metrorrhagia, may be explained by the direct effect of the activation of the coagulation and contact system driven by mast cell mediators.

AIMS:To study the association between peripheral blood metabolic and inflammatory factors and presence of diabetic macular edema (DME) and its related anatomic features in type 2 diabetic mellitus (T2DM) patients. MATERIAL AND METHODS:Observational cross-sectional study on a proof of concept basis. Seventy-six T2DM included patients were divided based on the presence (n = 58) or absence of DME (n = 18) according to optical coherence tomography (OCT). Ultra-widefield fluorescein angiography (UWFA) was performed in DME patients. Fasting peripheral blood sample testing included glycemia, glycated hemoglobin, creatinin and lipid levels among others. Serum levels of a broad panel of cytokines and inflammatory mediators were also analysed. OCT findings included central subfoveal thickness, diffuse retinal thickness (DRT), cystoid macular edema (CME), serous retinal detachment and epirretinal membrane. UWFA items included pattern of DME, presence of peripheral retinal ischemia and enlarged foveal avascular zone (FAZ). RESULTS:Metabolic and inflammatory factors did not statistically differ between groups. However, several inflammatory mediators did associate to certain ocular items of DME cases: IL-6 was significantly higher in patients with DRT (p = 0.044), IL-10 was decreased in patients with CME (p = 0.012), and higher IL-8 (p = 0.031) and VEGF levels (p = 0.031) were observed in patients with enlarged FAZ. CONCLUSION:Inflammatory and metabolic peripheral blood factors in T2DM may not be differentially associated to DME when compared to non-DME cases. However, some OCT and UWFA features of DME such as DRT, CME and enlarged FAZ may be associated to certain systemic inflammatory mediators.

Heat-shock protein (Hsp)10 is the co-chaperone for Hsp60 inside mitochondria, but it also resides outside the organelle. Variations in its levels and intracellular distribution have been documented in pathological conditions, e.g. cancer and chronic obstructive pulmonary disease (COPD). Here, we show that Hsp10 in COPD undergoes changes at the molecular and subcellular levels in bronchial cells from human specimens and derived cell lines, intact or subjected to stress induced by cigarette smoke extract (CSE). Noteworthy findings are: (i) Hsp10 occurred in nuclei of epithelial and lamina propria cells of bronchial mucosa from non-smokers and smokers; (ii) human bronchial epithelial (16HBE) and lung fibroblast (HFL-1) cells, in vitro, showed Hsp10 in the nucleus, before and after CSE exposure; (iii) CSE stimulation did not increase the levels of Hsp10 but did elicit qualitative changes as indicated by molecular weight and isoelectric point shifts; and (iv) Hsp10 nuclear levels increased after CSE stimulation in HFL-1, indicating cytosol to nucleus migration, and although Hsp10 did not bind DNA, it bound a DNA-associated protein.

ATP-dependent nucleosome-remodeling enzymes and covalent modifiers of chromatin set the functional state of chromatin. However, how these enzymatic activities are coordinated in the nucleus is largely unknown. We found that the evolutionary conserved nucleosome-remodeling ATPase ISWI and the poly-ADP-ribose polymerase PARP genetically interact. We present evidence showing that ISWI is target of poly-ADP-ribosylation. Poly-ADP-ribosylation counteracts ISWI function in vitro and in vivo. Our work suggests that ISWI is a physiological target of PARP and that poly-ADP-ribosylation can be a new, important post-translational modification regulating the activity of ATP-dependent nucleosome remodelers.

Nucleosome remodeling and covalent modifications of histones play fundamental roles in chromatin structure and function. However, much remains to be learned about how the action of ATP-dependent chromatin remodeling factors and histone-modifying enzymes is coordinated to modulate chromatin organization and transcription. The evolutionarily conserved ATP-dependent chromatin-remodeling factor ISWI plays essential roles in chromosome organization, DNA replication, and transcription regulation. To gain insight into regulation and mechanism of action of ISWI, we conducted an unbiased genetic screen to identify factors with which it interacts in vivo. We found that ISWI interacts with a network of factors that escaped detection in previous biochemical analyses, including the Sin3A gene. The Sin3A protein and the histone deacetylase Rpd3 are part of a conserved histone deacetylase complex involved in transcriptional repression. ISWI and the Sin3A/Rpd3 complex co-localize at specific chromosome domains. Loss of ISWI activity causes a reduction in the binding of the Sin3A/Rpd3 complex to chromatin. Biochemical analysis showed that the ISWI physically interacts with the histone deacetylase activity of the Sin3A/Rpd3 complex. Consistent with these findings, the acetylation of histone H4 is altered when ISWI activity is perturbed in vivo. These findings suggest that ISWI associates with the Sin3A/Rpd3 complex to support its function in vivo.

Background. Mitochondria can influence cancer cells both indirectly via reactive oxygen species mediation and directly through mitochondrial biogenesis. Energy production in mitochondria is crucial as it facilitates the synthesis of essential molecules needed for cellular biosynthesis, growth, and proliferation. The development of new anticancer drugs that target the energy metabolism of tumor cells shows promise in cancer treatment. Our study aimed to investigate how the thiazole derivative N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide (BF1), the polymeric nanoparticles based on the polyethylene glycol (PEG-PN, Th5), and their complex with BF1 (Th6) affect respiration and mitochondrial membrane potential in murine NK/Ly tumor cells. Materials and Methods. The study was performed on white wild-type male mice with grafted NK/Ly lymphoma. The test substances were added to the cell suspension at a final concentration of 10 μM and incubated for 15 min at 37 °C. Oxygen uptake rates in NK/Ly cells were measured using a polarographic method with Clark electrode. Changes in mitochondrial membrane potential were assessed using the tetramethylrhodamine methyl ester fluorescence dye. The fluorescence intensity was evaluated using the ImageJ computer program. Results. After incubating NK/Ly cells with BF1 (10 µM), Th5, or the BF1 + PEG-PN complex (Th6) for 15 min, no changes were observed in glucose-fueled basal respiration. However, the Th6 complex significantly activated FCCP-stimulated respiratory processes in NK/Ly lymphoma cells. Fluorescent microscopy data indicated that BF1 or Th5 alone did not affect mitochondrial membrane potential values. However, the Th6 complex significantly decreased mitochondrial membrane potential, suggesting a reduction in NK/Ly cell viability. Conclusions The investigated complex of thiazole derivative BF1 with PEG-based polymeric nanoparticles may realize its cytotoxic effect by depolarization of mitochondrial membrane in NK/Ly lymphoma cells.