The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023.

BACKGROUND: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. RESULTS: First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. CONCLUSIONS: The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.

Outcome improvement over time in reduced intensity conditioning hematopoietic transplantation: a 20-year experience.

The current study includes all consecutive patients (N = 484) who received a reduced-intensity conditioning regimen (RIC) allogeneic hematopoietic stem cell transplantation in our center from 1999 to 2020. Conditioning regimens were based on fludarabine with melphalan or busulfan, with low-dose thiotepa and pharmacological GVHD prophylaxis consisted of cyclosporine A (CsA)-methotrexate (MTX)/mofetil (MMF) (n = 271), tacrolimus-sirolimus (n = 145), and post-transplantation cyclophosphamide (PTCy)-tacrolimus (n = 68). The median time of overall follow-up in survivors was 8 years (1-22 years) and was at least 3 years in all three GVHD prophylaxis groups. Thirty-three percent had a high or very high disease risk index, 56% ≥ 4 European bone marrow transplantation risk, and 65% ≥ 3 hematopoietic stem cell transplantation comorbidity index score-age score. Neutrophil and platelet engraftment was longer for PTCy-tacro (p 0.0001). Cumulative incidence of grade III-IV aGVHD was 17% at 200 days, and that of moderate-severe cGvHD was 36% at 8 years. GVHD prophylaxis was the only prognostic factor in the multivariable analyses for the development of aGVHD and moderate-severe cGVHD (p 0.0001). NRM and relapse incidences were 29% and 30% at 8 years, while OS and PFS rates were 43% and 39% at 8 years. At 3 years, OS was highest in the PTCy-tacro group (68%) than in the tacro-siro (61%) and CsA-MTX/MMF (49%) cohorts (p < 0.01). In the three groups, respectively, the 200-day incidence of grade III-IV aGvHD (6% vs. 12% vs. 23%) and 3-year moderate-severe cGVHD (8% vs. 40% vs. 38%) were lower in the PTCy cohort. These better outcomes were confirmed in multivariable analyses. Based on our recent results, the PTCy could be considered as a real GvHD prophylaxis in the RIC setting due to improve best 3-year GvHD and survival outcomes.

Long-term care needs and the risk of household poverty across Europe: a comparative secondary data study.

PURPOSE: Population ageing and rising poverty are two of the most pressing issues today, even in Western European nations, growing as a result of the recent global economic crisis and the COVID-19 containment measures. This study explores the relationship between long-term care (LTC) needs and risk of poverty at household level in eight European countries, representing the different European care regimes. METHODS: The main international databases were scoured for study variables, categorized according to the following conceptual areas: home care, residential care, health expenditure, service coverage, cash benefits, private services, population, family, education, employment, poverty, disability and care recipients, and life expectancy. We initially identified 104 variables regarding 8 different countries (Austria, Finland, Germany, the Netherlands, Italy, Spain, Poland, Romania). Statistical analyses were conducted as described hereafter: analysis of the Pearson's Bivariate Correlation between the dependent variable and all other variables; a Multivariable Linear Regression Model between the Poverty Index (dependent variable) and the covariates identified in the preceding step; a check for geographical clustering effects and a reduced Multivariable Linear Regression Model for each identified European cluster. RESULTS: The variables that addressed the risk of poverty pertained to the area of policy intervention and service provision. Rising private out-of-pocket health expenditures and proportion of "poor" couples with at least one child are two factors that contributed significantly to poverty increasing. Moreover, rising private out-of-pocket health expenditures for covering LTC needs (even in presence of public financial contribution to the family) is the main contributor to household poverty increasing in presence of ADL disability. CONCLUSION: The results reveal the existence of a clear correlation between the need for LTC and the risk of poverty in households across Europe. These results highlight the central relevance of LTC policies, which are often still treated as marginal and sectoral, for the future sustainability of integrated care strategies.

The longitudinal impact of type 2 diabetes on brain gyrification.

Type 2 diabetes has an effect on brain structure, including cortical gyrification. The significance of these changes is better understood if assessed over time. However, there is a lack of studies assessing longitudinally the effect of this disease with complex aethology in gyrification. While changes in this feature have been associated mainly with genetic legacy, our study allowed to shed light on the effect of the variation of glycaemic profile over time in gyrification in this metabolic disease. In this longitudinal study, we analysed brain anatomical magnetic resonance images of 15 participants with type 2 diabetes and 13 healthy control participants to investigate the impact of this metabolic disease on the gyrification index over a 7-year period. We observed a significant interaction between time and group in six regions, four of which (left precentral gyrus, left gyrus rectus, left subcentral gyrus and sulci and right inferior temporal gyrus) showed an increase in gyrification in type 2 diabetes and a decrease in the control group and the two others (left pericallosal sulcus and right inferior frontal sulcus) the opposite pattern. The variation of the gyrification was correlated with the variation of the glycaemic profile. Following the interaction, the simple main effect of time in each group separately has shown that in the group with diabetes, there were more regions susceptible to alterations of gyrification. In sum, our results raise credit for the possibility that glycaemic control also might influence gyrification in type 2 diabetes.

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients.

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57). High complexity maintained its significance in the multivariate analysis for TTFT including TP53 and IGHV status when defined by CBA (hazard ratio [HR] 3.23; P<0.001) and GM (HR 2.74; P<0.001). Our findings suggest that both methods are useful but not equivalent for risk stratification of CLL patients. Validation studies are needed to establish the prognostic value of genome complexity based on GM data in future prospective studies.

Polycyclic aromatic hydrocarbons (PAHs) in human breast milk from Colombia: Spatial occurrence, sources and probabilistic risk assessment.

The diet is the main route that polycyclic aromatic hydrocarbons (PAHs) enter the body and measuring breast milk is one of the best ways to understand the maternal body burden and can be passed on to infants. In this study, it was determinate the concentrations of 23 PAHs in 60 milk samples taken from 3 cities in Colombia and to determine the potential routes of exposure and risk to human health. On average, concentration for the ∑PAHs across all locations was 186.6 ng g-1, lipid mass (LM), with city means of 260.1, 175.7, and 123.9 ng g-1 LM for Cartagena, Bogota and Medellin, respectively. Monte Carlo simulations were used to estimate the hazard quotient (HQ) and incremental lifetime cancer risk (ILCR) for infant dietary exposure to PAHs. HQs were below the safe thresholds (HQ = 1) while ILCRs were greater than the reference value equal to 10-6 (mg kg-1day-1). Dietary source assessment indicated that fish is a significant source of PAHs, with mothers that consumed fish at least once per week having ∼2.5 times greater PAH milk concentrations than other groups. While a disparity was also observed among consumers of exclusively marine (∑PAHs 198.5 ng g-1 LM) or freshwater fish (∑PAHs 85.7 ng g-1 LM). However, geographical considerations can be significant in this finding.

[Analysis of budgetary impact of COVID-19 vaccination in Latin AmericaAnálise do impacto orçamentário da vacinação contra a COVID-19 na América Latina]. / Análisis de impacto presupuestal de la vacunación contra COVID-19 en América Latina.

Objective: To estimate the budgetary impact of COVID-19 vaccination in six Latin American countries: Argentina, Brazil, Chile, Colombia, Mexico, and Peru, during the 2021-2022 biennium. Methods: Vaccines from Sinopharm (BBIBP-CorV), Janssen (JNJ-78436735), Gamaleya Institute (Gam-COVID-Vac), Sinovac (CoronaVac), CanSino (Convidecia), AstraZeneca (Vaxzevria), Moderna (mRNA-1273), and Pfizer (BNT162b2) were evaluated, according to their availability in each country. The health system perspective was adopted, so that only direct health care costs were included. The time horizon adopted took into account the implementation times of each vaccination plan, excluding children under 16 years of age and pregnant persons. The following costs were included: cost of vaccination/vaccine administration and costs of hospitalization (general isolation, stepdown care, and intensive care). Two vaccination scenarios were compared: 1) population wanting to be vaccinated (according to national surveys); and 2) population that should be vaccinated (total population susceptible to vaccination). The aggregate costs for each vaccination scenario were compared with the no-vaccination scenario. Deterministic and probabilistic sensitivity analyses were also performed. Results: The different COVID-19 vaccination regimens available in Latin America generate potential savings ranging from USD 100 million to USD 1.5 billion per country for the 2021-2022 biennium, assuming that the vaccination plan proposed for each country is fully implemented. Conclusions: COVID-19 vaccination is a strategy that not only reduces morbidity and mortality in Latin America, but also generates potential savings for health systems in the region.

Objetivo: Estimar o impacto orçamentário da vacinação contra a COVID-19 em seis países da América Latina: Argentina, Brasil, Chile, Colômbia, México e Peru, no período 2021-2022. Métodos: Foram avaliadas as vacinas da Sinopharm (BBIBP-CorV), Janssen (JNJ-78436735), Instituto Gamaleya (Gam-COVID-Vac), Sinovac (CoronaVac), CanSino (Convidecia), AstraZeneca (Vaxzevria), Moderna (mRNA-1273) e Pfizer (BNT162b2), conforme a disponibilidade para cada país. Adotou-se a perspectiva do sistema de saúde, de forma que só foram incluídos custos médicos diretos. O horizonte temporal foi adotado levando em consideração os tempos de implementação de cada plano de vacinação, excluindo crianças menores de 16 anos e gestantes. Foram incluídos os seguintes custos: custos de vacinação e aplicação, custos gerais de hospitalização, isolamento, e cuidados intermediários e intensivos. Compararam-se dois cenários de vacinação: 1) população disposta a se vacinar (com base em pesquisas nacionais) e 2) população que deveria ser vacinada (total elegível de vacinação). Os custos agregados para cada cenário de vacinação foram comparados com o cenário de não vacinação. Além disso, foram realizadas análises de sensibilidade determinísticas e probabilísticas. Resultados: Os diferentes esquemas de vacinação contra a COVID-19 disponíveis na América Latina geram economias potenciais entre 100 milhões e 1,5 bilhão de dólares por país para o período 2021-2022, considerando a implementação completa do plano de vacinação previsto em cada país. Conclusões: A vacinação contra a COVID-19 é uma estratégia que, além de reduzir a morbidade e a mortalidade na América Latina, gera economias potenciais para os sistemas de saúde da região.

Evaluation of Plant-Based Byproducts as Green Fining Agents for Precision Winemaking.

Consumers are increasingly looking for foods, including wine, that are free of animal-derived proteins. This study seeks to evaluate patatin, a new, plant-based and allergen-free fining agent, by comparing it with the fining agents polyvinipolypyrrolidone, bovine serum albumin, and methylcellulose. Specifically, its effects on the phenolic profile of enological tannins were analyzed with four spectrophotometric assays: OD 280 nm, Folin−Ciocâlteu, Adams−Harbertson, and methylcellulose. In addition, changes in the polyphenol composition of Sangiovese red wine were determined by UV-Vis spectrophotometry and HPLC with adsorption trials, and the solid−liquid interaction in a wine solution was modeled by both Langmuir and Freundlich equations. Our findings highlight the occurrence of systematic proportional error between the selected spectrophotometric assays. As a result, direct comparisons of protein precipitation assays can be made only among results obtained with the same spectrophotometric method. However, it is clear that patatin has an impact on the phenolic profile of Sangiovese red wine: it removes simple phenolics (gallic acid, (+)-catechin, (−)-epicatechin, epicatechin gallate, syringic acid, fertaric acid, coutaric acid, and rutin) as well as both oligomeric and polymeric tannins to different extents. In concentrations of less than 1 g/L, the patatin isotherm showed a linear relation between the equilibrium concentration and the quantity absorbed, obeying the Freundlich model reasonably well (KF 1.46; 1/n 1.07; R2 0.996 with 1/n > 1). Thus, the adsorption process is strongly dependent on the fining dosage.

A novel morphometric signature of brain alterations in type 2 diabetes: Patterns of changed cortical gyrification.

Type 2 diabetes is a chronic disease that creates atrophic signatures in the brain, including decreases of total and regional volume of grey matter, white matter and cortical thickness. However, there is a lack of studies assessing cortical gyrification in type 2 diabetes. Changes in this emerging feature have been associated mainly with genetic legacy, but environmental factors may also play a role. Here, we investigated alterations of the gyrification index and classical morphometric measures in type 2 diabetes, a late acquired disease with complex aetiology with both underlying genetic and more preponderant environmental factors. In this cross-sectional study, we analysed brain anatomical magnetic resonance images of 86 participants with type 2 diabetes and 40 healthy control participants, to investigate structural alterations in type 2 diabetes, including whole-brain volumetric measures, local alterations of grey matter volume, cortical thickness and the gyrification index. We found concordant significant decrements in total and regional grey matter volume, and cortical thickness. Surprisingly, the cortical gyrification index was found to be mainly increased and mainly located in cortical sensory areas in type 2 diabetes. Moreover, alterations in gyrification correlated with clinical data, suggesting an influence of metabolic profile in alterations of gyrification in type 2 diabetes. Further studies should address causal influences of genetic and/or environmental factors in patterns of cortical gyrification in type 2 diabetes.

Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact.

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.

Iodide conversion to iodate in aqueous and solid aerosols exposed to ozone.

The aqueous-phase and surface reactions of ozone (O3) with iodide (I-) in/on seawater have been recently found to be a strong atmospheric source of iodine. In addition, ozone also reacts with I- in solid and aqueous sea-salt aerosol. However, the primary products of the heterogeneous reactions of ozone with I- have not been clarified. In this paper, solid and aqueous KI aerosols have been exposed to ozone in an aerosol flow tube system and I- and iodate (IO3-) concentrations have been measured by UV-Vis spectroscopy. The results of these experiments have been combined with a kinetic model to elucidate the primary products of the aqueous and surface reactions. The reaction of ozone with aqueous iodide has been inferred to originate different products depending on whether it occurs at the surface via O3 adsorption (product I2-) or in the aqueous phase via O3 solvation (product IO-). The surface reaction of ozone with solid KI in the presence of water vapor forms KIO3, and other species, which are likely to be gaseous. Although the reactions have been studied in aerosols, the results can be extrapolated to aqueous solutions as well.

Low Rate of Invasive Fungal Infections During Induction and Consolidation Chemotherapy for Adults with De Novo Acute Myeloid Leukemia Without Anti-mold Prophylaxis: Single-Center 2002-2018 Empirical/Pre-emptive Approach.

Broad-spectrum antifungal prophylaxis is currently considered the standard of care for adults with de novo AML for the prevention of invasive fungal infections (IFIs), especially invasive pulmonary aspergillosis (IPA). Because fluconazole has been used in our center as anti-yeast prophylaxis, we sought to analyze in detail the incidence of IFIs over a 17-year period, as well as their impact on outcome. A standardized protocol of patient management, including serum galactomannan screening and thoracic CT-guided diagnostic-driven antifungal therapy, was used in all patients. A total of 214 consecutive adults with de novo AML who were treated in 3 CETLAM (Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias) protocols from 2002 to 2018 were included. The 90-day incidence of any IFI (including possible cases) was 11% (95% CI 4-15%), most cases occurred during induction chemotherapy (8%, 95% CI 4-12%), and most cases were probable/proven IPA (8%, 95% CI 3-13%). Developing an IFI during induction and consolidation had no impact on 1-year survival. A case-control study with 23 cases of IPA and 69 controls identified induction/re-induction chemotherapy, chronic pulmonary disease and age > 60 years/poor baseline performance status as potential pretreatment risk factors. The current study proves that inpatient induction and consolidation chemotherapy for de novo AML can be given in areas with "a priori" high-burden of airborne molds with fluconazole prophylaxis, while the selective use of anti-mold prophylaxis in patients at very high risk may further reduce the incidence of IFI in this specific clinical scenario.

CLINICAL DECISION MAKING IN OLDER ADULTS WITH COVID-19 IN DEVELOPING COUNTRIES: LOOKING BEYOND CHRONOLOGICAL AGE.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been declared a global pandemic. Older adults have been found as a vulnerable group for developing severe forms of disease and increased mortality. OBJECTIVE: The objective of the study was to propose a pathway to assist the decision-making process for hospital resource allocation for older adults with COVID-19 using simple geriatric assessment-based tools. METHODS: We reviewed the available literature at this point of the COVID-19 outbreak, focusing in older adult care to extract key recommendations for those health-care professionals who will be treating older adults in the hospital emergency ward (HEW) in developing countries during the COVID-19 pandemic. RESULTS: We listed a series of easy recommendations for non-geriatrician doctors in the HEW and suggested simple tools for hospital resource allocation during critical care evaluation of older adults with COVID-19 in low- and middle-income countries. CONCLUSIONS: Age must not be used as the sole criterion for resource allocation among older adults with COVID-19. Simple and efficient tools are available to identify components of the comprehensive geriatric assessment, which could be useful to predict outcomes and provide high-quality care that would fit the particular needs of older adults in resource-limited settings amidst this global pandemic.

Predicting Life Expectancy for Older Adults with Cancer in Clinical Practice: Implications for Shared Decision-making.

PURPOSE OF REVIEW: The calculation of noncancer-specific life expectancy can guide shared decision-making and avoid over- and undertreatment in older adults with cancer. Several factors determine life expectancy, including socio-demographic background, comorbidities, physical performance, and geriatric assessment variables. We present an overview of existing tools to estimate life expectancy, as well as practical examples of how to take into account the patient's noncancer-specific life expectancy when discussing screening decisions, initiation of treatment, and end-of-life care. RECENT FINDINGS: Life expectancy prognostication has been recently recommended by international societies as part of the initial assessment of all older adults with cancer. Additionally, online resources have been created in order to make life expectancy calculation tools accessible for clinicians. Understanding available methods to estimate life expectancy, as well as how to utilize them, is a fundamental part of geriatric oncology that should be integrated into everyday clinical practice.

A kinetic model for ozone uptake by solutions and aqueous particles containing I- and Br-, including seawater and sea-salt aerosol.

The heterogeneous interactions of gaseous ozone (O3) with seawater and with sea-salt aerosols are known to generate volatile halogen species, which, in turn, lead to further destruction of O3. Here, a kinetic model for the interaction of ozone (O3) with Br- and I- solutions and aqueous particles has been proposed that satisfactorily explains previous literature studies about this process. Apart from the aqueous-phase reactions X- + O3 (X = I, Br), the interaction also involves the surface reactions X- + O3 that occur via O3 adsorption on the aqueous surface. In single salt solutions and aerosols, the partial order in ozone and the total order of the surface reactions are one, but the apparent total order is second order because the number of ozone sites where reaction can occur is equal to the surficial concentration of X- ([X-]surf). In the presence of Cl-, the surface reactions are enhanced by a factor equal to , where and . Therefore, we have inferred that Cl- acts as a catalyst in the surface reactions X- + O3. The model has been applied to estimate ozone uptake by the reaction with these halides in/on seawater and in/on sea-salt aerosol, where it has been concluded that the Cl--catalyzed surface reaction is important relative to total ozone uptake and should therefore be considered to model Y/YO (Y = I, Br, Cl) levels in the troposphere.

Femoral-facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair.

Femoral-facial syndrome (FFS, OMIM 134780), also known as femoral hypoplasia-unusual face syndrome, is a rare sporadic syndrome associated with maternal diabetes, and comprising femoral hypoplasia/agenesis and a distinct facies characterized by micrognathia, cleft palate, and other minor dysmorphisms. The evaluation of 14 unpublished Brazilian patients, prompted us to make an extensive literature review comparing both sets of data. From 120 previously reported individuals with FFS, 66 were excluded due to: not meeting the inclusion criteria (n = 21); not providing sufficient data to ascertain the diagnosis (n = 29); were better assigned to another diagnosis (n = 3); and, being fetuses of the second trimester (n = 13) due to the obvious difficult to confirm a typical facies. Clinical-radiological and family information from 54 typical patients were collected and compared with the 14 new Brazilian patients. The comparison between the two sets of patients did not show any relevant differences. Femoral involvement was most frequently hypoplasia, observed in 91.2% of patients, and the typical facies was characterized by micrognathia (97%), cleft palate (61.8%), and minor dysmorphisms (frontal bossing 63.6%, short nose 91.7%, long philtrum 94.9%, and thin upper lip 92.3%). Clubfoot (55.9%) was commonly observed. Other observed findings may be part of FFS or may be simply concurrent anomalies since maternal diabetes is a common risk factor. While maternal diabetes was the only common feature observed during pregnancy (50.8%), no evidence for a monogenic basis was found. Moreover, a monozygotic discordant twin pair was described reinforcing the absence of a major genetic factor associated with FFS.

A revisit of the interaction of gaseous ozone with aqueous iodide. Estimating the contributions of the surface and bulk reactions.

The main source of atmospheric iodine is the heterogeneous reaction of aqueous iodide (I-) with ozone (O3), which takes place in surface seawater and probably in sea-salt aerosols. However, there are seemingly contradictory conclusions about whether this heterogeneous reaction occurs in the bulk of the aqueous phase, via O3 dissolution, or at the aqueous surface, via O3 adsorption. In this work, the ozone uptake coefficient has been calculated as a function of the concentration of aqueous iodide ([I-]aq) and gaseous ozone near the aqueous surface ([O3]gs) by estimating parameters of the resistor model using results of previous studies. The calculated uptake coefficients suggest that the aqueous-phase reaction dominates at low I- concentrations (about <10-4 mol L-1), regardless of [O3]gs, and also at sufficiently high [O3]gs (about >80 ppm), regardless of [I-]aq. In contrast, the surface reaction dominates at high [I-]aq (about >10-4 mol L-1) as long as [O3]gs is low enough (about <80 ppm). This trend is able to reconcile previous studies of this reaction, and is a consequence of several factors, including the high surface excess of both reactants ozone and iodide. Given the typical O3 concentrations in the troposphere and the possible I- concentrations and O3 solubilities in sea-salt aerosols, the surface reaction may compete with the aqueous-phase reaction in accumulation-mode aerosols, unlike in surface seawater, where the aqueous-phase reaction probably prevails. The rate constant of the surface reaction has been estimated as (3-40) × 10-13 cm2 molecule-1 s-1.

Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122.

Since most short-rib polydactyly phenotypes are due to genes involved with biogenesis and maintenance of the primary cilium, this group of skeletal dysplasias was recently designated as ciliopathies with major skeletal involvement. Beemer-Langer syndrome or short-rib polydactyly type IV, was first described in 1983, and has, thus far, remained without a defined molecular basis. The most recent classification of the skeletal dysplasias referred to this phenotype as an as-yet unproven ciliopathy. IFT122 is a gene that encodes a protein responsible for the retrograde transport along the cilium; it has been associated with this group of skeletal dysplasias. To date, mutations in this gene were only found in Sensenbrenner syndrome. Using a panel of skeletal dysplasias genes, including 11 related to SRP, we identified biallelic mutations in IFT122 ([c.3184G>C];[c.3228dupG;c.3231_3233delCAT]) in a fetus with a typical phenotype of SRP-IV, finally confirmed that this phenotype is a ciliopathy and adding to the list of ciliopathies with major skeletal involvement.