Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications

Background: The 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs). Methods: As a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis. Results: Our pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome. Conclusion: We show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications.

Germinação de sementes e emergência de plântulas de Oenocarpus minor Mart. (Arecaceae)

O presente trabalho teve como objetivo avaliar a influência da temperatura e do substrato na germinação, bem como determinar a profundidade ideal de semeadura para emergência de plântulas de Oenocarpus minor Mart. Utilizou-se o delineamento experimental inteiramente casualizado, em esquema fatorial 3x4 (temperatura x substrato), com três repetições de 30 sementes cada. As sementes foram colocadas no interior de caixas plásticas contendo substrato umedecido com água destilada e mantidas em câmaras de germinação à temperatura constante e com fotoperíodo de 12 horas. Para a emergência, foram usadas 4 repetições de 24 sementes, distribuídas em bandeja plásticas, com plantmax e vermiculita, em 0; 2 e 4 cm de profundidade de semeadura, mantidas em casa de vegetação. Baseado nos resultados obtidos, os substratos mais adequados para a germinação de sementes foram a areia e a vermiculita, e a melhor temperatura foi a de 30ºC. Profundidade superior a 2 cm é inadequada para a semeadura de Oenocarpus minor Mart.

Segurança no trabalho de preparo de calda no tanque de 2.000l do turbopulverizador com formulações líquidas de agrotóxicos registradas para a cultura de goiaba

Na atividade de preparo de caldas no tanque do turbopulverizador, há risco de intoxicação do trabalhador devido à exposição, à toxicidade e à concentração do ingrediente ativo tóxico na formulação. Objetivou-se quantificar as exposições dérmicas e respiratórias diárias às dez formulações líquidas de agrotóxicos registradas para a cultura da goiaba, na atividade de abastecimento de dez tanques de 2.000L do turbopulverizador, e a distribuição da exposição dérmica nas partes do corpo do trabalhador, avaliar a eficiência de dois conjuntos de vestimentas hidrorrepelentes, classificar as três condições de trabalho em seguras ou inseguras, e determinar as necessidades de controle das exposições e o número de preparos de caldas seguros. A exposição dérmica na atividade de preparo de caldas é de 13,35 mL de formulação/dia, e a respiratória, de 0, 000153 mL. Nesta atividade de preparo de caldas, as mãos do trabalhador são as partes do corpo mais expostas, com 70,6% da exposição dérmica. A eficiência do conjunto Agro Light, da empresa R&B, é de 92,8 % da exposição dérmica diária do preparador de caldas, e do Kit Tratorizado, da Azeredo, 94,2 %. As exposições dérmicas não controladas pelos conjuntos de proteção individual distribuem-se nas diversas partes do corpo do trabalhador. As atividades de preparo de caldas com as dez formulações líquidas de agrotóxicos registrados na cultura de goiaba são inseguras para o trabalhador. Com as vestimentas de proteção individual, apenas a atividade de preparo de caldas com o inseticida PROVADO (200 g de imidacloprido/L) é segura. Para as condições de trabalho inseguras, as necessidades de controle das exposições variam de 73,8 a 100% (sem proteção), de 26,9 a 99,7% (Agro Light) e de 9,4 a 99,6% (Kit tratorizado). O número de preparo de caldas seguro é de 0 tanques/dia sem proteção, de 0 a 5 ou 7 (Agro Light) ou a 7, 6 ou 9 (Kit Tratorizado).

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data.

BACKGROUND: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. METHODS: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. FINDINGS: We included 61 studies done between January, 1998, and December, 2012, and included 14200;327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). INTERPRETATION: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. FUNDING: Bill & Melinda Gates Foundation.

Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes.

Myc controls the metabolic reprogramming that supports effector T cell differentiation. The expression of Myc is regulated by the T cell antigen receptor (TCR) and pro-inflammatory cytokines such as interleukin-2 (IL-2). We now show that the TCR is a digital switch for Myc mRNA and protein expression that allows the strength of the antigen stimulus to determine the frequency of T cells that express Myc. IL-2 signalling strength also directs Myc expression but in an analogue process that fine-tunes Myc quantity in individual cells via post-transcriptional control of Myc protein. Fine-tuning Myc matters and is possible as Myc protein has a very short half-life in T cells due to its constant phosphorylation by glycogen synthase kinase 3 (GSK3) and subsequent proteasomal degradation. We show that Myc only accumulates in T cells exhibiting high levels of amino acid uptake allowing T cells to match Myc expression to biosynthetic demands. The combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during immune responses.

Endometrial cancer and oral contraceptives : an individual participant meta-analysis of 27200;276 women with endometrial cancer from 36 epidemiological studies.

BACKGROUND: Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors. METHODS: Individual participant datasets were sought from principal investigators and provided centrally for 27200;276 women with endometrial cancer (cases) and 115200;743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy. FINDINGS: The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27200;276 cases and 45200;625 (39%) of 115200;743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p<0·0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0·69, 95% CI 0·66-0·71) than sarcomas (0·83, 0·67-1·04; case-case comparison: p=0·02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2·3 to 1·3 per 100 women. INTERPRETATION: Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400200;000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200200;000 in the past decade (2005-14). FUNDING: Medical Research Council, Cancer Research UK.

Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.

OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels. DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n201;=201;13,664), artesunate-amodiaquine (n201;=201;11,337) and dihydroartemisinin-piperaquine (n201;=201;4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR)201;=201;1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR201;=201;1.50 (95 % CI: 1.06-2.13), P201;=201;0.022); severe anaemia (AOR201;=201;2.04 (95 % CI: 1.21-3.44), P201;=201;0.008); areas of low/moderate transmission setting (AOR201;=201;2.71 (95 % CI: 1.38-5.36), P201;=201;0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR201;=201;2.27 (95 % CI: 1.14-4.51), P201;=201;0.020, compared to dihydroartemisinin-piperaquine). CONCLUSIONS: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML.

Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (-Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), -Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p201;≤201;0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5-93.1), t(v; 22) 87 % (77.2-94.3), -Y 89.0 % (76.7-97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4-100) and major route 52.2 % (28.2-75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.

A qualitative study of adolescents with medically unexplained symptoms and their parents. Part 2: How is healthcare perceived?

Medically unexplained symptoms (MUS) are common among adolescents and an important cause of clinical visits. This study sought to understand the experiences with, and perceptions of, the healthcare of adolescents who have MUS and their parents. Using a qualitative approach, six focus groups and two individual interviews were conducted with a total of ten adolescents and sixteen parents. The participants were recruited in a university hospital in Switzerland. A thematic analysis was conducted in accordance with the Grounded Theory. Six main themes emerged: needing a label for the symptoms, seeking an etiology to explain the symptoms, negotiating the medical system, medication and treatments, interactions with doctors, and the inclusion of parents during consultations. Transcending these themes, however, was the need for good communication between the adolescents, their parents and the clinicians. When explaining the symptoms, clinicians should make sure to discuss the results, investigations and lack of organic origin.

Singling out individual inventors from patent data

An increasing number of studies in recent years have sought to identify individual inventors from patent data. A variety of heuristics have been proposed for using the names and other information disclosed in patent documents to establish who is who in patents. This paper contributes to this literature by describing a methodology for identifying inventors using patents applied to the European Patent Office, EPO hereafter. As in much of this literature, we basically follow a threestep procedure : 1- the parsing stage, aimed at reducing the noise in the inventor’s name and other fields of the patent; 2- the matching stage, where name matching algorithms are used to group similar names; and 3- the filtering stage, where additional information and various scoring schemes are used to filter out these similarlynamed inventors. The paper presents the results obtained by using the algorithms with the set of European inventors applying to the EPO over a long period of time.

Complications After Laparoscopic Roux-en-Y Gastric Bypass in 1573 Consecutive Patients: Are There Predictors?

BACKGROUND: Roux-en-Y gastric bypass (RYGBP), one of the commonest performed bariatric procedures, remains a technically challenging operation associated with significant morbidity in high-risk patients. This study was conducted in order to identify predictors of complications after laparoscopic RYGBP. METHODS: Our prospectively established database has been assessed to review 30-day and in-hospital complications graded according to a validated scoring system (Clavien-Dindo) and separated into minor (Clavien-Dindo I-IIIa) and major (Clavien-Dindo IIIb-IV) complications. Patient- and procedure-related factors were analyzed using univariate analysis. Significant factors associated with morbidity were introduced into a multivariate analysis to identify independent predictors. RESULTS: Between 1999 and 2012, 1573 patients underwent laparoscopic RYGBP, 374 male and 1199 female. Mean age was 41 years, and mean body mass index (BMI) was 44.5 kg/m(2). One hundred fifty-nine procedures were reoperations. One hundred fifty (9.5 %) patients developed at least one complication, and 43 (2.7 %) had major complications, leading to death in one case (0.06 %). Risk factors for morbidity were male gender (p201;=201;0.006) and overall experience of the team (p201;<201;0.0001). Prolonged 3-day antibiotic therapy was associated with significantly reduced overall (p201;<201;0.0001) and major (p201;=201;0.005) complication rates. Major complications were associated with smoking (p201;=201;0.016). CONCLUSIONS: The most significant individual risk factors for early complications after RYGBP are male gender, limited surgical experience, and single dose of antibiotics. RYGBP should be performed by experienced teams. Smoking should be discontinued before surgery. Prolonged antibiotic therapy could be considered, especially if a circular stapled gastrojejunostomy is performed with the anvil introduced transorally.

Intensidad de cuidados enfermeros: ¿cargas de trabajo o complejidad individual?

Objetivo: explorar la identificación de los factores individuales de complejidad de cuidados en enfermos hospitalizados. Método: se empleó un diseño cualitativo de investigación-acción participativa con el método de análisis directo de contenido de los breves relatos de los participantes, enfermeras y enfermeros de los hospitales del lnstituto Catalán de la Salud, sobre casos en los que hubieran experimentado situaciones de complejidad. La suficiencia muestral se estableció a partir del criterio de saturación de la información. Los participantes fueron invitados a formar parte de una ronda de talleres/sesiones de discusión que se hicieron durante 18 meses. Uno de los investigadores recogía por escrito las opiniones de los participantes, mientras el otro moderaba el debate y realizaba preguntas reflexivas sobre el contenido de la propuesta. Posteriormente se invitaba a los participantes a organizarse en pequeños grupos para discutir y registrar en un fomulario individual, breves narrativas sobre casos en los que hubieran experimentado situaciones de complejidad. Resultados: el número de relatos breves incluidos en el análisis final fue de 287. Los factores individuales de complejidad de cuidados incluye cinco dominios: (1) evolutivo, (2) mental y cognitivo, (3) psicoemocional, (4) sociocultural y (5) comorbilidad y complicaciones. La complejidad individual de cuidados se estructura fuentes, factores y especificaciones. Conclusiones: de los cinco ejes de complejidad identificados en el Modelo Vectorial de Complejidad de Safford, cuatro coinciden parcialmente con el análisis presentado. La arquitectura de la complejidad de cuidados debería incluir una consideración multiperspectiva, incluyendo los ejes de complejidad individual, terapéutica-procedimental y organizativa.

Intensidad de cuidados enfermeros: ¿cargas de trabajo o complejidad individual?

Objetivo: explorar la identificación de los factores individuales de complejidad de cuidados en enfermos hospitalizados. Método: se empleó un diseño cualitativo de investigación-acción participativa con el método de análisis directo de contenido de los breves relatos de los participantes, enfermeras y enfermeros de los hospitales del lnstituto Catalán de la Salud, sobre casos en los que hubieran experimentado situaciones de complejidad. La suficiencia muestral se estableció a partir del criterio de saturación de la información. Los participantes fueron invitados a formar parte de una ronda de talleres/sesiones de discusión que se hicieron durante 18 meses. Uno de los investigadores recogía por escrito las opiniones de los participantes, mientras el otro moderaba el debate y realizaba preguntas reflexivas sobre el contenido de la propuesta. Posteriormente se invitaba a los participantes a organizarse en pequeños grupos para discutir y registrar en un fomulario individual, breves narrativas sobre casos en los que hubieran experimentado situaciones de complejidad. Resultados: el número de relatos breves incluidos en el análisis final fue de 287. Los factores individuales de complejidad de cuidados incluye cinco dominios: (1) evolutivo, (2) mental y cognitivo, (3) psicoemocional, (4) sociocultural y (5) comorbilidad y complicaciones. La complejidad individual de cuidados se estructura fuentes, factores y especificaciones. Conclusiones: de los cinco ejes de complejidad identificados en el Modelo Vectorial de Complejidad de Safford, cuatro coinciden parcialmente con el análisis presentado. La arquitectura de la complejidad de cuidados debería incluir una consideración multiperspectiva, incluyendo los ejes de complejidad individual, terapéutica-procedimental y organizativa.