Lung ultrasound and postoperative follow-up of congenital diaphragmatic hernia.

Lung ultrasound (LU) has emerged as a valuable tool for assessing pulmonary aeration noninvasively, rapidly, and reliably in different neonatal conditions. However, its role in the preoperative and postoperative evaluation in congenital diaphragmatic hernia (CDH) is still poorly analyzed. We present a cohort of 8 patients diagnosed with CDH who underwent lung ultrasound examinations at various time points before and after surgical correction. The lung ultrasound patterns were compared between two groups: mechanical ventilation ≤ 7 days (MV ≤ 7) and mechanical ventilation > 7 days (MV > 7). The ultrasound findings were also compared to CT scans and chest X-ray images to assess its diagnostic capacity for identifying postoperative complications: pneumothorax, pleural effusion, and pneumonia. Group MV ≤ 7 exhibited a normal pattern even at 48 h postsurgery, while group MV > 7 presented interstitial or alveolointerstitial pattern in both lungs for prolonged periods (2-3 weeks). Furthermore, contralateral LU pattern may be predictive of respiratory evolution.  Conclusion: Lung ultrasound is a valuable tool for evaluating the progressive reaeration of the lung following surgical correction in CDH patients. It demonstrates the ability to diagnose common postoperative complications without the need for radiation exposure while offering the advantages of quick and serial assessments. These findings highlight the potential of lung ultrasound as an effective alternative to conventional imaging methods in the management of CDH. What is Known: • Lung ultrasound evaluates lung aeration and predicts respiratory outcomes in neonatal patients. What is New: • Lung ultrasound is useful in the postsurgical management of congenital diaphragmatic hernia patients, detecting reaeration and respiratory complications.

Trichoscopy: An Update. / Actualización en tricoscopia.

Trichoscopy is a simple, noninvasive office procedure that can be performed using a handheld or digital dermatoscope. This tool has gained popularity in recent years, because it provides useful diagnostic information for hair loss and scalp disorders by enabling the visualization and identification of distinctive signs and structures. We present an updated review of the trichoscopic features described for some of the most common hair loss disorders seen in clinical practice. Dermatologists should be familiar with these helpful features, as they can significantly aid the diagnosis and follow-up of numerous conditions, such as alopecia areata, trichotillomania, and frontal fibrosing alopecia.

Extensive morphological and behavioural diversity among fourteen new and seven described species in Phytophthora Clade 10 and its evolutionary implications.

During extensive surveys of global Phytophthora diversity 14 new species detected in natural ecosystems in Chile, Indonesia, USA (Louisiana), Sweden, Ukraine and Vietnam were assigned to Phytophthora major Clade 10 based on a multigene phylogeny of nine nuclear and three mitochondrial gene regions. Clade 10 now comprises three subclades. Subclades 10a and 10b contain species with nonpapillate sporangia, a range of breeding systems and a mainly soil- and waterborne lifestyle. These include the previously described P. afrocarpa, P. gallica and P. intercalaris and eight of the new species: P. ludoviciana, P. procera, P. pseudogallica, P. scandinavica, P. subarctica, P. tenuimura, P. tonkinensis and P. ukrainensis. In contrast, all species in Subclade 10c have papillate sporangia and are self-fertile (or homothallic) with an aerial lifestyle including the known P. boehmeriae, P. gondwanensis, P. kernoviae and P. morindae and the new species P. celebensis, P. chilensis, P. javanensis, P. multiglobulosa, P. pseudochilensis and P. pseudokernoviae. All new Phytophthora species differed from each other and from related species by their unique combinations of morphological characters, breeding systems, cardinal temperatures and growth rates. The biogeography and evolutionary history of Clade 10 are discussed. We propose that the three subclades originated via the early divergence of pre-Gondwanan ancestors > 175 Mya into water- and soilborne and aerially dispersed lineages and subsequently underwent multiple allopatric and sympatric radiations during their global spread. Citation: Jung T, Milenkovic I, Corcobado T, et al. 2022. Extensive morphological and behavioural diversity among fourteen new and seven described species in Phytophthora Clade 10 and its evolutionary implications. Persoonia 49: 1-57. https://doi.org/10.3767/persoonia.2022.49.01.

Electricity demand during pandemic times: The case of the COVID-19 in Spain.

Electricity demand and its typical load pattern are usually affected by many endogenous and exogenous factors to which the generation system must accordingly respond through utility operators. Lockdown measures to prevent the spread of COVID-19 imposed by many countries have led to sudden changes in socioeconomic habits which have had direct effects on the electricity systems. Therefore, a detailed analysis of how confinement measures have modified the electricity consumption in Spain, one of the countries most affected by this pandemic, has been performed in this work. Its electricity consumption has decreased by 13.49% from March 14 to April 30, compared to the average value of five previous years. Daily power demand profiles, especially morning and evening peaks, have been modified at homes, hospitals, and in the total power demand. These changes generate a greater uncertainty for the System Operator when making demand forecasts, but production deviations have increased by only 0.1%, thanks to the presence of a diversified generation mix, which has been modified during this period, increasing the proportion of renewable sources and decreasing CO2 emissions.

Impact of age on the use of adjuvant treatments in patients undergoing surgery for colorectal cancer: patients with stage III colon or stage II/III rectal cancer.

BACKGROUND: Many older patients don't receive appropriate oncological treatment. Our aim was to analyse whether there are age differences in the use of adjuvant chemotherapy and preoperative radiotherapy in patients with colorectal cancer. METHODS: A prospective cohort study was conducted in 22 hospitals including 1157 patients with stage III colon or stage II/III rectal cancer who underwent surgery. Primary outcomes were the use of adjuvant chemotherapy for stage III colon cancer and preoperative radiotherapy for stage II/III rectal cancer. Generalised estimating equations were used to adjust for education, living arrangements, area deprivation, comorbidity and clinical tumour characteristics. RESULTS: In colon cancer 92% of patients aged under 65 years, 77% of those aged 65 to 80 years and 27% of those aged over 80 years received adjuvant chemotherapy (χ2trends < 0.001). In rectal cancer preoperative radiotherapy was used in 68% of patients aged under 65 years, 60% of those aged 65 to 80 years, and 42% of those aged over 80 years (χ2trends < 0.001). Adjusting by comorbidity level, tumour characteristics and socioeconomic level, the odds ratio of use of chemotherapy compared with those under age 65, was 0.3 (0.1-0.6) and 0.04 (0.02-0.09) for those aged 65 to 80 and those aged over 80, respectively; similarly, the odds ratio of use of preoperative radiotherapy was 0.9 (0.6-1.4) and 0.5 (0.3-0.8) compared with those under 65 years of age. CONCLUSIONS: The probability of older patients with colorectal cancer receiving adjuvant chemotherapy and preoperative radiotherapy is lower than that of younger patients; many of them are not receiving the treatments recommended by clinical practice guidelines. Differences in comorbidity, tumour characteristics, curative resection, and socioeconomic factors do not explain this lower probability of treatment. Research is needed to identify the role of physical and cognitive functional status, doctors' attitudes, and preferences of patients and their relatives, in the use of adjuvant therapies.

[Efficacy of the strategy to improve the quality indicators of Diabetes Mellitus 2 Care Process in Advanced Diabetes Centre Macarena]. / Eficacia de una estrategia para mejorar los indicadores de calidad del Proceso Asistencial Integrado Diabetes Mellitus 2 en el Centro Avanzado de Diabetes Macarena.

INTRODUCTION: The assessment of the Diabetes Mellitus 2 Care Process (PAI-DM2) through the assessment tool for the chronic illness' care models (IEMAC-Diabetes) allows the design of health interventions for the improvement of medical care. OBJECTIVE: Analysing the quality of healthcare provided to DM2 patients. DESIGN: Quasiexperimental study before and after intervention with a not randomised control group. LOCATION: Health care district of primary care Sevilla. PARTICIPANTS: 12 groups of ascribed patients, 5 Primary Care Healthcenter, chosen in a discretionary way. INTERVENTION: Physicians and nurses from the 12 intervention groups took part in a training program, including an external rotation in the Diabetes Daycare Hospital. MAIN MEASUREMENTS: Number of included patients, glycated hemoglobin, feet exploration (FE), and ocular fundus (OF). RESULTS: 1,475 DM-2 patients were analysed. The proportion of included patients per group was 8.5%, 45.5% were women. At the beginning of the study, the rate of patients with HbA1c<7% were 38.9% in 2013 against 47.7% in 2014 and 40.2% in 2016; 33% of the patients had an OF in 2013 against 41.77% in 2014; 51.6% of patients had an EF against 54.7% in 2014. After the intervention, statistically significant differences were reached in HbA1c (p=0.01) and retinography requested (p=0.01). CONCLUSIONS: IEMAC-Diabetes allows spotting improvement areas in the PAI-DM2. The absence of statistically significant differences may be the result of contamination in the sample and/or Hawthorne effect.

CCR-CARESS score for predicting operative mortality in patients with colorectal cancer.

BACKGROUND: The aim of this study was to assess factors associated with outcomes after surgery for colorectal cancer and to design and internally validate a simple score for predicting perioperative mortality. METHODS: Patients undergoing surgery for primary invasive colorectal cancer in 22 centres in Spain between June 2010 and December 2012 were included. Clinical variables up to 30 days were collected prospectively. Multiple logistic regression techniques were applied and a risk score was developed. The Hosmer-Lemeshow test was applied and the area under the receiver operating characteristic (ROC) curve (AUC, with 95 per cent c.i.) was estimated. RESULTS: A total of 2749 patients with a median age of 68·5 (range 24-97) years were included; the male : female ratio was approximately 2 : 1. Stage III tumours were diagnosed in 32·6 per cent and stage IV in 9·5 per cent. Open surgery was used in 39·3 per cent, and 3·6 per cent of interventions were urgent. Complications were most commonly infectious or surgical, and 25·5 per cent of patients had a transfusion during the hospital stay. The 30-day postoperative mortality rate was 1·9 (95 per cent c.i. 1·4 to 2·4) per cent. Predictive factors independently associated with mortality were: age 80 years or above (odds ratio (OR) 2·76), chronic obstructive pulmonary disease (COPD) (OR 3·62) and palliative surgery (OR 10·46). According to the categorical risk score, a patient aged 80 years or more, with COPD, and who underwent palliative surgery would have a 23·5 per cent risk of death within 30 days of the intervention. CONCLUSION: Elderly patients with co-morbidity and palliative intention of surgery have an unacceptably high risk of death.

Predictors of 1- and 2-year mortality in patients with rectal cancer.

AIM: Tools are needed to aid in the assessment of the prognosis of patients with rectal cancer regarding the risk of medium-term mortality. The aim of this study was to develop and validate clinical prediction rules for 1- and 2-year mortality in patients undergoing surgery for rectal cancer. METHOD: A prospective cohort study of patients diagnosed with rectal cancer who underwent surgery was carried out. The main outcomes were mortality at 1 and 2 years after surgery. Background, clinical parameters and diagnostic test findings were evaluated as possible predictors. Multivariable survival models were used in the statistical analyses. RESULTS: Predictors of 1-year mortality were being a current smoker [hazard ratio (HR) 4.98], having a Charlson index adjusted by age > 5 (HR 2.61), the presence of vascular, perineural or lymphatic invasion (HR 3.30), the presence of residual tumour at the operation (R-stage) (HR 8.64) and TNM stage (HR for TNM IV 5.10) [concordance index (C-index) 0.799 (95% CI: 0.71-0.89)]. Age greater than 80 years (HR 2.19), being a current smoker (HR 2.20), the pre-intervention haemoglobin level (HR 2.02), need for blood transfusion (HR 2.12), vascular, perineural or lymphatic invasion (HR 2.59), R-stage of the operation (HR 6.13) and TNM stage (HR for TNM IV 4.43) were predictors of 2-year mortality [C-index 0.779 (0.718-0.840)]. Adjuvant chemotherapy was an additional predictor at both outcome durations. CONCLUSION: These clinical parameters show good predictive values and are easy and quick-to-use tools to help in clinical decision making.

Electrical velocimetry for non-invasive monitoring of the closure of the ductus arteriosus in preterm infants.

Closure of a patent ductus arteriosus (PDA) in preterm infants modifies cardiac output and induces adaptive changes in the hemodynamic situation. The present study aims to analyze those changes, through a non-invasive cardiac output monitor based on blood electrical velocimetry, in preterm babies. A prospective observational study of preterm infants with a gestational age of less than 28 weeks, and a hemodynamic significant PDA, requires intravenous ibuprofen or surgical closure. All patients were monitored with electrical velocimetry before treatment and through the following 72 h. Two groups were defined, ibuprofen and surgical closure. Variations of cardiac output were analyzed from the basal situation and at 1, 8, 24, 48, and 72 h on each group. During a 12-month period, 18 patients were studied. The median gestational age in the ibuprofen group (12/18) was 26+5 weeks (25+5-27+3) with a median birth weight of 875 (670-1010) g. The cardiac output index (CI) value was 0.29 l/kg/min (0.24-0.34). Among the patients with confirmed ductus closure (50%), a significant CI decrease was shown (0.24 vs 0.29 l/kg/min; P 0.03) after 72 h (three ibuprofen doses). A statistically significant decrease in systolic volume (SVI) was found: 1.62 vs 1.88 ml/kg, P 0.03 with a decrease in contractility (ICON), 85 vs 140, P 0.02. The gestational age in the surgical group (6/18) was 25+2 weeks (24-26+3) with a median weight of 745 (660-820) g. All patients in this group showed a decrease in the immediate postoperative CI (1 h after surgery) 0.24 vs 0.30 l/kg/min, P 0.05, and a significant decrease in contractility (ICON 77 vs 147, P 0.03). In addition, a no statistically significant decrease in SVI (1.54 vs 1.83 ml/kg, P 0.06), as well as an increase in systemic vascular resistance (10,615 vs 8797 dyn/cm2, P 0.08), were detected. This deterioration was transient without significant differences in the remaining periods of time evaluated. CONCLUSION: The surgical closure of the PDA in preterm infants causes a transient deterioration of cardiac function linked to a documented decrease in the left ventricular output. The hemodynamic changes detected after pharmacological PDA closure are similar but those patients present a better clinical tolerance to changes in the cardiac output. What is Known: • Surgical ductus closure generates acute hemodynamic changes in cardiac output and left ventricular function. What is New: • The hemodynamic changes detected after pharmacological ductus closure are similar to those found in the surgical closure. Electrical velocimetry can detect those changes.

Dissecting heterogeneity in paediatric Type 1 diabetes: association of TCF7L2 rs7903146 TT and low-risk human leukocyte antigen (HLA) genotypes.

AIMS: To test the hypothesis that non-obese individuals with childhood-onset Type 1 diabetes and the rs7903146 TT genotype would be less likely to have high-risk human leukocyte antigen (HLA) genotypes and alleles. METHODS: We studied a cohort of 105 non-obese participants in the T1D Exchange Biobank Residual Insulin Study who had childhood-onset Type 1 diabetes [mean (sd) age at onset and recruitment, respectively, 9.9 (4.15) and 14.4 (4.13) years; 84.8% non-Hispanic white]. We analysed islet autoantibodies (glutamic acid decarboxylase 65, islet cell autoantigen 512/islet antigen-2 and zinc transporter 8), non-fasting random C-peptide levels, HLA type and TCF7L2 single nucleotide polymorphism rs7903146 in this cohort. RESULTS: None of the 13 individuals with the rs7903146 TT genotype carried the highest Type 1 diabetes risk HLA genotype, i.e. DRB1*03:01/DR4 (DRB1*0401, *04:05 or *04:02), compared with 29.4% (27/92) of those without it (P=0.023). The DRB1*03:01 allele was present in 15.4% (2/13) of individuals with the single nucleotide polymorphism, compared with 59.8% (55/92) of those without it (P=0.003). Analyses restricted to autoantibody-positive individuals (n=80) yielded similar results. The HLA DRB1*15:01 allele, which affords dominant protection against Type 1 diabetes, was found in one participant, who had multiple islet autoantibodies and carried the rs7903146 TT genotype. CONCLUSIONS: These findings further support the hypothesis that TCF7L2 gene variation contributes to diabetogenesis in a subset of young people with Type 1 diabetes, opening possible new pathways for therapy and prevention.

Racial and ethnic differences among children with new-onset autoimmune Type 1 diabetes.

AIM: To compare demographic and clinical characteristics among children from ethnic minorities and non-Hispanic white children with new-onset autoimmune Type 1 diabetes. METHODS: We analysed a single-centre series of 712 children with new-onset autoimmune Type 1 diabetes between January 2008 and March 2011. The median (range) age was 9.7 (0.3-18.1) years, the mean (sd) BMI percentile was 69.7 (25.4) and 48.3% of the cohort were girls. The cohort comprised 57.3% non-Hispanic white, 20.5% Hispanic and 14.8% African-American children, and 7.4% were of other, mixed or unknown race. RESULTS: The Hispanic subgroup, compared with non-Hispanic white subgroup, had a higher mean (sd) C-peptide level [0.82 (1.62) vs 0.55 (0.47) ng/ml; P=0.004), and a greater proportion of children with elevated BMI (overweight or obesity; 49.6% vs 32.5%; P<0.001) and diabetic ketoacidosis (51.8% vs 38.2%; P=0.006). The African-American group had a higher mean (sd) glucose level [24.4 (12.8) vs 21.4 (10.7) mmol/l; P=0.017], a greater proportion of children with ketoacidosis (56.7% vs 38.2%; P=0.001), a greater proportion with elevated BMI (52.9% vs 32.5%; P<0.001), and a lower proportion of children at pre-pubertal stage (49.0% vs 61.6%; P=0.01), and tended to have higher C-peptide levels [0.65 (0.59) vs 0.55 [0.47] ng/ml; P=0.079) compared with the non-Hispanic white children. The differences in C-peptide levels compared with non-Hispanic white children persisted for Hispanic (P=0.01) but not African-American children (P=0.29) after adjustment for age, sex, BMI, ketoacidosis, glucose, Tanner stage and autoantibody number. CONCLUSION: At the onset of paediatric autoimmune Type 1 diabetes, Hispanic, but not African-American children had higher C-peptide levels, after adjustment for potential confounders, compared with non-Hispanic white children. These findings suggest that ethnicity may contribute to the heterogeneity of Type 1 diabetes pathogenesis, with possible implications for intervention.

DPD epitope-specific glutamic acid decarboxylase (GAD)65 autoantibodies in children with Type 1 diabetes.

AIM: To study whether DPD epitope-specific glutamate decarboxylase autoantibodies are found more frequently in children with milder forms of Type 1 diabetes. METHODS: We prospectively evaluated 75 children with new-onset autoimmune Type 1 diabetes, in whom we collected demographic, anthropometric and clinical data and measured islet autoantibodies. Glutamate decarboxylase 65 autoantibody-positive samples were analysed for epitope specificities using recombinant Fab against the DPD-defined epitope of glutamate decarboxylase 65. RESULTS: After adjustment for age, positive DPD epitope recognition was significantly associated with higher C-peptide levels at onset (P = 0.02, r2 =0.21, n = 35), and high DPD recognition in the highest quartile tended to be associated with HbA1c ≤ 53 mmol/mol (7%) at the last follow-up [mean (sd) follow-up 1.3 (0.4) years; P = 0.07; for the model, P = 0.044, n = 30)]. Age- and sex-adjusted BMI percentile was significantly correlated with recognition of the DPD-defined epitope (P < 0.03, r2 =0.14, n = 34), but this correlation was driven by the older age group (age ≥ 10 years; P = 0.016, r2 =0.27, n = 21) and was not significant in younger children (P = 0.93, n = 13). There were no independent associations with sex, race/ethnicity, diabetic ketoacidosis, HbA1c , HLA DR3-DQ2/DR4-DQ8 or autoantibody number. CONCLUSIONS: Our findings suggest that recognition of the DPD-defined glutamate decarboxylase 65 autoantibody epitope at Type 1 diabetes onset is directly associated with ß-cell function, BMI and age, which supports the hypothesis that immunological factors contribute to the clinical heterogeneity of Type 1 diabetes. Larger studies relating epitope-specific glutamate decarboxylase 65 autoantibody to clinical phenotype in children with Type 1 diabetes are warranted.

Modifiable causes of premature death in middle-age in Western Europe: results from the EPIC cohort study.

BACKGROUND: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death. METHODS: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models. RESULTS: We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31-32 %) and 14 % (95 % CI, 12-16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8-12 %) and high blood pressure (9 %; 95 % CI, 7-11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55-59 %), being 35 % (95 % CI, 32-37 %) among never smokers and 74 % (95 % CI, 73-75 %) among current smokers. CONCLUSIONS: While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed.

[A first step towards safer sedation and analgesia: A systematic evaluation of outcomes and level of sedation and analgesia in the mechanically ventilated critically ill patient]. / Un primer paso hacia una analgosedación más segura: evaluación sistemática de objetivos y grado de analgesia y sedación en el paciente crítico con ventilación mecánica.

INTRODUCTION: Safe analgesia and sedation strategies are necessary in order to avoid under or over sedation, as well as improving the comfort and safety of critical care patients. OBJECTIVES: To compare and contrast a multidisciplinary protocol of systematic evaluation and management of analgesia and sedation in a group of critical care patients on mechanical ventilation with the usual procedures. MATERIALS AND METHODS: A cohort study with contemporary series was conducted in a tertiary care medical-surgical ICU February to November during 2013 and 2014. The inclusion criteria were mechanical ventilation ≥ 24h and use of sedation by continuous infusion. Sedation was monitored using the Richmond agitation-sedation scale or bispectral index, and analgesia were measured using the numeric rating scale, or behavioural indicators of pain scale. The study variables included; mechanical ventilation time, weaning time, ventilation support time, artificial airway time, continuous sedative infusion time, daily dose and frequency of analgesic and sedative drug use, hospital stay, and ICU and hospital mortality, Richmond agitation-sedation scale, bispectral index, numeric rating scale, and behavioural indicators of pain scale measurements. Kruskal Wallis and Chi2, and a significance of p<.05 were used. RESULTS: The study included 153 admissions, 75 pre-intervention and 78 post-intervention, with a mean age of 55.7±13 years old, and 67% men. Both groups showed similarities in age, reason for admission, and APACHE. There were non-significant decreases in mechanical ventilation time 4 (1.4-9.2) and 3.2 (1.4-8.1) days, respectively; p= 0.7, continuous sedative infusion time 6 (3-11) and 5 (3-11) days; p= 0.9, length of hospital stay 29 (18-52); 25 (14-41) days; p= 0.1, ICU mortality (8 vs. 5%; p= 0.4), and hospital mortality (10.6 vs. 9.4%: p= 0.8). Daily doses of midazolam and remifentanil decreased 347 (227-479) mg/day; 261 (159-358) mg/day; p= 0.02 and 2175 (1427-3285) mcg/day; 1500 (715-2740) mcg/day; p= 0.02, respectively. There were increases in the use of remifentanil (32% vs. 51%; p= 0.01), dexmedetomidine (0 vs.6%; p= 0.02), dexketoprofen (60 vs. 76%; p= 0.03), and haloperidol (15 vs.28%; p= 0.04). The use of morphine decreased (71 vs. 54%; p= 0.03). There was an increase in the number of measurements and Richmond agitation-sedation scale scores 6 (3-17); 21 (9-39); p< 0.0001, behavioural indicators of pain scale 6 (3-18); 19(8-33); p< 0.001 and numeric rating scale 4 (2-6); 8 (6-17); p< 0.0001. CONCLUSIONS: The implementation of a multidisciplinary protocol of systematic evaluation of analgesia and sedation management achieved an improvement in monitoring and adequacy of dose to patient needs, leading to improved outcomes.

Sparse and incomplete factorial matrices to screen membrane protein 2D crystallization.

Electron crystallography is well suited for studying the structure of membrane proteins in their native lipid bilayer environment. This technique relies on electron cryomicroscopy of two-dimensional (2D) crystals, grown generally by reconstitution of purified membrane proteins into proteoliposomes under conditions favoring the formation of well-ordered lattices. Growing these crystals presents one of the major hurdles in the application of this technique. To identify conditions favoring crystallization a wide range of factors that can lead to a vast matrix of possible reagent combinations must be screened. However, in 2D crystallization these factors have traditionally been surveyed in a relatively limited fashion. To address this problem we carried out a detailed analysis of published 2D crystallization conditions for 12 ß-barrel and 138 α-helical membrane proteins. From this analysis we identified the most successful conditions and applied them in the design of new sparse and incomplete factorial matrices to screen membrane protein 2D crystallization. Using these matrices we have run 19 crystallization screens for 16 different membrane proteins totaling over 1300 individual crystallization conditions. Six membrane proteins have yielded diffracting 2D crystals suitable for structure determination, indicating that these new matrices show promise to accelerate the success rate of membrane protein 2D crystallization.

Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition.

STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.