Modulation of fast sodium current in airway smooth muscle cells by exchange protein directly activated by cAMP.

Airway smooth muscle (ASM) cells from mouse bronchus express a fast sodium current mediated by NaV1.7. We present evidence that this current is regulated by cAMP. ASM cells were isolated by enzymatic dispersal and studied using the whole cell patch clamp technique at room temperature. A fast sodium current, INa, was observed on holding cells under voltage clamp at -100 mV and stepping to -20 mV. This current was reduced in a concentration-dependent manner by denopamine (10 and 30 µM), a ß-adrenergic agonist. Forskolin (1 µM), an activator of adenylate cyclase, reduced the current by 35%, but 6-MB-cAMP (300 µM), an activator of protein kinase A (PKA), had no effect. In contrast, 8-pCPT-2-O-Me-cAMP-AM (007-AM, 10 µM), an activator of exchange protein directly activated by cAMP (Epac), reduced the current by 48%. The inhibitory effect of 007-AM was still observed in the presence of dantrolene (10 µM), an inhibitor of ryanodine receptors, and when cytosolic [Ca2+] was buffered by inclusion of 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, Sigma (BAPTA) (50 µM) in the pipette solution, suggesting that the inhibition of INa was not due to Ca2+-release from intracellular stores. When 007-AM was tested on the current-voltage relationship, it reduced the current at potentials from -30 to 0 mV, but had no effect on the steady-state activation curve. However, the steady-state inactivation V1/2, the voltage causing inactivation of 50% of the current, was shifted in the negative direction from -76.6 mV to -89.7 mV. These findings suggest that cAMP regulates INa in mouse ASM via Epac, but not PKA.NEW & NOTEWORTHY ß-adrenergic agonists are commonly used in inhalers to treat asthma and chronic obstructive pulmonary disease. These work by causing bronchodilation and reducing inflammation. The present study provides evidence that these drugs have an additional action, namely, to reduce sodium influx into airway smooth muscle cells via fast voltage-dependent channels. This may have the dual effect of promoting bronchodilation and reducing remodeling of the airways, which has a detrimental effect in these diseases.

Neonatal mortality risk of large-for-gestational-age and macrosomic live births in 15 countries, including 115.6 million nationwide linked records, 2000-2020.

OBJECTIVE: We aimed to compare the prevalence and neonatal mortality associated with large for gestational age (LGA) and macrosomia among 115.6 million live births in 15 countries, between 2000 and 2020. DESIGN: Population-based, multi-country study. SETTING: National healthcare systems. POPULATION: Liveborn infants. METHODS: We used individual-level data identified for the Vulnerable Newborn Measurement Collaboration. We calculated the prevalence and relative risk (RR) of neonatal mortality among live births born at term + LGA (>90th centile, and also >95th and >97th centiles when the data were available) versus term + appropriate for gestational age (AGA, 10th-90th centiles) and macrosomic (≥4000, ≥4500 and ≥5000 g, regardless of gestational age) versus 2500-3999 g. INTERGROWTH 21st served as the reference population. MAIN OUTCOME MEASURES: Prevalence and neonatal mortality risks. RESULTS: Large for gestational age was common (median prevalence 18.2%; interquartile range, IQR, 13.5%-22.0%), and overall was associated with a lower neonatal mortality risk compared with AGA (RR 0.83, 95% CI 0.77-0.89). Around one in ten babies were ≥4000 g (median prevalence 9.6% (IQR 6.4%-13.3%), with 1.2% (IQR 0.7%-2.0%) ≥4500 g and with 0.2% (IQR 0.1%-0.2%) ≥5000 g). Overall, macrosomia of ≥4000 g was not associated with increased neonatal mortality risk (RR 0.80, 95% CI 0.69-0.94); however, a higher risk was observed for birthweights of ≥4500 g (RR 1.52, 95% CI 1.10-2.11) and ≥5000 g (RR 4.54, 95% CI 2.58-7.99), compared with birthweights of 2500-3999 g, with the highest risk observed in the first 7 days of life. CONCLUSIONS: In this population, birthweight of ≥4500 g was the most useful marker for early mortality risk in big babies and could be used to guide clinical management decisions.

Stillbirths: Contribution of preterm birth and size-for-gestational age for 125.4 million total births from nationwide records in 13 countries, 2000-2020.

OBJECTIVE: To examine the contribution of preterm birth and size-for-gestational age in stillbirths using six 'newborn types'. DESIGN: Population-based multi-country analyses. SETTING: Births collected through routine data systems in 13 countries. SAMPLE: 125 419 255 total births from 22+0 to 44+6 weeks' gestation identified from 2000 to 2020. METHODS: We included 635 107 stillbirths from 22+0 weeks' gestation from 13 countries. We classified all births, including stillbirths, into six 'newborn types' based on gestational age information (preterm, PT, <37+0 weeks versus term, T, ≥37+0 weeks) and size-for-gestational age defined as small (SGA, <10th centile), appropriate (AGA, 10th-90th centiles) or large (LGA, >90th centile) for gestational age, according to the international newborn size for gestational age and sex INTERGROWTH-21st standards. MAIN OUTCOME MEASURES: Distribution of stillbirths, stillbirth rates and rate ratios according to six newborn types. RESULTS: 635 107 (0.5%) of the 125 419 255 total births resulted in stillbirth after 22+0 weeks. Most stillbirths (74.3%) were preterm. Around 21.2% were SGA types (PT + SGA [16.2%], PT + AGA [48.3%], T + SGA [5.0%]) and 14.1% were LGA types (PT + LGA [9.9%], T + LGA [4.2%]). The median rate ratio (RR) for stillbirth was highest in PT + SGA babies (RR 81.1, interquartile range [IQR], 68.8-118.8) followed by PT + AGA (RR 25.0, IQR, 20.0-34.3), PT + LGA (RR 25.9, IQR, 13.8-28.7) and T + SGA (RR 5.6, IQR, 5.1-6.0) compared with T + AGA. Stillbirth rate ratios were similar for T + LGA versus T + AGA (RR 0.7, IQR, 0.7-1.1). At the population level, 25% of stillbirths were attributable to small-for-gestational-age. CONCLUSIONS: In these high-quality data from high/middle income countries, almost three-quarters of stillbirths were born preterm and a fifth small-for-gestational age, with the highest stillbirth rates associated with the coexistence of preterm and SGA. Further analyses are needed to better understand patterns of gestation-specific risk in these populations, as well as patterns in lower-income contexts, especially those with higher rates of intrapartum stillbirth and SGA.

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Functional expression of NaV1.7 channels in freshly dispersed mouse bronchial smooth muscle cells.

Isolated smooth muscle cells (SMCs) from mouse bronchus were studied using the whole cell patch-clamp technique at ∼21°C. Stepping from -100 mV to -20 mV evoked inward currents of mean amplitude -275 pA. These inactivated (tau = 1.1 ms) and were abolished when external Na+ was substituted with N-Methyl-d-glucamine. In current-voltage protocols, current peaked at -10 mV and reversed between +20 and +30 mV. The V1/2s of activation and inactivation were -25 and -86 mV, respectively. The current was highly sensitive to tetrodotoxin (IC50 = 1.5 nM) and the NaV1.7 subtype-selective blocker, PF-05089771 (IC50 = 8.6 nM), consistent with NaV1.7 as the underlying pore-forming α subunit. Two NaV1.7-selective antibodies caused membrane-delineated staining of isolated SMC, as did a nonselective pan-NaV antibody. RT-PCR, performed on groups of ∼15 isolated SMCs, revealed transcripts for NaV1.7 in 7/8 samples. Veratridine (30 µM), a nonselective NaV channel activator, reduced peak current evoked by depolarization but induced a sustained current of 40 pA. Both effects were reversed by tetrodotoxin (100 nM). In tension experiments, veratridine (10 µM) induced contractions that were entirely blocked by atropine (1 µM). However, in the presence of atropine, veratridine was able to modulate the pattern of activity induced by a combination of U-46619 (a thromboxane A2 mimetic) and PGE2 (prostaglandin E2), by eliminating bursts in favor of sustained phasic contractions. These effects were readily reversed to control-like activity by tetrodotoxin (100 nM). In conclusion, mouse bronchial SMCs functionally express NaV1.7 channels that are capable of modulating contractile activity, at least under experimental conditions.

Understanding ethnic inequalities in stillbirth rates: a UK population-based cohort study.

OBJECTIVES: To investigate inequalities in stillbirth rates by ethnicity to facilitate development of initiatives to target those at highest risk. DESIGN: Population-based perinatal mortality surveillance linked to national birth and death registration (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK). SETTING: UK. PARTICIPANTS: 4 391 569 singleton births at ≥24+0 weeks gestation between 2014 and 2019. MAIN OUTCOME MEASURES: Stillbirth rate difference per 1000 total births by ethnicity. RESULTS: Adjusted absolute differences in stillbirth rates were higher for babies of black African (3.83, 95% CI 3.35 to 4.32), black Caribbean (3.60, 95% CI 2.65 to 4.55) and Pakistani (2.99, 95% CI 2.58 to 3.40) ethnicities compared with white ethnicities. Higher proportions of babies of Bangladeshi (42%), black African (39%), other black (39%) and black Caribbean (37%) ethnicities were from most deprived areas, which were associated with an additional risk of 1.50 stillbirths per 1000 births (95% CI 1.32 to 1.67). Exploring primary cause of death, higher stillbirth rates due to congenital anomalies were observed in babies of Pakistani, Bangladeshi and black African ethnicities (range 0.63-1.05 per 1000 births) and more placental causes in black ethnicities (range 1.97 to 2.24 per 1000 births). For the whole population, over 40% of stillbirths were of unknown cause; however, this was particularly high for babies of other Asian (60%), Bangladeshi (58%) and Indian (52%) ethnicities. CONCLUSIONS: Stillbirth rates declined in the UK, but substantial excess risk of stillbirth persists among babies of black and Asian ethnicities. The combined disadvantage for black, Pakistani and Bangladeshi ethnicities who are more likely to live in most deprived areas is associated with considerably higher rates. Key causes of death were congenital anomalies and placental causes. Improved strategies for investigation of stillbirth causes are needed to reduce unexplained deaths so that interventions can be targeted to reduce stillbirths.

Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers.

Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3ß suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426.

Eating difficulties in children born late and moderately preterm at 2 y of age: a prospective population-based cohort study.

BACKGROUND: Very preterm (<32 wk of gestation) infants are at increased risk of eating difficulties compared with their term-born peers. Little is known about the impact of late and moderately preterm (LMPT; 32-36 wk of gestation) birth on eating difficulties in early childhood. OBJECTIVES: The aims were to assess the prevalence of eating difficulties in infants born LMPT at 2 y corrected age and to explore the impact of neonatal and neurodevelopmental factors. DESIGN: A geographic population-based cohort of 1130 LMPT and 1255 term-born controls was recruited at birth. The parents of 651 (59%) LMPT and 771 (62%) term-born infants completed questionnaires at 2 y corrected age to assess neurodevelopmental outcomes. Parents also completed a validated questionnaire to assess eating behaviors in 4 domains: refusal/picky eating, oral motor problems, oral hypersensitivity, and eating behavior problems. Infants with scores >90th percentile were classified with eating difficulties in each domain. Neonatal data were collected at discharge, and sociodemographic information was collected via maternal interview. Poisson regression was used to assess between-group differences in eating difficulties and to explore associations with neonatal factors and neurodevelopmental outcomes at 2 y of age. RESULTS: In unadjusted analyses, LMPT infants were at increased risk of refusal/picky eating (RR: 1.53; 95% CI: 1.03, 2.25) and oral motor problems (RR: 1.62; 95% CI: 1.06, 2.47). Prolonged nasogastric feeding >2 wk (RR: 1.87; 95% CI: 1.07, 3.25), behavior problems (RR: 2.95; 95% CI: 1.93, 4.52), and delayed social competence (RR: 2.28; 95% CI: 1.49, 3.48) were independently associated with eating difficulties in multivariable analyses. After adjustment for these factors, there was no excess of eating difficulties in LMPT infants. CONCLUSIONS: Infants born LMPT are at increased risk of oral motor and picky eating problems at 2 y corrected age. However, these are mediated by other neurobehavioral sequelae in this population. This trial was registered on the UK Clinical Research Network Portfolio at http://public.ukcrn.org.uk/search/ as UKCRN Study ID 7441.

Early Emergence of Delayed Social Competence in Infants Born Late and Moderately Preterm.

OBJECTIVE: To assess behavioral outcomes and social competence at 2 years of age in infants born late and moderately preterm (LMPT; 32-36 wk gestation). METHOD: One thousand one hundred and thirty LMPT infants and 1255 term-born (≥37 wk) controls were recruited at birth to a prospective geographical population-based study. Parents completed the Brief Infant and Toddler Social Emotional Assessment (BITSEA) at 2 years corrected age to assess infants' behavior problems and social competence. Cognitive development was assessed using the Parent Report of Children's Abilities-Revised. Parent questionnaires at 2 years were completed for 638 (57%) LMPT and 765 (62%) term-born infants. Group differences in the prevalence of behavior problems and delayed social competence between LMPT infants and term-born controls were adjusted for age, sex, small-for-gestational-age, socioeconomic status and cognitive impairment. RESULTS: Late and moderately preterm infants were at significantly increased risk of delayed social competence compared with term-born controls (26.4% vs. 18.4%; adjusted-relative risk [RR] 1.28; 95% CI, 1.03-1.58), but there was no significant group difference in the prevalence of behavior problems (21.0% vs. 17.6%; adjusted-RR 1.13, 0.89-1.42). Non-white ethnicity (RR 1.68, 1.26-2.24), medium (RR 1.60, 1.14-2.24) and high (RR 1.98, 1.41-2.75) socioeconomic risk and recreational drug use during pregnancy (RR 1.70, 1.03-2.82) were significant independent predictors of delayed social competence in LMPT infants. CONCLUSION: Birth at 32 to 36 weeks of gestation confers a specific risk for delayed social competence at 2 years of age. This may be indicative of an increased risk for psychiatric disorders later in childhood.

Neurodevelopmental outcomes following late and moderate prematurity: a population-based cohort study.

OBJECTIVE: There is a paucity of data relating to neurodevelopmental outcomes in infants born late and moderately preterm (LMPT; 32(+0)-36(+6) weeks). This paper present the results of a prospective, population-based study of 2-year outcomes following LMPT birth. DESIGN: 1130 LMPT and 1255 term-born children were recruited at birth. At 2 years corrected age, parents completed a questionnaire to assess neurosensory (vision, hearing, motor) impairments and the Parent Report of Children's Abilities-Revised to identify cognitive impairment. Relative risks for adverse outcomes were adjusted for sex, socio-economic status and small for gestational age, and weighted to account for over-sampling of term-born multiples. Risk factors for cognitive impairment were explored using multivariable analyses. RESULTS: Parents of 638 (57%) LMPT infants and 765 (62%) controls completed questionnaires. Among LMPT infants, 1.6% had neurosensory impairment compared with 0.3% of controls (RR 4.89, 95% CI 1.07 to 22.25). Cognitive impairments were the most common adverse outcome: LMPT 6.3%; controls 2.4% (RR 2.09, 95% CI 1.19 to 3.64). LMPT infants were at twice the risk for neurodevelopmental disability (RR 2.19, 95% CI 1.27 to 3.75). Independent risk factors for cognitive impairment in LMPT infants were male sex, socio-economic disadvantage, non-white ethnicity, preeclampsia and not receiving breast milk at discharge. CONCLUSIONS: Compared with term-born peers, LMPT infants are at double the risk for neurodevelopmental disability at 2 years of age, with the majority of impairments observed in the cognitive domain. Male sex, socio-economic disadvantage and preeclampsia are independent predictors of low cognitive scores following LMPT birth.

Gender differences in mental health expectancies in early- and midlife in six European countries.

BACKGROUND: Health expectancies, taking into account both quality and quantity of life, have generally been based on disability and physical functioning. AIMS: To compare mental health expectancies at age 25 and 55 based on common mental disorders both across countries and between males and females. METHOD: Mental health expectancies were calculated by combining mortality data from population life tables and the age-specific prevalence of selected common mental disorders obtained from the European Study of the Epidemiology of Mental Disorders (ESEMeD). RESULTS: For the male population aged 25 (all countries combined) life expectancy was 52 years and life expectancy spent with a common mental disorder was 1.8 years (95% CI 0.7-2.9), 3.4% of overall life expectancy. In comparison, for the female population life expectancy at age 25 was higher (57.9 years) as was life expectancy spent with a common mental disorder (5.1 years, 95% CI 3.6-6.6) and as a proportion of overall life expectancy, 8.8%. By age 55 life expectancy spent with a common mental disorder had reduced to 0.7 years (males) and 2.3 years (females). CONCLUSIONS: Age and gender differences underpin our understanding of years spent with common mental disorders in adulthood. Greater age does not mean living relatively more years with common mental disorder. However, the female population spends more years with common mental disorders and a greater proportion of their longer life expectancy with them (and with each studied separate mental disorder).

Methodology and reporting of systematic reviews and meta-analyses of observational studies in psychiatric epidemiology: systematic review.

BACKGROUND: Relatively little is known of the use of systematic review and synthesis methods of non-randomised psychiatric epidemiological studies, which play a vital role in aetiological research, planning and policy-making. AIMS: To evaluate reviews of psychiatric epidemiological studies of functional mental disorders that employed synthesis methods such as systematic review or meta-analysis, or other forms of quantitative review. METHOD: We searched the literature to identify appropriate reviews published during the period 1996 to April 2009. Selected reviews were evaluated using published review guidelines. RESULTS: We found 106 reviews in total, of which 38 (36%) did not mention method of data abstraction from primary studies at all. Many failed to mention study quality, publication bias, bias and confounding. In 73 studies that performed a meta-analysis, 58 (79%) tested for heterogeneity and of these, 47 found significant heterogeneity. Studies that detected heterogeneity made some allowance for this. A major obstacle facing reviewers is the wide variation between primary studies in the use of instruments to measure outcomes and in sampling methods used. CONCLUSIONS: Many deficiencies found in systematic reviews are potentially remediable, although synthesis of primary study findings in a field characterised by so many sources of heterogeneity will remain challenging.

The effect of dementia trends and treatments on longevity and disability: a simulation model based on the MRC Cognitive Function and Ageing Study (MRC CFAS).

BACKGROUND: the numbers with dementia are projected to double between 2001 and 2040, in line with continued increases in life expectancy. Projections have failed to account for the impact of changing risk factors on future numbers with dementia or disability. OBJECTIVE: to estimate the size of the disabled population over the next 20 years and explore the impact of treatments that delay onset of cognitive impairment and associated disability. METHODS: a dynamic macro-simulation projection model was used to calculate the numbers of older people with disability to 2026. Transition rates to disability and death conditional on a range of conditions, calculated from the MRC Cognitive Function and Ageing Study, were applied to the 1992 England and Wales population. Scenarios for trends in dementia incidence, risk factors and treatment were devised from a systematic review and applied. FINDINGS: population ageing alone resulted in 39% more older people between 2006 and 2026 and 82% more with disability. A combination of reduced incidence of cognitive impairment and disabling consequences alongside improved survival provided the largest reductions in the disabled population (15,000) and the numbers cognitively impaired (302,000) compared with ageing of the population alone. INTERPRETATION: population ageing alone will increase the disabled older population by over 80% and the numbers cognitively impaired by almost 50% over the next 20 years with serious implications for the provision of care. Research priorities should focus on earlier detection of dementia and its risk factors, thereby allowing earlier and more targeted treatment to alleviate its associated disability.

Efungumab and caspofungin: pre-clinical data supporting synergy.

OBJECTIVES: Heat shock protein 90 (hsp90) is targeted by the humoral response in invasive candidiasis. This paper tests for synergy between caspofungin and efungumab--a human antibody fragment against hsp90. METHODS: The MIC-0, MIC-2 values and FICI were determined for a range of yeasts against efungumab and caspofungin. These yeasts were injected intravenously into mice with: 100 microL of saline plus 100 microL of formulation buffer; 100 microL of caspofungin (1 or 4 mg/kg) plus 100 microL of formulation buffer; or 100 microL of caspofungin (1 or 4 mg/kg) plus 100 microL of efungumab 2 mg/kg. Yeast counts were determined for kidney, liver and spleen. Electron microscopy was performed on efungumab-stained Candida grown with and without caspofungin. RESULTS: The FICIs of efungumab and caspofungin at MIC-0 and MIC-2, respectively, were: fluconazole-susceptible Candida albicans: 0.5, 0.52; fluconazole-resistant C. albicans, Candida tropicalis and Candida krusei: 0.5, 0.5; Candida parapsilosis: 2, 0.5; Candida glabrata: 0.26, 0.28; and Candida guilliermondii: 2, 0.27. A statistically significant reduction in colony counts or increase in the number of negative biopsies (P < 0.05) was seen in mice on combination therapy at 1 mg/kg caspofungin for the renal biopsies of C. glabrata, liver biopsies of fluconazole-resistant C. albicans, C. krusei and C. guilliermondii and spleen biopsies of C. guilliermondii, and at 4 mg/kg for the renal biopsies of C. tropicalis, the liver biopsies of C. parapsilosis and the spleen biopsies of C. guilliermondii and C. glabrata. Electron microscopy confirmed extracellular hsp90 up-regulated by growth in caspofungin. CONCLUSIONS: Efungumab increased the susceptibility of Candida to caspofungin.

Cohort differences in disease and disability in the young-old: findings from the MRC Cognitive Function and Ageing Study (MRC-CFAS).

BACKGROUND: Projections of health and social care need are highly sensitive to assumptions about cohort trends in health and disability. We use a repeated population-based cross-sectional study from the Cambridgeshire centre of the UK Medical Research Council Cognitive Function and Ageing Study to investigate trends in the health of the young-old UK population METHODS: Non-overlapping cohorts of men and women aged 65-69 years in 1991/2 (n = 689) and 1996/7 (n = 687) were compared on: self-reported diseases and conditions; self-rated health; mobility limitation; disability by logistic regression and four-year survival by Cox Proportional Hazards Regression models, with adjustments for differences in socio-economic and lifestyle factors. RESULTS: Survival was similar between cohorts (HR: 0.91, 95% CI: 0.62 to 1.32). There was a significant increase in the number of conditions reported between cohorts, with more participants reporting 3 or more conditions in the new cohort (14.2% vs. 10.1%). When individual conditions were considered, there was a 10% increase in the reporting of arthritis and a significant increase in the reporting of chronic airways obstruction (OR: 1.36, 95% CI: 1.04 to 1.78). CONCLUSION: This study provides evidence of rising levels of ill-health, as measured by the prevalence of self-reported chronic conditions, in the newer cohorts of the young-old. Though changes in diagnosis or reporting of disease cannot, as yet, be excluded, to better understand whether our findings reflect real increases in ill-health, investment should be made into improved population-based databases, linking self-report and objective measures of health and function, and including those in long-term care.

The burden of diseases on disability-free life expectancy in later life.

BACKGROUND: The consequences of diseases in later life have been judged predominantly through mortality, resulting in an emphasis on the fatal rather than the nonfatal disabling conditions. We use a longitudinal study with follow-up at 2, 6, and 10 years to assess the impact of different diseases on both total life expectancy (TLE) and disability-free life expectancy (DFLE). METHODS: The Medical Research Council Cognitive Function and Ageing Study investigators interviewed 13,004 people aged 65 years and older from five U.K. centers starting in 1991. Persons aged 75 years and older were oversampled. Disability (mild, moderate, and severe) was assessed through basic Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales at baseline and at follow-ups at 2, 6, and 10 years. TLE and DFLE were compared for persons with and without each of nine conditions. RESULTS: At age 65, men had a TLE of 15.3 years of which 12.1 (79%) were free of any disability, whereas women of the same age had an average TLE of 19.4 years, 11.0 years (57%) disability-free. Men (women) aged 65 years without stroke had 4.8 (4.6) more years of TLE and 6.5 (5.8) more years DFLE. Without diabetes, men (women) lived 4.4 (5.6) years longer and had 4.1 (5.1) years disability-free. CONCLUSIONS: More disability-free years were gained than total life years in persons free of stroke, cognitive impairment, arthritis, and/or visual impairment at baseline. This finding suggests that elimination of these conditions would result in a compression of disability.

Educational differences in the dynamics of disability incidence, recovery and mortality: Findings from the MRC Cognitive Function and Ageing Study (MRC CFAS).

BACKGROUND: This study aims to establish the extent of educational differences in the disability transitions of incidence, recovery and mortality in people aged 65 years and over, whether these can be explained by differentials in disease burden and their relative contribution to educational differences in prevalence and disability-free life expectancy (DFLE). METHODS: A stratified random sample of 13 004 participants in five areas in England and Wales were interviewed in 1991-94 and followed up at 2, 6 (one centre only) and 10 years. Two levels of disability were analysed: mobility difficulty and activities of daily living (ADL) disability. We fitted logistic regression models to model educational differences in disability prevalence, incidence, recovery and mortality transitions. DFLE was calculated to assess the combined effect of the dynamic transitions. RESULTS: Those with < or =9 years education had higher ADL and mobility disability prevalence and higher incidence and lower recovery of mobility disability. Differences in disability incidence remained after adjustment for comorbidity. Women with the lowest education had shorter life expectancies (1.7 years less at the age of 65 years) than the most educated and had even shorter DFLE (1.9 years free of ADL disability and 2.8 years free of mobility difficulty at the age of 65 years). CONCLUSIONS: Differentials in education continue to contribute to prevalence of disability at ages beyond 65 years in both men and women and independently of diseases. These appear to be driven predominantly by differentials in disability incidence that also compound to produce greater differentials in DFLE between education groups than in total years lived.

A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis.

BACKGROUND: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.