Association of Multi-Domain Factors with Cognition in the UK Biobank Study.

BACKGROUND: Dementia is a multifactorial syndrome attributable to a combination of vascular risk factors, lifestyle factors and neurodegeneration. However, little is known about the relative contribution of all these factors and their combined effects on cognition among the older population. OBJECTIVE: To examine the association of four domains of risk factors (sociodemographic, vascular risk factors, neuroimaging markers, lifestyle and psychosocial factors) with cognition in older adults. DESIGN: A cross-sectional study. SETTING: Data was obtained from a large-scale population-based study, UK Biobank study, at the first imaging visit assessment. PARTICIPANTS: Participants are citizen or permanent residents of UK, aged 60 years old and above. MEASURES: Cognitive function was assessed using the general cognitive ability score (g-factor score) derived from principal components analysis estimates of six cognitive tests. Associations with cognition were examined using multivariable linear regression for each domain and in combination. RESULTS: The study included 19,773 participants (mean age 68.5 ± 5.3 years SD, 9,726 (49%) male). Participants with lower cognitive scores (poorer cognition) were older, female, non-whites individuals, less educated and more socially deprived than participants with better cognitive scores. Participants with lower cognitive scores also tended to have higher vascular risk factors, lower brain volumes and more adverse lifestyle behaviours. The multivariable analysis found associations between adverse lifestyle and psychosocial factors with poorer cognition, i.e., being obese by measure of body fat percentage, having diabetes, higher white matter hyperintensity volume, increased sedentary screen time watching TV, being socially isolated and having depression were independently associated with poorer cognition. While larger hippocampal volume, having optimal sleep duration, adherence to a heathy diet, current and former alcohol drinking, increased wine consumption and sedentary screen time using a computer were associated with better cognition. CONCLUSION: A combination of adverse lifestyle and psychosocial factors were independently associated with poorer cognition in older adults. Findings in this study can potentially support public health communications to promote cognitive function and independence among older adults. This research has been conducted using the UK Biobank Resource under Application Number 71022.

The role of genomics in common variable immunodeficiency disorders.

The advent of next-generation sequencing (NGS) and 'omic' technologies has revolutionized the field of genetics, and its implementation in health care has the potential to realize precision medicine. Primary immunodeficiencies (PID) are a group of rare diseases which have benefited from NGS, with a massive increase in causative genes identified in the past few years. Common variable immunodeficiency disorders (CVID) are a heterogeneous form of PID and the most common form of antibody failure in children and adults. While a monogenic cause of disease has been identified in a small subset of CVID patients, a genomewide association study and whole genome sequencing have found that, in the majority, a polygenic cause is likely. Other NGS technologies such as RNA sequencing and epigenetic studies have contributed further to our understanding of the contribution of altered gene expression in CVID pathogenesis. We believe that to unravel further the complexities of CVID, a multi-omic approach, combining DNA sequencing with gene expression, methylation, proteomic and metabolomics data, will be essential to identify novel disease-associated pathways and therapeutic targets.

Fatal neuroglycopaenia after accidental use of a glucose 5% solution in a peripheral arterial cannula flush system.

A patient on an Intensive Care Unit who was recovering from multiple organ failure was being given an intravenous infusion of insulin to maintain normoglycaemia. On her 20th day in the unit, she suddenly became unresponsive. A cerebrovascular accident was suspected as other clinical and laboratory parameters remained normal apart from a blood glucose value of 20.6 mmol.l(-1). The insulin infusion rate had been increased to treat hyperglycaemia. Subsequent bedside finger prick blood testing suggested that the blood sugar was low but no numerical reading was provided. Repeat blood glucose analysis using a further sample drawn from the arterial line and measured in the blood gas analyser gave a value of 10.1 mmol.l(-1). Confirmatory laboratory blood tests revealed severe hypoglycaemia (0.1 mmol.l(-1)) and intravenous glucose 50% was given immediately. Examination showed that a glucose 5% solution had been inadvertently used in the arterial cannula flush system rather than saline, contaminating earlier samples drawn from the arterial line and giving falsely high blood glucose values. The prolonged period of severe hypoglycaemia led to neuroglycopaenia and irreversible brain injury. The patient died 9 days later without regaining consciousness. Such a complication has not previously been reported in this context and has particular significance given the increasing use of insulin therapy to maintain normoglycaemia in critically ill patients.

Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide.

Octreotide may extend survival in hepatocellular carcinoma (HCC). Forty-one per cent of HCCs have high-affinity somatostatin receptors. We aimed to determine the feasibility, safety, and activity of long-acting octreotide in advanced HCC; to identify the best method for assessing somatostatin receptor expression; to relate receptor expression to clinical outcomes; and to evaluate toxicity. Sixty-three patients with advanced HCC received intramuscular long-acting octreotide 20 mg monthly until progression or toxicity. Median age was 67 years (range 28-81 years), male 81%, Child-Pugh A 83%, and B 17%. The aetiologies of chronic liver disease were alcohol (22%), viral hepatitis (44%), and haemochromatosis (6%). Prior treatments for HCC included surgery (8%), chemotherapy (2%), local ablation (11%), and chemoembolisation (6%). One patient had an objective partial tumour response (2%, 95% CI 0-9%). Serum alpha-fetoprotein levels decreased more than 50% in four (6%). Median survival was 8 months. Thirty four of 61 patients (56%) had receptor expression detected by scintigraphy; no clear relationship with clinical outcomes was identified. There were few grade 3 or 4 toxicities: hyperglycaemia (8%), hypoglycaemia (2%), diarrhoea (5%), and anorexia (2%). Patients reported improvements in some symptoms, but no major changes in quality of life were detected. Long-acting octreotide is safe in advanced HCC. We found little evidence of anticancer activity. A definitive randomised trial would identify whether patients benefit from this treatment in other ways.

Cognitive-behavioural rehabilitation programme for patients with an implanted cardioverter defibrillator: a pilot study.

OBJECTIVES: The effectiveness of a comprehensive 12-week CR programme for ICD patients was evaluated. DESIGN: All surviving and suitable ICD patients being cared for by a regional implantation centre were invited to attend a 12-week cognitive-behavioural cardiac rehabilitation programme that had been modified to meet the needs of this group. Patients assenting were randomized to either an immediate treatment or a waiting treatment group. Measures were taken prior to randomization, at the end of the treatment or waiting period, at the end of the second treatment group for that group only and at three months post-treatment for both groups. OUTCOME MEASURES: The Hospital Anxiety and Depression Scale, the Total Concerns Questionnaire, the Quality of Life after Myocardial Infarction Questionnaire, the EuroQual (subjective health rating scale), the Shuttle Test and a number of ICD shocks and ATP episodes were used in this study. RESULTS: For those patients willing and able to attend, the cognitive-behavioural CR programme produced significant benefits in terms of psychological and functional adaptation to living with the device. CONCLUSIONS: A comprehensive 12-week CR programme that incorporated both psychological and exercise-based components significantly reduced anxiety and depression and improved quality of life of ICD patients. It is not clear if these benefits are sustained.

Comparison of transvaginal digital examination with intrapartum sonography to determine fetal head position before instrumental delivery.

OBJECTIVE: To investigate the accuracy of intrapartum transvaginal digital examination in defining the position of the fetal head before instrumental delivery. PATIENTS AND METHODS: In 64 singleton pregnancies undergoing instrumental delivery the fetal head position was determined by transvaginal digital examination by the attending obstetrician. Immediately after or before the clinical examination, the fetal head position was determined by transabdominal ultrasound by a trained sonographer who was not aware of the clinical findings. The digital examination was considered to be correct if the fetal head position was within +/- 45 degrees of the ultrasound finding. The accuracy of the digital examination was examined in relation to maternal and fetal characteristics. RESULTS: Digital examination failed to define the correct fetal head position in 17 (26.6%) cases. In 12 of 17 (70.6%) errors the difference was >/= 90 degrees and in five (29.4%) the difference was between 45 degrees and 90 degrees. The accuracy of vaginal digital examination was 83% for occiput-anterior and 54% for occiput-lateral + occiput-posterior positions. Logistic regression analysis demonstrated significant independent contributions in explaining the variance in the accuracy of vaginal examination for the station of the fetal head, the position of the fetal head and the experience of the examining obstetrician. CONCLUSIONS: Digital examination during instrumental delivery fails to identify the correct fetal head position in about one quarter of cases.

Using a revised asthma morbidity index to identify varying patterns of morbidity in U.K. general practices.

Both in terms of morbidity and mortality, the therapeutic and organizational management of asthma pose a considerable and continuing challenge to healthcare delivery. One element in attempts to meet this challenge is the recognition of appropriate outcome measures to assess progress in tackling the burden of this disease. This study therefore aimed to assess pragmatically the effectiveness of a revised asthma morbidity index in identifying varying patterns of morbidity in U.K. general practices. A postal survey was conducted of 2,762 patients believed to have or have had asthma from the lists of 12 general practices within the Eden Valley in Cumbria, using a questionnaire which combined the revised Jones morbidity index with questions on age, medication and perception of current asthma. Prescribing data were also recovered for 11 of the practices for the quarter within which the postal survey was conducted. Responses were obtained from 2,123 subjects (77%), of whom 1,474 (70%) believed themselves to be currently asthmatic. In this group, 18% reported low morbidity 34% medium morbidity and 48% high morbidity Age and inhaled steroid use were both positively and significantly associated with high morbidity. Those taking inhaled steroids were 1.4 times more likely to report high morbidity than those nottaking steroids. The prescribed corticosteroid/bronchodilator ratio for cost was both negatively and significantly associated with high morbidity. The revised morbidity index is a simple tool of use in the surveillance of asthma in primary care. It identifies spectra of morbidity which vary between practices, which may be of use in assessing the quality of asthma care provided in the community.

Healthy workplace indicators: costing reasons for sickness absence within the UK National Health Service.

Sandwell Healthcare NHS Trust has been developing a tool for monitoring the reasons and costs of long-term sick leave (> 7 days). The data obtained from this process has been used to modify the type of occupational health and safety services provided for the Trust. Adoption of more standardized tools of this nature throughout the National Health Service (NHS) would help trusts to compare, and where appropriate enhance, the services provided by occupational health. Musculo-skeletal and mental health problems, account for the greatest costs arising from long-term sickness absence. It may therefore be prudent for NHS employers and their occupational health services to target their efforts on these particular problems.

Delayed luteo-placental shift of progesterone production in IVF pregnancy.

OBJECTIVE: To observe absolute and relative levels of progesterone, 17 alpha-hydroxyprogesterone (17-OHP) and human chorionic gonadotrophin (hCG) in in vitro fertilization (IVF) pregnancies after withdrawal of luteal support. METHOD: Single blood samples were obtained from 41 pregnant women following IVF treatment and 43 normal pregnant women at various weeks gestation within the first trimester. Progesterone, 17-OHP and hCG were measured by immunoassay. RESULTS: Serum levels of progesterone, but not of hCG, in IVF pregnancies were significantly greater than in normal pregnancies up to 8 weeks post-conception, despite discontinuing luteal support 2 weeks after conception. The ratio of progesterone to 17-OHP, a predominantly ovarian product, in normal pregnancies rose between 4 and 9 weeks but did not change over the same period in IVF pregnancies. CONCLUSION: The luteal contribution to maternal serum levels of progesterone is much higher in IVF pregnancies compared with normal pregnancies. This is sustained throughout the first trimester without the need for luteal support and obscures the placental contribution of progesterone for much longer than in normal pregnancies. Progesterone or hCG supplements may therefore be unnecessary in IVF pregnancy.

Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects.

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of sildenafil in men with broad-spectrum erectile dysfunction (ED), with reference to age-matched healthy control subjects. METHODS: One hundred eleven patients were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, 12-week, flexible-dose study. Efficacy assessments included the International Index of Erectile Function (IIEF), a global assessment question, and patient event log data. In a separate, nontreatment study, 109 control subjects also completed the IIEF. RESULTS: Mean IIEF scores at baseline were significantly lower for patients with ED than for control subjects without a history of ED. After treatment, mean IIEF scores for patients receiving sildenafil approached values observed in control subjects and were significantly higher than mean scores for patients receiving placebo (P<0.01). Responses to the global assessment question and patient log data corroborated the IIEF results. Sildenafil was well tolerated, with no discontinuations because of adverse events. CONCLUSIONS: The results indicate that sildenafil, an effective oral therapy for the treatment of broad-spectrum ED, is associated with a near normalization of patient erectile function.

Effects of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine on sperm function in vitro.

This in-vitro study was designed to investigate the effects of commonly prescribed antibiotics on sperm movement characteristics, viability and the ability of spermatozoa to undergo the acrosome reaction. Spermatozoa were obtained by swim-up from normozoospermic semen and cultured for 24 h with increasing concentrations of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine. Tetracycline at concentrations as low as 2.5 microg/ml led to a significant dose-dependent inhibition in percent rapid-moving spermatozoa, mean path velocity (VAP), straight-line velocity (VSL) and curvilinear velocity (VCL), but at 50 microg/ml tetracycline all spermatozoa were static. Erythromycin had significant effects on rapid movement, VAP, VSL and VCL only at concentrations >100 microg/ml. In contrast, percent rapid-moving spermatozoa was significantly enhanced at low concentrations of chloroquine (5 microg/ml), but significantly inhibited by higher concentrations. Co-trimoxazole did not adversely affect percent rapid-moving spermatozoa below 500 microg/ml, at which concentration movement was decreased by 34%. The mean lateral head displacement (ALH) was significantly enhanced by 5 microg/ml co-trimoxazole and reduced at 1 mg/ml erythromycin. The effects of these drugs were mostly irreversible. Amoxycillin had no effect on sperm movement characteristics over the dose range used, though it inhibited viability at high doses. Viability was significantly reduced at concentrations of all drugs which affect rapid sperm movement; these concentrations of drugs did not appear to affect the ability of spermatozoa to undergo the acrosome reaction. The results from this study, when combined with known effects on spermatogenesis, should facilitate the choice of drugs for the treatment of both genitourinary and unrelated infections in men who are attempting to conceive.

A bridge to intracytoplasmic sperm injection--high insemination concentrations benefit patients who have a reduced chance of fertilization with standard in-vitro fertilization.

This study was carried out to determine whether high insemination concentrations (HIC) could improve fertilization and pregnancy rates in patients who had either previously demonstrated poor fertilization rates in vitro using standard protocols (Group 1) or in whom a reduced chance of fertilization was indicated at semen assessment prior to in-vitro fertilization (IVF) (Groups 2 and 3). Forty nine patients were recruited for the study. Standard IVF was carried out in 1 ml volumes using 10(5) spermatozoa/ml. HIC treatment involved co-culture of spermatozoa and oocytes in microdroplets with insemination concentrations increased 10-50 fold higher than standard IVF. Fertilization and pregnancy rates were compared between standard IVF and HIC in individual patients either in consecutive cycles (Group 1) or using sibling oocytes in the same cycle (Group 2). Group 3 patients were treated with HIC for their first treatment cycle. HIC significantly improved the fertilization rate compared with standard IVF for Groups 1 (59.7 +/- 10.7 versus 19.6 +/- 5.4% respectively) and 2 (54.9 +/- 8.5 versus 34.0 +/- 8.5% respectively). HIC increased the pregnancy rate from 0% with standard IVF to 20% per embryo transfer in Group 1 patients. A single pregnancy derived from the transfer of HIC and IVF embryos occurred in Group 2. The fertilization rate (47.2 +/- 7.6%) and pregnancy rate (31.3% per embryo transfer) for Group 3 patients was higher than predicted. There was no increase in the rate of polyploidy with HIC. Provided there are sufficient numbers of motile spermatozoa, HIC may be offered as an initial form of treatment, thus permitting referral of only the poorest responders for intracytoplasmic sperm injection (ICSI).

Serum is more effective than albumin in promoting human embryo development and implantation.

OBJECTIVE: To compare the effects of serum with those of Albuminar-5 (Armour Pharmaceutical Co., Eastbourne, Sussex, United Kingdom) as medium supplements to Earl's balanced salt solution (EBSS) for IVF and subsequent embryo development. DESIGN: A retrospective study. Gametes and embryos from 318 patients were cultured in the presence of serum (group 1). Gametes and embryos from 130 patients were cultured in the presence of Albuminar-5 (group 2). Embryos obtained from IVF were replaced into the uterus within 48 hours after insemination. Surplus bipronucleate embryos were cultured up to 14 days with either serum or Albuminar-5. SETTING: Two tertiary referral fertility clinics; university teaching hospital. PATIENTS: Four hundred forty-eight patients with a wide spectrum of causes of subfertility, ranging in age from 24 to 43 years. MAIN OUTCOME MEASURES: Fertilization rate, pregnancy rate (PR), implantation rate, and surplus embryo development in vitro. RESULTS: The PR for group 1 patients was higher than that of group 2 (27.0% versus 15.4%, respectively). Although fertilization rates were identical in the two groups, cumulative embryo scores and implantation rates were significantly higher in group 1. There was no difference between the groups in age distribution, types of ovarian stimulation, numbers of patients with day 1 or day 2 transfers, or luteal phase support. Of 31 embryos cultured with serum, 54.8% reached the fully expanded blastocyst stage and 25.8% hatched. Of 19 embryos cultured with Albuminar-5, only 5.3% reached the fully expanded blastocyst stage and none hatched. CONCLUSIONS: The results suggest that, under certain conditions, serum supplementation yields better results than protein supplementation alone. The latter may be suitable only in conjunction with additional components.

Sonographic diagnosis of infantile hypertrophic pyloric stenosis.

Twenty-five consecutive sonographic examinations performed at Flinders Medical Centre for possible infantile hypertrophic pyloric stenosis (IHPS) were analyzed retrospectively. The results and a pyloric muscle index calculated by a formula using length, diameter, muscle thickness, and body weight were compared with the clinical outcome (surgery or conservative management). In the children without IHPS, the calculated pyloric muscle index was less than 0.2, whereas in infants with proven pyloric stenosis, the index was greater than 0.2 (P < 0.001). This result suggested that the published index upper limit of > 0.4 to 0.46 was not valid in our institution. Pyloric length to muscle thickness ratio was also found to predict IHPS. A simplified index, including only length and muscle thickness, is proposed, whereby length (mm) plus 3.64 times thickness (mm), when greater than 25, implies IHPS.

Morbidity after termination of pregnancy in first trimester.

The outcome of termination of pregnancy was observed in relation to the preoperative clinical and microbiological findings in 167 women attending a day care abortion unit in Liverpool. Before termination, Chlamydia trachomatis was isolated from the cervix of 19 (11%) of the patients and high counts (greater than 10(4) colour changing units (ccu) per ml of specimen) of mycoplasmas were found in 30 (18%). Coexistent infections with chlamydiae and high counts of mycoplasmas occurred in only seven (4%) women. Trichomonas vaginalis, yeasts, or pathogenic bacteria were found in vaginal swabs from 30 (18%) women. After undergoing termination, seven (4%) women developed pelvic inflammatory disease (PID), five (71%) of whom had yielded C trachomatis before undergoing termination. A further 13 (8%) patients developed minor morbidity of the upper genital tract; high count mycoplasmal infection had been found in seven (54%) and chlamydial infection in three (23%) of these women before termination. In contrast, C trachomatis had been isolated from only 11 (8%) and high counts of mycoplasmas from 23 (16%) of the 147 women who had uneventful recoveries after undergoing termination. No correlation was apparent between the presence of vaginal pathogens before termination and the development of untoward sequelae postoperatively. Neither the history nor clinical examination before termination would have indicated that chlamydial or mycoplasmal infections were present, or that postoperative complications were likely to occur. Abnormal cervical cytology, however, was found in 86 (52%) of women overall, including 15 (79%) of the 19 women with chlamydial infection.