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There is increasing recognition that a single, monoploid reference genome is a poor universal reference structure for human genetics, because it represents only a tiny fraction of human variation. Adding this missing variation results in a structure that can be described as a mathematical graph: a genome graph. We demonstrate that, in comparison to the existing reference genome (GRCh38), genome graphs can substantially improve the fractions of reads that map uniquely and perfectly. Furthermore, we show that this fundamental simplification of read mapping transforms the variant calling problem from one in which many non-reference variants must be discovered de-novo to one in which the vast majority of variants are simply re-identified within the graph. Using standard benchmarks as well as a novel reference-free evaluation, we show that a simplistic variant calling procedure on a genome graph can already call variants at least as well as, and in many cases better than, a state-of-the-art method on the linear human reference genome. We anticipate that graph-based references will supplant linear references in humans and in other applications where cohorts of sequenced individuals are available.

The government's community care proposals give importance to the role of voluntary and not-for-profit organisations in meeting the needs of elderly and disabled people, and underline the need for local authorities to foster their development. To do this, they must ensure their financial security. This paper reports the decline of the specialist clothing workshops which, because of changes in government funding, have dwindled from more than 20 in 1988 to five at present. The importance of this service to disabled people is discussed. Although many value skilled advice and sympathetic personal attention, for a few there is no other alternative than specially made or adapted clothing. It enhances self-esteem, independence and participation, as well as practical benefits. However it is an expensive service, so that subsidy is essential. Recommendations for the future of the service are outlined.

Previously published studies investigating the oral benzodiazepine ethanol interaction have utilized a single dose of ethanol, a single dose of oral benzodiazepine, and measured plasma benzodiazepine concentration over varying time periods. Most studies reported an increase or no change in benzodiazepine plasma concentrations following ethanol administration, which the investigators usually ascribed to an ethanol-induced increase in the benzodiazepine absorption rate constant. However, ethanol decreases the hepatic clearance of benzodiazepines that are biotransformed via the P450 enzyme system and this effect was not taken into account in evaluation of the results of these studies. Computer simulations have been used to investigate possible mechanisms of the oral benzodiazepine-ethanol interaction. The effects of a constant or transient decrease in clearance and an increase in absorption rate constant upon maximum concentration, time of maximum concentration, and area under the benzodiazepine plasma concentration curve (AUC) have been examined. A transient 75% decrease in benzodiazepine clearance resulted in a 13.6% increase in AUC (0-36 hr), a 3.4% increase in Cmax and a 5.7% increase in tmax. These changes are qualitatively consistent with, but quantitatively shy, of those observed in most studies. Consequently, an effect of ethanol upon benzodiazepine absorption must still be considered.

SummaryOne-hundred husbands, diagnosed as suffering from alcoholism, and their wives, were followed up twelve months after initial consultation and assessment. Follow-up information was complete in 89 cases. On the basis of both husband and wife accounts of the husband's drinking behaviour during the follow-up period, and their assessment of the drinking problem at twelve-months follow-up, 28 were classified as having a ‘good’ outcome and 29 as having a ‘bad’ outcome. In the remaining 32 cases outcome was considered ‘equivocal‘.A composite measure of marital cohesion was predictive of twelve-month outcome classification, cohesive marriages being significantly more likely to have a good outcome. The measure of marital cohesion was based upon husband and wife reports of mutual affection and of husband involvement in family tasks, favourable spouse perceptions and meta-perceptions, and optimism about the future of the marriage. Composite measures of dominance balance within the marriage were not predictive of outcome.Husband's job status, husband's self-esteem, and wife's reported hardship were not independent of marital cohesion, and were themselves predictive of twelve-months outcome. When these variables were partially controlled it was found that marital cohesion remained predictive for husbands with relatively low status jobs and husbands with relatively low levels of self-esteem. It is an over-simplification to state that either the marriage, the spouse, or the severity of the patient's condition is alone the cause of variation in outcome.It is possible to integrate these findings with those of other studies on the influence of family variables on the outcome of conditions other than alcoholism. Together these studies suggest a general hypothesis linking a breakdown in the cohesiveness, or mutual rewardingness, of family relationships and unfavourable outcomes following treatment or consultation for psychological disorder.

Thirty depressed patients were compared with 39 controls for their plasma norepinephrine (NE) levels in relation to a cold challenge (placing a hand in ice cold water for 1 minute). Depressed patients showed significantly higher plasma NE levels than controls. Unipolar, but not bipolar patients, had significantly higher plasma NE levels than age- and sex-matched controls. Unipolar melancholic patients who were nonsuppressors on the dexamethasone suppression test showed a strong trend to have higher plasma NE levels than suppressors. These results are further evidence that the NE system is dysregulated in depression.

Pharmacokinetic interactions of ethanol with other drugs, including its effects upon drug metabolite disposition, are reviewed in terms of clearance concepts. This approach is particularly useful in understanding the mechanisms of ethanol-drug interactions, i.e. in separating the effects of ethanol upon drug clearance, volume of distribution and plasma protein binding. The application of clearance concepts provides the basis for understanding the qualitative differences in ethanol interactions with low and high hepatic extraction ratio drugs. The effects of short and long term ethanol consumption upon different types of drug metabolism (oxidative, acetylation and glucuronidation) have been considered. Long term ethanol consumption may increase the clearance of a drug by induction of oxidative metabolism whereas short term consumption may decrease the clearance of such a drug. Clearance by N-acetylation appears to be increased in the presence of ethanol, and clearance by conjugation to glucuronic acid is decreased for some drugs by single-dose consumption of ethanol.

Metabolism, synthesis rates, and pharmacokinetics of major metabolites of endogenous norepinephrine were investigated in 38 drug-free depressed patients receiving a low monoamine diet on a closed ward. In a group of 21 patients, plasma and cerebrospinal fluid (CSF) concentrations of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) correlated positively, but not significantly. In two groups of eight patients each, effects of desipramine and zimelidine on the central production rate of MPHG were examined using CSF and urine data. Both desipramine and zimelidine significantly reduced the central production rate of MHPG.

The frequency of the use of coping behavior by wives of alcoholics was found to be related to their husband's drinking outcome. In general, a high frequency of coping behavior was associated with a poor outcome, but some components of coping behavior were more likely than others to be linked with a poor prognosis.

Sleeping time was measured in groups of old and young rats following the intraperitoneal injection of pentobarbital (39.5 mg.kg-1), diazepam (30 mg.kg-1) and ethanol (3 g.kg-1). Concentrations of pentobarbital, and unbound and total diazepam in serum, and ethanol in breath were quantified; as well as whole brain concentrations of diazepam and N-demethyldiazepam. Healthy old rats slept significantly longer than young rats after receiving diazepam and ethanol but not pentobarbital. There were no significant differences in serum or whole brain concentrations of diazepam or N-demethyldiazepam between healthy young and old rats. There were also no changes in the serum pentobarbital or breath ethanol concentrations between the young and old rats. Increases in pharmacologic effect that occur with aging may be caused by alterations in pharmacokinetic parameters or changes at the site of drug action. The cause of an increased pharmacodynamic effect depends upon the specific drug, possibly because these compounds affect the same receptorionophore complex at different sites.

Alcoholism is three times more prevalent in men than in women. We studied responses of thyrotropin to protirelin (thyrotropin releasing hormone) in nine sons and eight daughters of patients with familial alcoholism and in eight control boys and seven control girls. Basal and protirelin stimulated triiodothyronine, prolactin, and growth hormone concentrations were also measured. The controls were matched for age, sex, and past alcohol exposure with the index children. The sons of familial alcoholics had significantly higher basal thyrotropin levels, peak thyrotropin levels, and thyrotropin areas under the curve than did the control boys. The daughters of patients with familial alcoholism showed no differences from the control girls. Analyses of triiodothyronine, prolactin, and growth hormone concentrations revealed no differences between the index children and controls. We believe that this is the first report of a male-limited neuroendocrine difference between children of alcoholics and control children. Further studies are needed to elucidate the clinical significance of our preliminary findings.

In a study of 99 patients receiving amitriptyline or nortriptyline alone and 60 patients receiving one of these antidepressants in combination with perphenazine, the patients receiving the combination medication had up to 70% higher antidepressant plasma levels than patients receiving the antidepressant alone. The groups did not differ significantly in sex, age, smoking behavior, or antidepressant dose level. Due to the possibility of side effects from such combination medication, the authors recommend that depressed patients not responding to the tertiary amine tricyclic antidepressants receive a trial of high doses of the drugs before antidepressant-neuroleptic combinations are administered.

Two groups of alcoholics received either one counseling session or several months of in- and outpatient treatment. One year later there were no significant differences in outcome between the two groups.

In the U.K., the treatment of alcoholism has been based more on inpatient care than on outpatient clinics. Forty alcohol-dependent men who had no other severe physical or mental illness and who agreed to accept either treatment were randomised to inpatient or outpatient therapy. The average stay in hospital was 8·9 weeks for inpatients, while outpatients on average spent 7·7 weeks in " intensive treatment". A correlation analysis showed a relation between demographic and personality factors, drinking chronology, and " complications of drinking" but did not reveal any significant prognostic factors. All patients were followed up to 1 year with monthly assessment of progress made on a 2-point scale by independent raters. There was no significant difference between groups. The bearing of these results on the planning of future treatment is discussed and it is suggested that emphasis should now be on development of the comprehensive treatment service, which would integrate inpatient and outpatient services and also provide hostel care. The specialised inpatient unit is probably of value, but criteria for admission need to be much more strictly defined.

• We examined the intercorrelations among urinary outputs of norepinephrine (NE) and its three major metabolites in unipolar depressed patients (n = 28) and normal controls (n = 24). Among the depressed patients, levels of NE correlated with normetanephrine (NM), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA), and VMA correlated with NM and MHPG. In the total group of depressed and control subjects (n = 52), the sum of NE and its major metabolites correlated with urinary outputs of NE, NM, MHPG, and VMA. These highly significant correlations among urinary outputs of NE and its major metabolites replicate a previous report of strong correlations among these same four urinary substances in a smaller group of depressed patients.