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Background Numerous inclusion and exclusion criteria are involved in phase III moderate to severe psoriasis trials investigating the safety and efficacy of biologics. This questions the generalization of results. Methods In this cohort study, we applied inclusion/exclusion criteria for phase III trials from original protocols (adalimumab - REVEAL, ustekinumab - PHOENIX, brodalumab - AMAGINE, secukinumab FIXTURE) to all patients enrolled in the PsoBioTeq prospective registry who received a biological agent for the first time between July 2012 and November 2017. We then compared the efficacy, drug survival and occurrence of adverse events between patients who satisfied/did not satisfy the eligibility criteria for these phase III trials. Results A total of 1267 patients were enrolled, of whom 993 (78.4%) were not eligible for at least one RCT (randomized controlled trial) and 251 (19.1%) did not meet the PASI/PGA severity requirements. Apart from disease severity, the most frequent criteria resulting in exclusion were as follows: non-plaque psoriasis (12.6%), significant cardiac disease (8.4%), significant liver disease (7.3%), elevated liver enzymes (4.9-9.6%) and personal history of diabetes (9.2%). There was no difference in drug survival between the two groups. The incidence ratio of adverse events was significantly lower in eligible versus non-eligible patients [0.78 (95% CI 0.62-0.97) (P = 0.03)]. Conclusion The majority of patients treated with biologics in the PsoBioTeq real-life registry would not have been eligible for phase III moderate to severe psoriasis trials. Patients not eligible for psoriasis phase III clinical trials have a higher incidence of adverse events.

International audience; Since the coronavirus disease 2019 (COVID 19) outbreak was first reported in the Chinese city of Wuhan on December 31, 2019, it has stricken more than 1,000,000 persons worldwide, of whom over 50,000 have died (1). Having been infected by severe acute respiratory syndrome coronavirus 2 (SARS‐COV‐2), patients with COVID‐19 mainly present with fever and respiratory symptoms (2). Isolated sudden onset anosmia has also frequently been reported (3). Less frequently, rhinorrhea, diarrhoea and dysgeusia may be associated. While only a few reports have evoked cutaneous manifestations (4), we read with interest an initial study on the topic entitled “Cutaneous manifestations in COVID‐19: a first perspective ” by Recalcati S. (5).

Background Biological agents targeting IL-17 are very effective for clearing moderate to severe psoriasis. There is limited information regarding the frequency and pattern of psoriasis relapse upon treatment cessation. Objective To investigate the pattern of psoriasis recurrence in patients who were treated with brodalumab following Amgen's decision to stop the clinical program in June 2015. Materials and Methods Between June 2015 and March 2016, we constructed a retrospective multicenter cohort study including patients who were treated with brodalumab in Amgen's protocols after the abrupt interruption of the drug development program. The relapse was defined as the request of patient to initiate a new treatment after brodalumab withdrawal. Results Seventy seven patients were followed up. At the time brodalumab treatment was stopped, 67 (87%) patients had reached PASI 90. After brodalumab discontinuation, all 77 patients relapsed after a follow up of 9 months. The median time to relapse was 46 days (range 7 to 224 days). Concerning the type of relapse, 73 patients presented with plaque psoriasis, one patient presented with erythrodermic psoriasis and 3 patients experienced pustular psoriasis. In 7 patients who had no previous history of psoriatic arthritis (PsA), the relapse of psoriasis was associated with inflammatory joint pain suggestive of PsA. At week 36, eight patients who had a limited relapse were controlled with topical treatment, 43 patients received a biological agent, two patients were included in a clinical trial with an investigational drug and 15 patients were treated with conventional systemic agents. Conclusion Abrupt cessation of brodalumab is associated with a rapid relapse of psoriasis with some patients experiencing a rebound. It seems not advisable to stop treatment with IL-17 receptor antagonists abruptly even in patients who experience complete clearance of psoriasis. This article is protected by copyright. All rights reserved.

Legal action to separate newborn babies from their parents is regarded as ‘draconian’ by the courts and subject to intense scrutiny. This paper outlines current legal and social work issues relating to such intervention and discusses the potential benefits of the ‘pre-proceedings process’ to address them. This process enables parents to have legal representation in a discussion with children’s services when care proceedings are contemplated. The paper reports the findings of recent socio-legal research by the authors into the use of the process in England and Wales. In six local authorities, 30 per cent of 120 cases where the pre-proceedings process was used related to unborn babies; a pre-proceedings letter was sent in 75 per cent of unborn baby cases where care proceedings were considered, compared with 57 per cent of cases overall. The process could help to secure parental cooperation for pre-birth assessments and short-term protective arrangements at birth, thus avoiding emergency intervention. Families were diverted from care proceedings in 30 per cent of the cases where this was a possibility. Furthermore, the process was valued by social workers and lawyers as being fairer to parents.

This paper assesses the nature of parental participation and legal representation in pre-proceedings meetings in England and Wales. These are called when a local authority is considering care proceedings on a child. The parent(s) are invited to a meeting to discuss the concerns, and are entitled to attend with a lawyer. The paper draws on findings from a study of the process which included a file survey of over 200 cases, observations of 36 meetings and interviews with more than 90 key informants, including parents. The aim of the process is (usually) to reach an agreement to prevent the case going to court, but the families are usually well known to children's services, and have been through many meetings and agreements before. What then are the possibilities for parental participation and legal representation in the meetings? The study shows that they may help bring a greater degree of clarity to the local authority's proposals, but are not expected to challenge them. Paradoxically, they serve to reinforce the authority's position. The meetings can help divert cases, but it is important to be realistic about the chances of change in these often long-standing ‘edge of care’ cases.

This paper examines the issue of parental engagement where children's services have brought court proceedings to protect children, from the perspective of specialist lawyers who represent parents. It draws on an in-depth, qualitative study of parents' representation conducted between 2008 and 2010. Parental non-co-operation with children's services is a common feature in these cases. Lawyers are partisans with duties to follow clients' instructions. They seek to build a trusting relationship and keep clients engaged in the process by giving advice, taking instructions and providing emotional support. Lawyers accept that parents have an absolute right to contest but use their power and authority to encourage their most vulnerable clients to concede. They are largely successful in keeping clients engaged in proceedings but parents rarely make the necessary changes in parenting.

A new approach to care proceedings, introduced in April 2008 with revised Children Act 1989 Guidance Volume 1 and the Public Law Outline (PLO), a procedural guide for the courts, adds a semi-formal pre-proceedings stage. This paper critiques the aims and objectives of the pre-proceedings process in the light of what is known about the families who become subject to care proceedings. Drawing on the Care Profiling Study, the analysis of a random sample of 386 court files for care proceedings brought in 2004 and the Ministry of Justice's preliminary study of the operation of care proceedings under the PLO, it questions whether formalizing communication between the local authority and the parents immediately before proceedings can produce the intended benefits of diverting cases from the courts and improving the preparation of court applications. It considers how the new processes fit with existing safeguarding and planning procedures, the impact on workers and families, and whether the procedures will help produce good, long-term arrangements for children at risk of significant harm more quickly.

The need for Quality standards in non-regulated research is a matter of considerable current debate. Whilst a number of such guidelines have been developed over recent years, their successful implementation remains a challenge to all. In order to assess whether research standards are indeed improving on the bench following the instigation of such a quality system, a question posed by both senior management and scientists alike, an independent compliance programme is required. However, given the lack of predicate rules, naivety to audit process and general sensitivity to external scrutiny within the scientific ranks, then work in this ‘Grey Area’ generates high exposure for the conventional GLP, GCP or GMP auditor. We have developed, tried, and tested a highly effective, novel audit model for assessing the quality of non-regulated research. This simple system can be applied successfully irrespective of scientific discipline or field. Whilst common principles will always apply during any quality system audit, the refinements and idiosyncrasies we describe here will, as we have found, help underpin success. Our intentional assumption is that this is a first time endeavour for the quality professional. Copyright © 2009 John Wiley & Sons, Ltd.

summary Blood was collected from 53 normal women in the 38th week of pregnancy. The plasma concentration of unconjugated oestriol, total oestriol and oestriol sulphate was measured and also human placental lactogen and pregnancy specific β1 glycoprotein. The normal spread of the two proteins was found to be slightly smaller than that of the oestrogens. The concentrations of unconjugated and of total oestriol were related; otherwise these substances varied independently of one another. The concentration of these substances was not related to other obstetric parameters.

This paper will explore the idea of the local authority as a reluctant parent. It will consider the extent to which this reluctance is produced by the care proceedings system and its consequences for children. Local authorities are both expected to refrain from intervening (care proceedings are a measure of last resort) and to be fully prepared for intervention (whilst leaving children with their parents). Amongst the themes which will be developed here are the impact of the juridification of social work and the emphasis on the courts for holding local authorities to account; the balance between voluntary accommodation and compulsory care; and the problems of resourcing care services. Its main focus will be on children who enter care because of abuse or neglect. Its thesis is that the conflicting expectations on local authorities, resource constraints, and considerations of legal process make them reluctant parents.

The inquiry into the death of Victoria Climbie was portrayed as the most wide-ranging inquiry into failure to protect a child. It was instrumental in the development of the new safeguarding agenda and joined-up children's services in the Children Act 2004. Both its process and outcome appear to fit with New Labour's agenda for joined-up government. A social constructionist analysis reveals it as a narrower project which ignored key issues and failed to make links between government policy, the law, and local authority action. Three issues -i) parental responsibility, ii) treating intra-family child abuse as a crime, and Hi) local authorities' responsibilities for family support -exemplify the inquiry's restrictive approach and the impossibility of joined-up services if central government seeks to retain authority without taking responsibility. Despite its success in changing policy, the Climbie Report shows again the inadequacy of such inquiries as a basis for reform. Language: en

Summary OBJECTIVE This study assessed whether functional ovarian cysts may prevent suppression of serum oestradiol levels even after pituitary desensitization had been achieved with buserelin. PATIENTS OI 288 in-vitro fertilization (IVF) cycles studied 10 patients were found to have cysts with serum oestradiol levels > 200 pmol/l despite 3 weeks of buserelin. DESIGN AND MEASUREMENTS The 10 patients with cysts were given 01 mg GnRH and serum gonadotrophins were measured at time 0, 30 and 60 minutes subsequently. Immediately following the GnRH stimulation test the cysts were aspirated transvaginally under ultrasound guidance. Serum oestradiol levels were again measured 3 days after cyst aspiration. RESULTS Basal LH and FSH levels were < 3 U/I and there was no significant rise in response to GnRH. On the day of cyst aspiration serum oestradiol levels varied between 244 and 1127 pmol/l, and in all cases serum oestradiol levels fell to < 200 pmol/l within 3 days of cyst aspiration. CONCLUSION In the presence of a functional ovarian cyst, failure to suppress the serum oestradiol level does not necessarily imply a failure of pituitary desensitization with a GnRH agonist.

High-affinity melatonin receptors are present in rat suprachiasmatic nuclei (SCN), and their density exhibits a daily rhythm regulated by the light/dark cycle. In this study we demonstrate that the light regulation of these receptors depends on a circadian mechanism. Pinealectomized rats kept in constant darkness were subjected to 1-hr light pulses delivered across the circadian cycle. The density of melatonin receptors was significantly increased when photic exposure was performed during subjective night, and not different from control animals kept in darkness when the light pulse was applied during subjective day. The protein product (Fos) of the immediate early gene c-fos studied in the same paradigm showed globally the same circadian sensitivity phase. These results clearly show that, although the rhythmic appearance of melatonin receptor density in SCN follows and is directly regulated by the standard light/dark cycle, this light regulation is not passive. As is the case with Fos-like protein, it is only during a precise phase of the circadian cycle that light is able to regulate the density of melatonin receptors in SCN.

The results of weekly colposcopy review meetings have been audited for 1 year and cases where there was a discrepancy between the referral cervical smear and the initial colposcopy biopsy have been analysed. New referrals (n = 476) for colposcopy were studied. In the final outcome 80% of 326 women referred for moderate or severe dyskaryosis were found to have cervical intraepithelial neoplasia (CIN) grade II or III or invasive carcinoma. Three women found to have invasive carcinoma had been referred for severely dyskaryotic smears. Twenty women were referred for smears with cell changes suggesting glandular neoplasia: five were found to have adenocarcinoma in situ, whereas eight had CIN and seven had negative biopsies. The results justify the referral policy and demonstrate the need for further investigation when initial colposcopic biopsies are negative.

Summary Aims Atypical anti-psychotic drugs (APDs) are widely used in psychotic disorders refractory to conventional neuroleptic agents. Results Three cases of new-onset diabetes are reported in Caucasian men who were on clozapine (one) or olanzapine (two) for 3–6 months. They had a distinct presentation: weight loss, ketosis (one ketoacidosis), severe hyperglycaemia requiring insulin therapy, and relative insulin deficiency as reflected by glucagon stimulatory tests. In all cases, insulin was stopped within 1 month after the APD was discontinued. Conclusions Novel APDs not only induce diabetes as a result of weight gain in predisposed patients, but can also lead to a reversible state of insulin deficiency, and sometimes ketoacidosis.

Background Displaced intracapsular fractures may be treated by either reduction and internal fixation, which preserves the femoral head, or by replacement of the femoral head with an arthroplasty. This is an update of a Cochrane review first published in 2003 and previously updated in 2006. Objectives To compare the relative effects (benefits and harms) of any type of internal fixation versus any type of arthroplasty for intracapsular femoral fractures in adults. Search methods We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (August 2010), The Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (1966 to August 2010), EMBASE (1988 to 2010 Week 36), and other sources. Selection criteria All randomised and quasi-randomised controlled trials comparing internal fixation with arthroplasty for intracapsular hip fractures in adults. Data collection and analysis Both authors independently assessed trial quality and extracted data. Wherever appropriate, results were pooled. Main results Nineteen trials, of which two were newly included in this update, involving 3044 participants, were included. There was considerable variation in the types of implants and techniques used for both internal fixation and arthroplasty in the included trials. The risk of selection bias was low in just three trials, unclear in 13 trials and high in the three quasi-randomised trials. Just three trials reported assessor blinding of functional outcomes. Length of surgery, operative blood loss, need for blood transfusion and risk of deep wound infection were significantly less for internal fixation compared with arthroplasty. Fixation had a significantly higher re-operation rate in comparison with arthroplasty (40% versus 11%; risk ratio 3.22, 95% CI 2.31 to 4.47, 19 trials). No definite differences for hospital stay, mortality, or regain of pre-injury residential state were found. Limited information from some studies suggested pain was less and function was better for a cemented arthroplasty in comparison with fixation. Authors' conclusions Internal fixation is associated with less initial operative trauma but has an increased risk of re-operation on the hip. Definite conclusions cannot be made for differences in pain and residual disability between the two groups. Future studies should concentrate on better reporting of final outcome measures and function. There is still a need for studies to define which patient groups are better served by the different treatment methods.

Summary. The incidence of early conceptual loss was studied in 27 subfertile women by measuring their serum and urine hCG levels in the luteal phase. Eleven patients eventually had clinically confirmed pregnancies, nine of whom had had significant hCG elevations in previous menstrual cycles. In the remaining 16 patients, who have so far failed to achieve a clinical pregnancy, only three had had elevated hCG results. Thus ‘apparent’ early conceptual loss in non-pregnancy cycles was found to be more often associated with the fertile group of patients.

Summary. Serum concentrations of human chorioni gonadotrophin (hCG). schwangerschaftsprotein l(SPl), progesterone and oestradiol were measured in 116 pregnant women experiencing varying degrees of nausea and vomiting or no nausea at all at between 9 and 16 weeks gestation. The patients were categorized into four groups, namely asymptomatic, nausea alone, nausea and vomiting and hyperemesis gravidarum. The distribution of levels for each group were examined in relation to the calculated normal ranges. Statistically higher hCG levels were found in out-patients with nausea alone or nausea and vomiting than in the asymptomatic women. No significant differences were found between the groups for any of the other measured variables, including the progesterone/oestradiol concentration ratio.

Summary The renal clearance of unconjugated oestriol, oestriol glucosiduronate and oestriol sulphate by the kidney in late human pregnancy has been compared with simultaneous measurements of inulin clearance. The results for the fractions not bound to protein indicate that after glomerular filtration, unconjugated oestriol is completely reabsorbed, oestriol glucosiduronate is both filtered and excreted actively by the tubules, and that oestriol sulphate is filtered but not excreted or absorbed by the tubules; the administration of probenecid confirms these observations on tubular handling. The possibility of using endogenous oestriol sulphate as a means of measuring the glomerular filtration rate in pregnancy is suggested.

Summary Serial measurements were made of the concentration of plasma oestriol in normal pregnancy. The mean curve and limits of normal variation have been defined. The mean curve was analyzed and the correlations between various features of the pregnancy and plasma oestriol concentrations at particular stages of gestation were examined. Serial plasma oestriol concentrations seemed to give a better indication of feto-placental function than serial urinary oestriol excretion values.

Summary Serial plasma oestriol values were measured in nine insulin-dependent diabetics during pregnancy. While the plasma oestriol values wete lower than those in uncomplicated non-diabetic pregnancy the curves were of similar shape. It is suggested that serial plasma oestriol determinations in assessing feto-placental function in diabetic pregnancy should be interpreted with caution.

To determine the relationship of plasma estriol and retarded intrauterine fetal growth, 14 primiparous and 4 multiparous pregnant women with suspected intrauterine growth retardation were studied by radioimmunoassay of weekly blood samples, and compared with 25 normal pregnant women as controls. The plasma estriol levels in all 4 hypertensive mothers who gave birth to infants of low birthweight were all much less than the normal averages. Estriol levels were also less than average, though not as significantly, in 7 of the 9 normotensive patients with low birthweight infants, and in the 5 patients with low weight gain but normal-weight infants. Thus, a dramatic reduction in estriol concentration occurs in hypertensive patients with intrauterine fetal growth retardation. No correlation was found between predelivery plasma estriol concentration and infant birthweight or incidence of fetal distress. Though both have growth retardation, hypertensive patients have a much higher incidence of fetal distress (75%) than normotensive patients (29%). Further research is being conducted on the relationship of plasma estriol and blood pressure in this regard.

Summary The concentration of unconjugated oestriol, of oestriol glucosiduronate and of oestriol sulphate was measured by a radioimmunoassay technique in the plasma of five normal primigravidae before and during labour. The only consistent changes in the concentration of any of oestriol fractions was a tendency for the concentration of unconjugated oestriol to rise to a peak immediately before the onset of labour.

This paper develops multi-stage connection networks in which each input terminal can be connected to any number of output terminals. Conditions are given such that these networks are strictly nonblocking or are rearrangeable. Rearrangement algorithms and upper bounds on the required number of moves are developed and it is shown that such networks have fewer cross-points than the product of input and output terminals for a sufficiently large number of input and output terminals.