Global birth prevalence of Robin sequence in live-born infants: a systematic review and meta-analysis.

Robin sequence (RS), a congenital disorder of jaw maldevelopment and glossoptosis, poses a substantial healthcare burden and has long-term health implications if airway obstruction is suboptimally treated. This study describes the global birth prevalence of RS and investigates whether prevalence estimates differ by geographical location, ethnicity or study data source (registry versus non-registry data). The protocol was prospectively registered with PROSPERO.Databases were searched using keywords and subject terms for "Robin sequence", "epidemiology", "incidence" and "birth prevalence". Meta-analysis was performed fitting random effects models with arcsine transformation.From 34 eligible studies (n=2722 RS cases), pooled birth prevalence was 9.5 per 100 000 live births (95% CI 7.1-12.1) with statistical heterogeneity. One third of studies provided a case definition for RS and numerous definitions were used. A total of 22 countries were represented, predominantly from European populations (53% of studies). There was a trend towards higher birth prevalence in European populations and lower prevalence from registry-based studies. Only two studies reported ethnicity.This study indicates that RS occurs globally. To investigate geographical differences in prevalence, additional studies from non-European populations and reporting of ethnicity are needed. Heterogeneity of estimates may be due to variable diagnostic criteria and ascertainment methods. Recently published consensus diagnostic criteria may reduce heterogeneity among future studies.

Conservative and Surgical Modalities in the Management of Pediatric Parapneumonic Effusion and Empyema: A Living Systematic Review and Network Meta-Analysis.

BACKGROUND: The optimal treatment for community-acquired childhood pneumonia complicated by empyema remains unclear. RESEARCH QUESTION: In children with parapneumonic effusion or empyema, do hospital length of stay and other key clinical outcomes differ according to the treatment modality used? STUDY DESIGN AND METHODS: A living systematic review of randomized controlled trials (RCTs) was conducted by searching the Cochrane Central Register of Controlled Trials, Embase, Latin American and Caribbean Health Sciences Literature, Ovid MEDLINE, and Web of Science Core Collection databases. Eligible RCTs included patients aged < 18 years and compared two of the following treatment modalities: antibiotics alone, chest tube insertion with or without fibrinolytics, video-assisted thoracoscopic surgery (VATS), and decortication via thoracotomy. A network meta-analysis was performed to evaluate treatment effects on hospital length of stay (LOS), the primary outcome. RESULTS: Eleven trials including a total of 590 patients were selected for the network meta-analysis. Compared with a chest tube alone, a chest tube with fibrinolytics, thoracotomy, and VATS were all associated with shorter LOS, with a mean difference of 5.05 days (95% CI, 2.46-7.64), 6.33 days (95% CI, 3.17-9.50), and 5.86 days (95% CI, 3.38-8.35), respectively. No substantial differences in LOS were observed between the latter three interventions. None of the 11 RCTs compared antibiotics alone vs other types of treatment. Most trials reported peri-procedural complications and the need for reintervention, but the descriptions differed significantly between trials, preventing meta-analysis. In trials reporting health care-associated costs, fibrinolytics had cost advantages compared with VATS. Short- and long-term morbidity and mortality were very low, regardless of the treatment modality. INTERPRETATION: The results of this network meta-analysis showed that a chest tube alone was associated with a longer LOS compared with other treatment modalities. The lower cost associated with a chest tube plus fibrinolytics warrants consideration when choosing between treatment options, given similar LOS and clinical outcomes compared with the other modalities.

Epidemiology of Robin sequence in the UK and Ireland: an active surveillance study.

BACKGROUND: Birth prevalence of Robin sequence (RS) is commonly reported as 1 case per 8000-14 000 live births. These estimates are based on single-source case ascertainment and may miss infants who did not require hospital admission or those without overt upper airway obstruction at birth. OBJECTIVES: To identify the true birth prevalence of RS with cleft palate in the UK and Ireland from a population-based birth cohort with high case ascertainment. METHODS: Active surveillance of RS with cleft palate was carried out in the UK/Ireland using dual sources of case ascertainment: British Paediatric Surveillance Unit (BPSU) reporting card and nationally commissioned cleft services. Clinical data were collected from notifying clinicians at two time points. RESULTS: 173 live-born infants met the surveillance case definition, giving a birth prevalence of 1 case per 5250 live births (19.1 per 100 000 (95% CI 16.2 to 21.9)), and 1:2690 in Scotland. 47% had non-isolated RS, with Stickler syndrome the most common genetic diagnosis (12% RS cases). Birth prevalence derived from the combined data sources was significantly higher than from BPSU surveillance alone. CONCLUSIONS: Birth prevalence of RS in the UK/Ireland derived from active surveillance is higher than reported by epidemiological studies from several other countries, and from UK-based anomaly registries, but consistent with published retrospective data from Scotland. Dual case ascertainment sources enabled identification of cases with mild or late-onset airway obstruction that were managed without hospital admission. Studies of aetiology and equivalent well-designed epidemiological studies from other populations are needed to investigate the identified geographical variability in birth prevalence.

Another Brick to Confirm the Efficacy of Rigosertib as Anticancer Agent.

Rigosertib is a small molecule in preclinical development that, due to its characteristics as a dual PLK1 and PI3K inhibitor, is particularly effective in counteracting the advance of different types of tumors. In this work, we evaluated the efficacy of Rigosertib and the expression of p53 in five different human tumor cell lines in vitro, A549 (lung adenocarcinoma), MCF-7 and MDA-MB231 (breast cancer cells), RPMI 8226 (multiple myeloma), and U87-MG (glioblastoma). We demonstrated that in all cell lines, the effect was dose- and time-dependent, but A549 cells were the most sensible to the treatment while higher concentrations were required for the most resistant cell line U87-MG. Moreover, the highest and lowest p53 levels have been observed, respectively, in A459 and U87-MG cells. The alterations in the cell cycle and in cell-cycle-related proteins were observed in A549 at lower concentrations than U87-MG. In conclusion, with this article we have demonstrated that Rigosertib has different efficacy depending on the cell line considered and that it could be a potential antineoplastic agent against lung cancer in humans.

Brown-Norway chromosome 1 mitigates the upregulation of proinflammatory pathways in mTAL cells and subsequent age-related CKD in Dahl SS/JrHsdMcwi rats.

Chronic kidney disease (CKD) has a strong genetic component; however, the underlying pathways are not well understood. Dahl salt-sensitive (SS)/Jr rats spontaneously develop CKD with age and are used to investigate the genetic determinants of CKD. However, there are currently several genetically diverse Dahl SS rats maintained at various institutions and the extent to which some exhibit age-related CKD is unclear. We assessed glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF) in 3- and 6-mo-old male and female SS/JrHsdMcwi, BN/NHsd/Mcwi [Brown-Norway (BN)], and consomic SS-Chr 1BN/Mcwi (SS.BN1) rats, in which chromosome 1 from the BN rat was introgressed into the genome of the SS/JrHsdMcwi rat. Rats were fed a 0.4% NaCl diet. GS (31 ± 3% vs. 7 ± 1%) and TIF (2.3 ± 0.2 vs. 0.5 ± 0.1) were significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi rats, and CKD was exacerbated in males. GS was minimal in 6- and 3-mo-old BN (3.9 ± 0.6% vs. 1.2 ± 0.4%) and SS.BN1 (2.4 ± 0.5% vs. 1.0 ± 0.3%) rats, and neither exhibited TIF. In SS/JrHsdMcwi and SS.BN1 rats, mean arterial blood pressure was significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi (162 ± 4 vs. 131 ± 2 mmHg) but not SS.BN1 (115 ± 2 vs. 116 ± 1 mmHg) rats. In 6-mo-old SS/JrHsdMcwi rats, blood pressure was significantly greater in females. RNA-sequencing analysis revealed that inflammatory pathways were upregulated in isolated medullary thick ascending tubules in 7-wk-old SS/JrHsdMcwi rats, before the development of tubule pathology, compared with SS.BN1 rats. In summary, SS/JrHsdMcwi rats exhibit robust age-related progression of medullary thick ascending limb abnormalities, CKD, and hypertension, and gene(s) on chromosome 1 have a major pathogenic role in such changes.NEW & NOTEWORTHY This study shows that the robust age-related progression of kidney disease in Dahl SS/JrHsdMcw rats maintained on a normal-salt diet is abolished in consomic SS.BN1 rats. Evidence that medullary thick ascending limb segments of SS/JrHsdMcw rats are structurally abnormal and enriched in proinflammatory pathways before the development of protein casts provides new insights into the pathogenesis of kidney disease in this model.

Potentially inappropriate prescribing in older adults with cancer receiving specialist palliative care: a retrospective observational study.

BACKGROUND: Older adults (≥ 65 years) with cancer receiving palliative care often have other health conditions requiring multiple medications. AIM: To describe and assess the appropriateness of prescribing for older adults with cancer in the last seven days of life in an inpatient palliative care setting. METHOD: Retrospective observational study of medical records for 180 patients (60.6% male; median age: 74 years; range 65-94 years) over a two-year period. Medication appropriateness was assessed using: STOPPFrail, OncPal deprescribing guideline and criteria for identifying Potentially Inappropriate Prescribing in older adults with Cancer receiving Palliative Care (PIP-CPC). RESULTS: 94.5% of patients had at least one other health condition (median 3, IQR 2-5). The median number of medications increased from five (IQR 3-7) seven days before death, to 11 medications on the day of death (IQR 9-15). The prevalence of PIP varied depending on the tool used: STOPPFrail (version 1: 17.2%, version 2: 19.4%), OncPal (12.8%), PIP-CPC (30%). However, the retrospective nature of the study limited the applicability of the tools. Increasing number of medications had a statistically significant effect on risk of PIP across all tools (STOPPFrail (version 1: 1.29 (1.13-1.37), version 2: 1.30 (1.16-1.48)); OncPal 1.13 (1.01-1.27); PIP-CPC 0.70 (0.61-0.82)). CONCLUSION: This study found that the number of medications prescribed to older adults with cancer increased as time to death approached, and the prevalence of PIP varied with the application of different tools. The study also highlights the difficulties of examining PIP in this patient cohort.

An infant with congenital respiratory insufficiency and diaphragmatic paralysis: A novel BICD2 phenotype?

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.

Conservative and surgical modalities in the management of paediatric parapneumonic effusion and empyema: a protocol for a living systematic review and network meta-analysis.

INTRODUCTION: Parapneumonic effusion and empyema are common complications of paediatric pneumonia. Acceptable treatment modalities for large parapneumonic effusions include antibiotics alone or in conjunction with surgical interventions. Clear guidelines on the best treatment approach are lacking and mostly based on evidence prior to widespread pneumococcal conjugate 13-valent vaccination (PCV-13). METHODS AND ANALYSIS: A living systematic review and network meta-analysis will be performed comparing the five treatment modalities: (1) antibiotics alone; (2) chest tube drainage without fibrinolytics; (3) chest tube drainage with fibrinolytics; (4) video-assisted thoracoscopic surgery and (5) open thoracotomy. The review protocol is reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. Eligible studies are randomised controlled trials comparing any pair of interventions in paediatric patients with empyema or parapneumonic effusion. The following databases will be searched: Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, LILACS and Google Scholar. Citation screening and data extraction will be completed using a validated crowdsourcing methodology using InsightScope. To assess the risk of bias, we will use the revised Cochrane risk of bias tool for randomised trials. The primary outcome of the study is the length of stay. Secondary outcomes are (1) periprocedural complications and (2) need for re-intervention. A frequentist network meta-analysis design will be implemented with a random-effects model comparing different interventions. In a subgroup analysis, studies and patients will be stratified by the size of pleural effusion and the date of trial (pre/post-PCV-13). Eligible citations and available results will be uploaded to an online database, hosted on Open Science Framework. The database will be updated at least every 4 months with any newly published research. ETHICS AND DISSEMINATION: No ethics review is required for this study. Results will be published in a peer-reviewed journal. Data will be available as part of an online database summarising the evidence of this living systematic review. PROSPERO REGISTRATION: Pending peer review.

Continuous positive airway pressure for obstructive sleep apnea in children.

QUESTION: A 12-year-old child underwent adenotonsillectomy for treatment of obstructive sleep apnea (OSA) but continues to snore at night and struggles with attentiveness at school. The child's parent uses a continuous positive airway pressure (CPAP) machine at night and wonders whether the same therapy could be used in children. ANSWER: Unlike in adults, pediatric OSA is commonly related to adenotonsillar hypertrophy and is often amenable to treatment with adenotonsillectomy. As an alternative to surgery or in cases of postsurgical persistence of OSA, CPAP has shown effectiveness in improving both polysomnographic parameters and daytime neurobehavioural symptoms in children with OSA. Adherence to CPAP therapy is a challenge in children and requires parental education and special considerations such as a mask acclimatization period.

Epidemiology of Robin sequence with cleft palate in the East of Scotland between 2004 and 2013.

BACKGROUND: Robin sequence (RS) is a congenital disorder characterized by cleft palate, micrognathia, and glossoptosis which can result in clinically significant upper airway obstruction (UAO). Historically, incidence of RS in the UK has been estimated as 1 in 8500 live births. Our study describes birth prevalence, clinical characteristics, and management of RS in the East of Scotland (EoS) region. METHODS: Retrospective case note review of infants born in EoS from 2004 to 2013 with a clinical diagnosis of RS. Cases were identified by searching the regional cleft service patient database and review of Hospital Activity Statistics data. Regional live birth rate provided the denominator for incidence calculations. RESULTS: A total of 105 cases of RS were identified, giving a birth prevalence of 1:2685 live births. No trends in annual incidence were observed over the 10-year period. Intrauterine exposure to potentially teratogenic agents was identified in 17% cases, including Methadone in 8% cases. Signs of UAO were present in 93% of infants, 63% of whom required active airway management. Nasopharyngeal airway (NPA) was the most commonly used intervention (53% cases), whilst only 7% required surgical management. Infants with an underlying syndrome or additional anomalies (RS+) were significantly more likely to be admitted to a tertiary center and require surgical airway or feeding support compared to those with isolated RS. CONCLUSIONS: RS incidence in EoS is substantially higher than that reported within other populations, and than previously reported in the UK. A possible association with intrauterine Methadone exposure warrants further investigation.

Hypersensitivity reactions to intravenous antibiotics in cystic fibrosis.

Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required.

Quantifying fluctuation in glucose levels to identify early changes in glucose homeostasis in cystic fibrosis.

BACKGROUND: Cystic fibrosis related diabetes (CFRD) is associated with increased morbidity in CF. Variability in physiological systems is associated with dysfunctional homeostasis. We examined whether fluctuation in glucose is a marker of CFRD or "pre-diabetes". METHODS: Using a machine learning approach, we compared glucose IQR to current diagnostic criteria in a review of continuous glucose monitoring data. RESULTS: Analysis was performed on 248 studies from 142 children. Calculated IQR (cIQR) was increased between children with CFRD, normal glucose homeostasis and indeterminate status (p<0.0001) and impaired glucose tolerance (p<0.05, Kruskal-Wallis test). In subjects who developed CFRD (n=20), cIQR increased between baseline and diagnosis (1.4mmol/L versus 2.4mmol/L, p<0.0001, Wilcoxon test). Area under the curve for CFRD on the basis of cIQR was 0.865 (p<0.0001). Neither episodes of hypoglycaemia nor cIQR at baseline predicted CFRD. CONCLUSIONS: Glucose fluctuation on CGMS can be quantified by calculating the IQR. This information may improve early recognition of abnormal glucose homeostasis.

Habit-tic cough: Presentation and outcome with simple reassurance.

OBJECTIVES: Our therapeutic approach to a habit/tic cough is simple reassurance in a single consultation. To quality assure our practice, we followed up children to determine outcomes at least 3 months after diagnosis. DESIGN: Consecutive children diagnosed over 6 years were studied. Medical records were analyzed retrospectively and parents answered a scripted verbal survey. RESULTS: Fifty-five patients were diagnosed (median age 9.9 years), with a median cough duration of 3 months (IQR 2-7.5 months, range up to 3 years). In 51/55 (93%) cases, cough was absent during sleep. 51/55 (93%) received prior medications with median 3 therapeutic trials, none of which resolved the cough. Follow-up was possible in 39/55 (71%) children after a median duration of 1.9 years. In 32/39 (82%), the cough had resolved completely (59% within 4 weeks, including 12% on the day), and it improved in 6/39 (15%). In the 26/39 (67%) parents who said they believed the diagnosis, there was 96% resolution of the cough, versus the 13/39 (33%) who were sceptical or disbelieving, when there was only 54% resolution. 7/39 (18%) children were later diagnosed with a tic disorder, functional symptoms, or a behavioural/psychiatric disorder. CONCLUSIONS: Habit cough can be diagnosed from the characteristic history; the crucial question is whether the cough disappears during sleep. We have shown successful long term outcomes following a single consultation with simple reassurance, but it is important that the child and parents believe the explanation. It is not uncommon for subsequent tic disorders or behavioral issues to emerge.

Concomitant thyroid disease and primary hyperparathyroidism in patients undergoing parathyroidectomy or thyroidectomy.

BACKGROUND: Thyroid abnormalities have been found intraoperatively during parathyroidectomy and have resulted in concomitant thyroidectomy. The identification of concomitant disease is important prior to primary operation in order to minimize reoperations. This study investigates the incidence of concomitant primary hyperparathyroidism (PHPT) and thyroid nodular disease in patients undergoing thyroidectomy or parathyroidectomy. METHODS: We performed a retrospective review of prospectively gathered data for 621 patients who underwent thyroidectomy, parathyroidectomy, or both at Tulane Medical Center. Information obtained included initial referral, initial thyroid stimulating hormone (TSH), initial parathyroid hormone (PTH), fine needle aspiration (FNA) results, ultrasound results, type of operation performed, final diagnosis, and final pathology. RESULTS: Among the 400 patients referred primarily for thyroid disease, 13.50% underwent a thyroidectomy and parathyroidectomy (PTX) simultaneously and 10.75% received a final diagnosis of thyroid and concomitant parathyroid disease. Among the 103 patients referred primarily for parathyroid disease, 26.21% underwent a PTX and thyroidectomy and 24.27% received a final diagnosis of both thyroid and parathyroid disease. Patients referred primarily for parathyroid disease were more likely to receive a final diagnosis of both parathyroid and thyroid disease and were more likely to undergo a combined operation. CONCLUSIONS: Concomitant thyroid and parathyroid disease occur and preoperative analysis is important to avoid increased complications from reoperations.

WA40†The good neighbour partnership: why do we need it? who is going to do it? how on earth are we going to evaluate it?

: This one-hour symposium considers Milford Care Centre's Compassionate Communities Good Neighbour Partnership and it's evaluation by an international team, led by Maynooth University and funded by the All Ireland Institute of Hospice and Palliative Care, The Irish Cancer Society, The Irish Hospice Foundation and Milford Care Centre. The symposium will be divided into three sections: 1. The Good Neighbour Partnership: Why do we need it? In this section we will describe the findings from a recent scoping study to determine the social and practical needs of community dwelling adults (and their families) living with advanced life limiting illness at home. We will consider the rationale for specialist palliative care services, working with community groups, to lead the development of a volunteer-based social model of care to address unmet need. 2. The Good Neighbour Partnership: How do we recruit and train volunteers? We will share our process and experience of recruiting and training 15 Compassionate Communities Volunteers to assess unmet social and practical need, and to mobile the person's circle of community to meet those needs. An understanding of the motivating factors of volunteers will be shared. 3. The Good Neighbour Partnership: How on earth are we going to evaluate it? Here we describe the INSPIRE study - Investigating Social and Practical Supports at the End of life. An exploratory delayed intervention randomised controlled trial (framed by the MRC Framework for Complex Interventions) to assess the feasibility, acceptability and potential effectiveness of the Good Neighbour Partnership.

Peptide antagonists of the calcitonin gene-related peptide (CGRP) receptor with improved pharmacokinetics and pharmacodynamics.

Antagonism of the calcitonin gene-related peptide (CGRP) receptor may be a useful approach for migraine treatment. Selective PEGylated peptide antagonists to the CGRP receptor are described, derived from CGRP(8-37) with polymer derivatization at an engineered lysine-25 residue. Potent PEGylated peptides with improved pharmacokinetics were identified through peptide side-chain modification to mitigate metabolic liabilities. PEGylated Ac-Trp-[Cit(11,18),hArg(24),Lys(25),Asp(31),Pro(34),1-Nal(35)]CGRP(8-37)-NH2, 9, elicits a dose-dependent reduction of intradermal CGRP-induced local blood flow in rodents with an ED50 of 0.52 mg kg(-1) without any overt adverse effects.

Direct quantitative analysis of a 20 kDa PEGylated human calcitonin gene peptide antagonist in cynomolgus monkey serum using in-source CID and UPLC-MS/MS.

PEGylation is a successful strategy to improve the pharmacokinetic and pharmaceutical properties of therapeutic peptides. However, quantitative analysis of PEGylated peptides in biomatrix by LC-MS/MS poses significant analytical challenge due to the polydispersity of the polyethylene glycol (PEG), and the multiple charge states observed for both the peptide and PEG moieties. In this report, a novel LC-MS/MS method for direct quantitative analysis of 20 kDa PEGylated CGRP[Cit, Cit] in cynomolgus monkey serum is presented. CGRP[Cit, Cit] is an investigational human calcitonin gene peptide receptor antagonist with amino acid sequence Ac -WVTH[Cit]LAGLLS[Cit]SGGVVRKNFVPT DVGPFAF-NH(2). In-source collision-induced dissociation (in-source CID) of 20 kDa PEGylated peptide was used to generate CGRP[Cit, Cit] fragment ions, among which the most abundant b(8)(+) ion was selected and measured as a surrogate for the 20 kDa PEGylated peptide. A solid phase extraction (SPE) method was used to extract the PEGylated peptides from the biomatrix prior to the UPLC-MS/MS analysis. This method achieved a lower limit of quantitation (LLOQ) of 5.00 ng/mL with a serum sample volume of 100 µL, and was linear over the calibration range of 5.00 to 500 ng/mL in cynomolgus monkey serum. Intraday and interday accuracy and precision from QC samples were within ±15%. This method was successfully applied to a pharmacokinetic study of the 20 kDa PEGylated CGRP[Cit, Cit] in cynomolgus monkeys.

Identification of potent, selective, and metabolically stable peptide antagonists to the calcitonin gene-related peptide (CGRP) receptor.

Calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that can be converted to a CGRP(1) receptor antagonist by the truncation of its first seven residues. CGRP(8-37), 1, has a CGRP(1) receptor K(i) = 3.2 nM but is rapidly degraded in human plasma (t(1/2) = 20 min). As part of an effort to identify a prolonged in vivo circulating CGRP peptide antagonist, we found that the substitution of multiple residues in the CGRP peptide increased CGRP(1) receptor affinity >50-fold. Ac-Trp-[Arg(24),Lys(25),Asp(31),Pro(34),Phe(35)]CGRP(8-37)-NH(2), 5 (K(i) = 0.06 nM) had the highest CGRP(1) receptor affinity. Using complimentary in vitro and in vivo metabolic studies, we iteratively identified degradation sites and prepared high affinity analogues with significantly improved plasma stability. Ac-Trp-[Cit(11,18),hArg(24),Lys(25),2-Nal(27,37),Asp(31),Oic(29,34),Phe(35)]CGRP(8-37)-NH(2), 32 (K(i) = 3.3 nM), had significantly increased (>100-fold) stability over 1 or 5, with a cynomolgus monkey and human in vitro plasma half-life of 38 and 68 h, respectively.

A visitor with Munchausen's syndrome.

The arrival on the hospital ward of a person who was fabricating an illness was an unsettling experience for the medical and nursing staff involved. As the patient was expected only to be present for a short time and claimed to have a proven diagnosis, the approach may have been less rigorous than usual. The article describes the experience of three members of staff with a patient who proved to have Munchausen's syndrome, and their reaction to discovering the truth.