Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud \ud PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud \ud RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud \ud CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud \u

Longitudinal changes in acylated versus unacylated ghrelin levels may be involved in the underlying mechanisms of the switch in nutritional phases in Prader-Willi syndrome

Introduction: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite-regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls. Methods: A longitudinal study was conducted in 134 children with PWS and 157 healthy controls, from the Netherlands, France, and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored. Results: The AG/UAG ratio was lower in the first years of life in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p = 0.114), while the UAG levels decreased from 290 pg/mL in phase 1a to 137 pg/mL in phase 2b (p &lt; 0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p = 0.012). Conclusions: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia

Planck intermediate results. XLI. A map of lensing-induced B-modes

The secondary cosmic microwave background (CMB) $B$-modes stem from the post-decoupling distortion of the polarization $E$-modes due to the gravitational lensing effect of large-scale structures. These lensing-induced $B$-modes constitute both a valuable probe of the dark matter distribution and an important contaminant for the extraction of the primary CMB $B$-modes from inflation. Planck provides accurate nearly all-sky measurements of both the polarization $E$-modes and the integrated mass distribution via the reconstruction of the CMB lensing potential. By combining these two data products, we have produced an all-sky template map of the lensing-induced $B$-modes using a real-space algorithm that minimizes the impact of sky masks. The cross-correlation of this template with an observed (primordial and secondary) $B$-mode map can be used to measure the lensing $B$-mode power spectrum at multipoles up to $2000$. In particular, when cross-correlating with the $B$-mode contribution directly derived from the Planck polarization maps, we obtain lensing-induced $B$-mode power spectrum measurement at a significance level of $12\,\sigma$, which agrees with the theoretical expectation derived from the Planck best-fit $\Lambda$CDM model. This unique nearly all-sky secondary $B$-mode template, which includes the lensing-induced information from intermediate to small ($10\lesssim \ell\lesssim 1000$) angular scales, is delivered as part of the Planck 2015 public data release. It will be particularly useful for experiments searching for primordial $B$-modes, such as BICEP2/Keck Array or LiteBIRD, since it will enable an estimate to be made of the lensing-induced contribution to the measured total CMB $B$-modes.Comment: 20 pages, 12 figures; Accepted for publication in A&A; The B-mode map is part of the PR2-2015 Cosmology Products; available as Lensing Products in the Planck Legacy Archive http://pla.esac.esa.int/pla/#cosmology; and described in the 'Explanatory Supplement' https://wiki.cosmos.esa.int/planckpla2015/index.php/Specially_processed_maps#2015_Lensing-induced_B-mode_ma

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

The management of the painful bipartite patella: a systematic review

Purpose: This study aimed to identify the most effective method for the treatment of the symptomatic bipartite patella. Methods: A systematic review of the literature was completed, and all studies assessing the management of a bipartite patella were included. Owing to the paucity of randomised controlled trials, a narrative review of 22 studies was completed. A range of treatments were assessed: conservative measures, open and arthroscopic fixation or excision and soft tissue release and excision. Results: All of the methods provided results ranging from good to excellent, with acceptable complication rates. Conclusions: This is a poorly answered treatment question. No firm guidance can be given as to the most appropriate method of treating the symptomatic bipartite patella. This study suggests that there are a number of effective treatments with acceptable complication rates and it may be that treatments that conserve the patella are more appropriate for larger fragments

Predicting sequelae and death after bacterial meningitis in childhood: A systematic review of prognostic studies

Background: Bacterial meningitis (BM) is a severe infection responsible for high mortality and disabling sequelae. Early identification of patients at high risk of these outcomes is necessary to prevent their occurrence by adequate treatment as much as possible. For this reason, several prognostic models have been developed. The objective of this study is to summarize the evidence regarding prognostic factors predicting death or sequelae due to BM in children 0-18 years of age. Methods: A search in MEDLINE and EMBASE was conducted to identify prognostic studies on risk factors for mortality and sequelae after BM in children. Selection of abstracts, full-text articles and assessment of methodological quality using the QUIPS checklist was performed by two reviewers independently. Data on prognostic factors per outcome were summarized. Results: Of the 31 studies identified, 15 were of moderate to high quality. Due to substantial heterogeneity in study characteristics and evaluated prognostic factors, no quantitative analysis was performed. Prognostic factors found to be statistically significant in more than one study of moderate or high quality are: complaints > 48 hours before admission, coma/impaired consciousness, (prolonged duration of) seizures, (prolonged) fever, shock, peripheral circulatory failure, respiratory distress, absence of petechiae, causative pathogen Streptococcus pneumoniae, young age, male gender, several cerebrospinal fluid (CSF) parameters and white blood cell (WBC) count. Conclusions: Although several important prognostic factors for the prediction of mortality or sequelae after BM were identified, the inability to perform a pooled analysis makes the exact (independent) predictive value of these factors uncertain. This emphasizes the need for additional well-conducted prognostic studie

Acromioclavicular joint augmentation at the time of coracoclavicular ligament reconstruction fails to improve functional outcomes despite significantly improved horizontal stability

Purpose: Acromioclavicular joint reconstruction is a well-established and frequently performed procedure. Recent scientific and commercial interest has led to a drive to develop and perform surgical techniques that more reliably restore horizontal stability in order to improve patient outcomes. The aim of this systematic review was to evaluate the biomechanical evidence for procedures directed at restoring horizontal stability and determine whether they are associated with superior clinical results when compared to well-established procedures. Methods: A review of the online databases Medline and EMBASE was conducted in accordance with the PRISMA guidelines on the 23rd December 2017. Biomechanical and clinical studies reporting either static or dynamic horizontal displacement following acromioclavicular joint reconstruction (Coracoclavicular reconstruction or Weaver-Dunn) were included. In addition, biomechanical and clinical studies reporting outcomes after additional augmentation of the acromioclavicular joint were included. The studies were appraised using the Methodological index for non-randomised studies tool. Results: The search strategy identified 18 studies eligible for inclusion: six biomechanical and 12 clinical studies. Comparative biomechanical studies demonstrated that acromioclavicular augmentation provided significantly increased horizontal stability compared to the coracoclavicular reconstruction and Weaver–Dunn procedure. Comparative clinical studies demonstrated no significant differences between coracoclavicular reconstruction with and without acromioclavicular augmentation in terms of functional outcomes (American Shoulder and Elbow Surgeon and Constant score), complication or revision rates. However, one comparative study did demonstrate an improvement in Taft (p = 0.018) and Acromioclavicular Joint Instability scores (p = 0.0001) after acromioclavicular augmentation. Conclusion: In conclusion, coracoclavicular reconstruction with augmentation of the acromioclavicular joint has been shown to provide improved horizontal stability in both biomechanical and clinical studies compared to isolated coracoclavicular reconstruction. However, comparative studies have shown no clinical advantage with respect to American Shoulder and Elbow Surgeon or Constant scores and, therefore, the results of this systematic review do not support acromioclavicular augmentation in routine clinical practice. Level of evidence: IV

The developmental impact of prenatal stress, prenatal dexamethasone and postnatal social stress on physiology, behaviour and neuroanatomy of primate offspring: studies in rhesus macaque and common marmoset

RATIONALE: Exposure of the immature mammalian brain to stress factors, including stress levels of glucocorticoids, either prenatally or postnatally, is regarded as a major regulatory factor in short- and long-term brain function and, in human, as a major aetiological factor in neuropsychiatric disorders. Experimental human studies are not feasible and animal studies are required to demonstrate causality and elucidate mechanisms. A number of studies have been conducted and reviewed in rodents but there are relatively few studies in primates. OBJECTIVES: Here we present an overview of our published studies and some original data on the effects of: (1) prenatal stress on hypothalamic-pituitary-adrenal (HPA) re/activity and hippocampus neuroanatomy in juvenile-adolescent rhesus macaques; (2) prenatal dexamethasone (DEX) on HPA activity, behaviour and prefrontal cortex neuroanatomy in infant-adolescent common marmosets; (3) postnatal daily parental separation stress on HPA re/activity, behaviour, sleep and hippocampus and prefrontal cortex neuroanatomy in infant-adolescent common marmoset. RESULTS: Prenatal stress increased basal cortisol levels and reduced neurogenesis in macaque. Prenatal DEX was without effect on HPA activity and reduced social play and skilled motor behaviour in marmoset. Postnatal social stress increased basal cortisol levels, reduced social play, increased awakening and reduced hippocampal glucocorticoid and mineralocorticoid receptor expression in marmoset. CONCLUSIONS: Perinatal stress-related environmental events exert short- and long-term effects on HPA function, behaviour and brain status in rhesus macaque and common marmoset. The mechanisms mediating the enduring effects remain to be elucidated, with candidates including increased basal HPA function and epigenetic programming