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The aims of this study were to determine the current prevalence of regurgitation and reingestion (R/R) and gain an insight on the occurrence of coprophagy in the Association of Zoos & Aquariums (AZA) gorilla (Gorilla gorilla gorilla) population. To do this, an online survey was sent to all AZA accredited gorilla institutions in 2018. This survey collected information on the severity of R/R at the individual level and the occurrence of coprophagy at the zoo level. Previous research suggests more than half of zoo-housed gorillas in the North American population engaged in R/R and coprophagy to some extent. The current study had a 100% response and completion rate; data were collected on all 296 noninfant gorillas in the population. Responses indicated that 60% of the AZA gorilla population engages in R/R to some degree and 24% of the population are observed exhibiting coprophagy on a weekly basis. With this preliminary information on coprophagy, and the realization that the Zoo community has been unsuccessful at eliminating R/R over the past 30 years, the next steps should be aimed at empirically assessing the potential drivers of these behaviors. Continuing efforts to further understand and eliminate R/R and coprophagy in zoo-housed primates is important not only because these behaviors are unsightly to visitors, but more importantly, R/R and coprophagy may signal deficiencies in current practices surrounding animal care.

Since March 2020, families across the United States have faced challenges due to the novel coronavirus (COVID-19) pandemic and its subsequent restrictions. Although some experts have voiced concern over the impact of COVID-19 on family well-being, few studies have been conducted thus far. This study utilized n = 250 responses from an online survey that was administered between May and June 2020 to gauge family stress and resilience among mothers of children ages 0 to 5 during the pandemic. Adverse childhood experiences were negatively associated with parental resilience among this sample. Furthermore, frequency of child care was positively linked to protective factors and resilience. Implications for practice, policy, and research are discussed, with a particular focus on the role of child care and school openings during the pandemic.

Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.

IntroductionIdiopathic congenital talipes equinovarus (CTEV) is the most common congenital limb deformity. Non-operative intervention using the Ponseti method has shown to be superior to soft tissue release and has become the gold standard for first-line treatment. However, numerous deviations from the Ponseti protocol are still reported following incomplete correction or deformity relapse. Significant variation in treatment protocols and management is evident in the literature. Reducing geographical treatment variation has been identified as one of The James Lind Alliance priorities in children’s orthopaedics. For this reason, the British Society of Children’s Orthopaedic Surgery (BSCOS) commissioned a consensus document to form a benchmark for practitioners and ensure consistent high quality care for children with CTEV.Methods and analysisThe consensus will follow an established Delphi approach aiming at gaining an agreement on the items to be included in the consensus statement for the management of primary idiopathic CTEV up to walking age. The process will include the following steps: (1) establishing a steering group, (2) steering group meetings, (3) a two-round Delphi survey aimed at BSCOS members, (4) final consensus meeting and (5) dissemination of the consensus statement. Degree of agreement for each item will be predetermined. Descriptive statistics will be used for analysis of the Delphi survey results.Ethics and disseminationNo patient involvement is required for this project. Informed consent will be assumed from participants taking part in the Delphi survey. Study findings will be published in an open access journal and presented at relevant national and international conferences. Charities and associations will be engaged to promote awareness of the consensus statement.

This study examined the relationship between ACE score and substance use, mental health, and parenting competence among a sample of Latino caregivers at-risk for child maltreatment. This study sought to increase our understanding of ACEs and outcomes among Latino caregivers that had at least two risk factors for child maltreatment. Surveys were administered to caregivers with children between 0 and 5 years of age who enrolled in child maltreatment prevention programs and completed by N= 417 Spanish-speaking Latino caregivers before or shortly after beginning the prevention program. Results suggest that ACE scores are positively associated with mental health issues and substance use, but the relationship between ACE scores and parenting competence is more complex. Furthermore, foreign-born caregivers fared better in terms of mental health and parenting competence than their U.S.-born counterparts among this sample of Spanish-speaking at-risk Latino caregivers. Implications for future research include incorporating other measures of more current exposure to adversity, such as immigration trauma, when working with recent immigrants. Furthermore, practitioners should be aware of policies related to immigration and how these might impact potential service usage and overall wellbeing among Spanish-speaking clients. More research is needed to better understand other factors that might impact parenting, mental health, and substance use associated with ACEs among Latino families.

Flatfoot is commonly encountered in the paediatric population and describes a spectrum of clinical and radiological presentations which encompass both normally developing and pathological feet. Flatfoot can be categorised as flexible or rigid, a distinction which has important implications when considering the potential underlying aetiology and treatment options, and therefore imaging is an important component of the diagnostic workup. Weight-bearing plain radiographs are established initial investigations, although the significance of a number of the commonly derived quantitative parameters in children remains unclear. CT and MRI are important additional imaging modalities reserved for the investigation of symptomatic cases or those in which an underlying structural abnormality is suspected, rigid flatfoot commonly falling into one of these two categories. We review and illustrate the multimodality imaging of the paediatric flatfoot, with reference to both qualitative and quantitative radiographic assessment and cross-sectional imaging appearances.

Since March 2020, families across the U.S. have faced challenges due to the novel Coronavirus (COVID-19) and its subsequent restrictions. Prior literature has linked family stress to negative outcomes, such as parent and child mental health, increased risk of child maltreatment, and overall well-being, as well as protective factors that may help families navigate and respond to stressors. Furthermore, parental history of trauma, such as exposure to adversity in one’s own childhood, has been linked to stress and resilience. Although some experts have voiced concern over the impact of COVID-19 on family well-being, few studies have been conducted thus far. This study utilized N = 523 responses from an online survey that was administered between May and June 2020 to gauge family stress and resilience among parents of children ages zero-to-five during the pandemic. There was a negative relationship between ACE score and parental resilience among this sample. Furthermore, frequency of childcare was positively linked to protective factors and resilience, while childcare barriers were negatively linked to resilience. Implications for practice, policy, and research are discussed, with a particular focus on the role of childcare and school openings during the pandemic.

Inequities and the resulting disparities that exist in mental health for a variety of socially disadvantaged groups have roots in the history and ongoing processes of medical and mental health research, as well as in persisting implicit bias in our society and health care system. The inclusion of historically excluded communities in the research to practice pipeline is vital to ensuring that treatments and interventions are developed to increase equity in mental health. A research framework is proposed based on the integration of community-based participatory research and human-centered design as an avenue for removing inequities and barriers in mental health.

IntroductionAntimicrobial resistance (AMR) is a major public health challenge worldwide, threatening the important gains that have been made in reducing mortality due to infectious diseases. Despite current World Health Organization guidelines restricting antibiotics to a small subset of children with dysentery or suspected cholera, many children with diarrhea continue to be treated with antibiotics. We aim to determine the impact of a 3-day course of azithromycin on the risk of AMR at 90 and 180 days after treatment, among a subset of children and their household contacts enrolled into a multi-country, randomized, double-blind, placebo-controlled clinical trial of azithromycin children under 2 years with diarrhea in low income settings,Methods and analysisThe AntiBiotics for Children with Diarrhea (ABCD) trial is testing the efficacy of a 3-day course of azithromycin, compared to placebo, in reducing mortality and linear growth faltering in the subsequent 6 months among 11,500 children aged 2-23 months of age across multiple sites in Bangladesh, India, Kenya Malawi, Mali, Pakistan and Tanzania with diarrhea and one or more of the following; dehydration, severe stunting, or moderate wasting (https://clinicaltrials.gov/ct2/show/NCT03130114). A sub-set of enrolled children are randomly selected to participate in a sub-study of AMR. A fecal sample (stool or rectal swab) will be collected at baseline from all enrolled children. A fecal sample and a nasopharyngeal (NP) swab will be collected at day 90 and 180 after enrolment from participating children and a close household child contact. Escherichia coli and Streptococcus pneumoniae will be isolated and Minimum Inhibitory Concentration for azithromycin and other commonly used antibiotics will be determined and compared between trial arms.Ethics and disseminationThis study was reviewed by an independent ethical review committee. Dissemination of results is planned to local and international policy makers and the public.Registration details (Parent ABCD trial)https://clinicaltrials.gov/ct2/show/NCT03130114Strengths and limitations of this study (3-5 points)✤This study will provide evidence from a randomized controlled trial regarding the risk of short term azithromycin use on resistance to azithromycin and selected commonly used antibiotics, 90 and 180 days after administration in treated children and their household contacts. Few RCTs of antibiotics for diarrhoea have provided such long-term follow-up and close contact data, both of which are key to understanding the potential risk of short-term antibiotic use in the context of diarrhoea.✤This study will also provide data on antibiotic resistance from multiple countries in sub-Saharan Africa and Asia where availability of such data is limited.✤Escherichia coli and Streptococcus pneumoniae will be used as indicator organisms to monitor the impact of empiric antibiotic azithromycin administration on the development of resistance in bacteria colonising the gut and nasopharynx respectively – both are suitable for this purpose as they have pathogenic potential and are also commensal organisms which may act as reservoirs of transmissible genetic resistance elements.✤With only two follow-up visits at 90 and 180 days, lack of culturing of other bacterial pathogens, and minimal collection of information on other antibiotic use during follow-up, this study will not evaluate impact of azithromycin beyond 180 days, the impact on other pathogenic bacteria, nor the added impact of the use of other antibiotics on resistance profiles

Mental health concerns related to the COVID-19 pandemic and the resulting economic and societal changes are an important matter of public health. We examined the state-level association between new cases of COVID-19 reported and mental health, as measured through Google search trends, on a daily basis. Our analyses indicate a significant positive association, such that increases in mental health Google searches should be expected on days when relatively more new cases of COVID-19 are announced. The overall effect and state-level variation were analyzed via a multi-level model and full results are included here. Implications and public policy suggestions are discussed.

Objective: The objective of this work was to assess the ability of peripheral blood cell-free DNA (cfDNA) levels to identify ischaemic stroke early in the acute phase of care, as well as to examine the relationship between peripheral blood cfDNA levels and stroke-induced innate immune system activation. Methods: Upon emergency department admission, peripheral blood samples were obtained from 43 patients experiencing acute ischaemic stroke and 20 patients identified as stroke mimics. Plasma cfDNA levels were measured using quantitative polymerase chain reaction (qPCR), infarct volume and NIH stroke scale (NIHSS) were used to assess injury severity, and peripheral blood neutrophil count was used as a measure of innate immune system status.Results: Peripheral blood cfDNA levels were significantly elevated in patients suffering stroke relative to those diagnosed as stroke mimics, and could differentiate between groups with 86% (95% CI = 72–95%) sensitivity and 75% (95% CI = 51–91%) specificity. Furthermore, cfDNA levels displayed significant positive associations between both infarct volume and peripheral blood neutrophil count within the stroke group. Conclusions: These findings suggest that assessment of peripheral blood cfDNA levels may be useful for the identification of ischaemic stroke in the acute care setting, and provide associative evidence that cfDNA is a potential activator of the peripheral innate immune system in response to cerebral ischaemia.

Purpose Complete fibula absence often presents with significant lower-limb deformity. Parental counselling regarding management is paramount in achieving the optimum functional outcome. Amputation offers a single surgical event with minimal complications. This study compares outcomes with an amputation protocol to those using an extension prosthesis. Method Thirty-two patients were identified. Nine patients (2 males, 7 females; median age at assessment of 23.5 years) used an extension prosthesis. Twenty-three patients (16 males, 7 females; median age at assessment of eight years) underwent 25 amputations during childhood. Mobility was assessed using SIGAM and K scores. Quality of life was assessed using the PedsQL inventory questionnaire; pain by a verbal severity score. Results The 19 Syme and one Boyd amputation in 19 patients were performed early (mean age 15 months). Four Syme and one trans-tibial amputation in four patients took place in older children (mean age 6.6 years). Only two underwent tibial kyphus correction to aid prosthetic fitting. K scores were significantly higher (mean 4 vs 2) and pain scores lower in the amputation group allowing high impact activity compared with community ambulation with an extension prosthesis. The SIGAM and PedsQL scores were all better in the amputation group, but not significantly so. Conclusion Childhood amputation for severe limb length inequality and foot deformity in congenital fibula absence offers excellent short-term functional outcome with prosthetic support. The tibial kyphus does not need routine correction and facilitates prosthetic suspension. Accommodative extension prostheses offer reasonable long-term function but outcome scores are lower.

To use biomarkers to gain insight into and gauge the residual (post-treatment) level of inflammation in two groups of intensively treated patients with severe chronic pain.Three study groups were analyzed, and included: (i) patients (n = 90) with chronic intractable pain (CIP), (ii) patients (n = 26) with chronic pain and MRI-documented arachnoiditis (ARC) and (iii) normal subjects without a diagnosis of chronic pain (n = 86). We determined and compared the serum concentrations of Alpha-1 Antitrypsin (A1AT), Myeloperoxidase (MPO) and soluble Tumor Necrosis Factor receptor type 2 (sTNFR2) in each of the patient populations studied.Patients treated for ARC or CIP had higher serum levels of A1AT and MPO than normal untreated subjects without a diagnosis of chronic pain. ARC patients had an A1AT mean serum concentration of 167.9 ± 41.9 mg/dL as compared to 148.9 ± 35.2 mg/dL for normal subjects (p = 0.023). CIP patients had the highest mean serum A1AT level 183.6 ± 39.2 mg/dL with p values of0.0001 or 0.08 when compared to normal subjects or ARC patients respectively. ARC patients had an MPO mean serum concentration of 344.6 ± 227.9 ng/mL as compared to 188.2 ± 107.5 ng/mL for normal subjects (p = 0.0001). CIP patients had a similar mean serum MPO level of 352.3 ± 164 ng/mL with p values of0.0001 or 0.85 when compared to normal subjects or ARC patients respectively. In addition, we noted a difference in the pattern of MPO expression in patients with ARC in that 34% had levels of MPO at normal or below and 31% had levels 2-fold or greater than normal.This data supports the concept that in centralized pain, sites of neuroinflammation elaborate MPO and other inflammatory factors which may not be completely cleared from the system despite extensive and complex treatment regimens.

Background Acute diarrhoea is a common cause of illness and death among children in low-middle-income settings. WHO guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death in 90-days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea associated mortality and morbidity. We designed the ‘Antibiotics for Childhood Diarrhoea’ (ABCD) trial to test this intervention. Methods ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2-23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania, are randomized (1:1) to oral azithromycin 10mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are (i) all-cause mortality during the 180 days post-enrolment and (ii) change in linear growth 90 days post-enrolment. Discussion Expanding treatment of acute watery diarrhoea in high risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present WHO diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines.

Acute patellar instability is part of the spectrum of patellofemoral maltracking problems, which can manifest as pain, subluxation or frank dislocation. Dislocation itself is usually the result of trauma, particularly in the presence of pre-existing structural abnormalities. Sequelae of acute dislocations include osteochondral injuries and recurrent instability; however, in the absence of osteochondral injuries or major morphological abnormalities, the gold standard of treatment is nonoperative. In this chapter, the patellofemoral joint anatomy is examined alongside the risk factors for instability. Causes of acute patellar instability are discussed, as well as management.

Aims Our aim was to assess the effectiveness of a protocol involving a standardised closed reduction for the treatment of children with developmental dysplasia of the hip (DDH) in maintaining reduction and to report the mid-term results. Methods A total of 133 hips in 120 children aged less than two years who underwent closed reduction, with a minimum follow-up of five years or until subsequent surgery, were included in the study. The protocol defines the criteria for an acceptable reduction and the indications for a concomitant soft-tissue release. All children were immobilised in a short- leg cast for three months. Arthrograms were undertaken at the time of closed reduction and six weeks later. Follow-up radiographs were taken at six months and one, two and five years later and at the latest follow-up. The Tönnis grade, acetabular index, Severin grade and signs of osteonecrosis were recorded. Results A total of 67 hips (51%) were Tönnis grade 3/4 hips. By 12 months, 20 reductions (15%) had not been maintained, and these required open reduction. In all, 55% of these were Severin 1; the others were Severin 2, due to minor acetabular dysplasia. Of the 113 successful closed reductions, 98 hips (87%) were Severin 1. Surgery for residual DDH was offered for ten hips. Osteonecrosis was seen in 32 hips (29%) but was transient in 28. In total, two children (1.5%) had severe osteonecrosis. Bilateral dislocations were significantly more likely to fail and most Tönnis 4 hips failed. Conclusion Closed reduction, with concomitant adductor and psoas release when required and the use of a short leg plaster of Paris cast for three months, can produce good mid-term results in children with DDH aged less than two years. This protocol is not recommended for Tönnis 4 hips. Cite this article: Bone Joint J 2016;98-B:1548–53.

To identify possible underlying causes of poor oral opioid effectiveness.Ninety-five (95) adults who were referred for evaluation and medical management of their intractable pain were screened to determine if oral opioids provided enough pain relief to physically and mentally function and carry out activities of daily living. A clinical evaluation included history, physical examination, cytochrome P450 enzyme testing and a hydromorphone injection to help confirm lack of oral opioid effectiveness.Twenty (20; 21.1%) of the 95 patients reported that three or more oral opioids had not provided enough pain relief to allow them to mentally and physically function and carry out activities of daily living. Patients all reported some typical symptoms of malabsorption including nausea and steatorrhea, and 14 (70.0%) reported that they had observed undigested medication in their stools. Fifteen (15; 75.0%) had experienced pain relief with an injectable opioid. Two major causes for lack of oral opioid effectiveness were apparent: (1) gastrointestinal disorder (11; 55.0%) and (2) cytochrome P450 enzymatic defects (9; 45.0%). In addition to these basic causes, a number of other possible contributing factors were identified which included abdominal, pelvic and spine surgeries, traumatic brain and neck injury, and autoimmune disorders.There is a group of intractable pain patients who do not effectively metabolize oral opioids. Although gastrointestinal disease and cytochrome P450 enzymatic defects appeared to be dominant causes of oral opioid ineffectiveness, there were other possible contributing factors such as abdominal, pelvic and spine surgeries, head and neck trauma, and autoimmune disease. Pain patients who report poor oral opioid effectiveness should be evaluated for the presence of underlying pathologic conditions which may interfere with oral opioid metabolism and, if found, be considered for nonoral opioid treatment.

Childhood adversity has been linked to negative outcomes related to health, behavior, and interpersonal relationships among adults. Research has explored how a parental history of adverse childhood experiences (ACEs) can impact the health and wellbeing of their own children. A parental history of ACEs can heighten the risk of perpetuating intergenerational patterns of trauma transmission. However, few studies have examined connections between a parental history of ACEs and protective factors that could mitigate such risk. This study used survey results to examine relationships between parental ACEs and protective factors among a sample of 581 parents with young children (≤5 years) who were enrolled in child maltreatment prevention programs. Results indicated that a parental history of ACEs can attenuate overall levels of protective factors, specifically resilience and social connections. Similar relationships were also found between demographic variables related to socioeconomic status, living arrangement, and some protective factors. Our preliminary findings support the need to screen at-risk parents for a history of ACEs. Directions for future research include study replication and the development of trauma-informed interventions meant to enhance these protective factors among at-risk parents with a history of ACEs.

Background Bilateral developmental dysplasia of the hip (DDH) is believed to have a worse outcome than unilateral DDH with the optimal treatment unclear. To define indications for treatment we report a retrospective series of 92 hips (46 patients) who underwent closed reduction (CR) and/or open reduction (OR). Methods A total of 58 hips in 29 patients underwent attempted CR using our standardized protocol. In the same 12 year time period, 54 hips in 27 patients underwent an OR. Outcome measures included resolution of acetabular dysplasia, need for further surgery, development of osteonecrosis (ON), and modified Severin Grade. Results CR was successful in 57% of hips; in this group secondary surgery was required in 15% and ON was seen in 12%. In the OR group, 11% failed to stabilize and required further early surgery: ON rate was 15% overall, and secondary surgery was required in 5%. In Tonnis 2/3 hips younger than 2 years, Severin grading was comparable following CR and OR, with 92% and 90% graded as Severin 1, respectively. The rate of significant ON was higher after CR in Tonnis 2/3 hips (12%) than after OR (0%). Overall, Tonnis 4 hips did badly: 94% failed CR and following OR, further surgery for redislocation/residual dysplasia was required in 21%. Conclusions CR can be successful in Tonnis 2/3 bilateral hips, with acceptable rates of secondary surgery, ON, and Severin grading, the latter equivalent to open reduction. Importantly, persisting with casting of a unilateral dislocation, to allow the contra-lateral hip to stabilize, does not have an adverse effect. CR is not advised in Tonnis 4 bilateral hips. Parents should be counseled that the outcome of surgery for bilateral hips is not as good as for unilateral DDH, particularly for Tonnis 4 hips which are more difficult to stabilize and more likely to require supplementary surgery even after open reduction. Level of evidence Level IV-Therapeutic Study.

Summary Background Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p Interpretation Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. Funding National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Some patients with severe and chronic pain fail to obtain adequate pain relief with standard pharmacologic treatment agents, including low to moderate dosages of opioids. Understandably, physicians might not believe patients who claim that a standard opioid dosage is an ineffective treatment. These patients may be severely impaired, nonfunctional, and bedridden or housebound. To help characterize these individuals and develop treatment strategies for them, a serum hormone profile consisting of adrenocorticotropin, cortisol, pregnenolone, progesterone, dehydroepiandrosterone, and testosterone was obtained on 61 chronic pain patients who failed standard treatments; 49 patients (80.3%) demonstrated ≥ 1 hormone abnormality defined as a serum concentration or level above or below the normal range, and 7 patients (11.5%) showed a severe pituitary-adrenal-gonadal deficiency as indicated by deficient serum levels of adrenocorticotropin and ≥ 2 adrenal-gonadal hormones. Hormone serum abnormalities are biomarkers of severe, uncontrolled pain, and, in a patient who has failed standard treatment, they are an indicator that enhanced analgesia is required and that hormone replacement may be indicated.

Our group recently identified a panel of ten genes whose RNA expression levels in whole blood have utility for detection of stroke. The purpose of this study was to determine the mechanisms by which these genes become differentially expressed during stroke pathology. First, we assessed the transcriptional distribution of the ten genes across the peripheral immune system by measuring their expression levels on isolated neutrophils, monocytes, B-lymphocytes, CD-4+ T-lymphocytes, CD-8+ T-lymphocytes, and NK-cells generated from the blood of healthy donors (n = 3). Then, we examined the relationship between the whole-blood expression levels of the ten genes and white blood cell counts in a cohort of acute ischemic stroke patients (n = 36) and acute stroke mimics (n = 15) recruited at emergency department admission. All ten genes displayed strong patterns of lineage-specific expression in our analysis of isolated leukocytes, and their whole-blood expression levels were correlated with white blood cell differential across the total patient population, suggesting that many of them are likely differentially expressed in whole blood during stroke as an artifact of stroke-induced shifts in leukocyte counts. Specifically, factor analysis inferred that over 50% of the collective variance in their whole-blood expression levels across the patient population was driven by underlying variance in white blood cell counts alone. However, the cumulative expression levels of the ten genes displayed a superior ability to discriminate between stroke patients and stroke mimics relative to white blood cell differential, suggesting that additional less prominent factors influence their expression levels which add to their diagnostic utility. These findings not only provide insight regarding this particular panel of ten genes, but also into the results of prior stroke transcriptomics studies performed in whole blood.

CD163 is a scavenger receptor expressed on innate immune cell populations which can be shed from the plasma membrane via the metalloprotease ADAM17 to generate a soluble peptide with lympho-inhibitory properties. The purpose of this study was to investigate CD163 as a possible effector of stroke-induced adaptive immune system suppression. Liquid biopsies were collected from ischemic stroke patients (n = 39), neurologically asymptomatic controls (n = 20), and stroke mimics (n = 20) within 24 hours of symptom onset. Peripheral blood ADAM17 activity and soluble CD163 levels were elevated in stroke patients relative to non-stroke control groups, and negatively associated with post-stroke lymphocyte counts. Subsequent in vitro experiments suggested that this stroke-induced elevation in circulating soluble CD163 likely originates from activated monocytic cells, as serum from stroke patients stimulated ADAM17-dependant CD163 shedding from healthy donor-derived monocytes. Additional in vitro experiments demonstrated that stroke-induced elevations in circulating soluble CD163 can elicit direct suppressive effects on the adaptive immune system, as serum from stroke patients inhibited the proliferation of healthy donor-derived lymphocytes, an effect which was attenuated following serum CD163 depletion. Collectively, these observations provide novel evidence that the innate immune system employs protective mechanisms aimed at mitigating the risk of post-stroke autoimmune complications driven by adaptive immune system overactivation, and that CD163 is key mediator of this phenomenon.

Our group recently identified 16 genes whose peripheral blood expression levels are differentially regulated in acute ischemic stroke. The purpose of this study was to determine whether the early expression levels of any of these 16 genes are predictive for post-stroke blood brain barrier (BBB) disruption. Transcriptional expression levels of candidate genes were measured in peripheral blood sampled from ischemic stroke patients at emergency department admission, and BBB permeability was assessed at 24 hour follow up via perfusion-weighted imaging. Early heightened expression levels of AKAP7, a gene encoding a protein kinase A-binding scaffolding molecule, were significantly associated with BBB disruption 24 hours post-hospital admission. We then determined that AKAP7 is predominantly expressed by lymphocytes in peripheral blood, and strongly co-expressed with ITGA3, a gene encoding the adhesion molecule integrin alpha 3. Subsequent in vitro experiments revealed that heightened expression of AKAP7 and ITGA3 in primary human lymphocytes is associated with a highly adherent phenotype. Collectively, our results suggest that AKAP7 expression levels may have clinical utility as a prognostic biomarker for post-stroke BBB complications, and are likely elevated early in patients who later develop post-stroke BBB disruption due to the presence of an invasive lymphocyte population in the peripheral blood.

Objective: The identification of stroke-associated biomarkers represents a means by which prehospital triage could be expedited to increase the probability of successful intervention. Thus, the objective of this work was to use high-throughput transcriptomics in combination with basic machine learning techniques to identify a pattern of gene expression in peripheral whole blood which could be used to identify acute ischemic stroke (AIS) in the acute care setting. Methods: A two-stage study design was used which included a discovery cohort and an independent validation cohort. In the discovery cohort, peripheral whole blood samples were obtained from 39 AIS patients upon emergency department admission, and from 24 neurologically asymptomatic controls. Microarray was used to measure the expression of over 22,000 genes and a pattern recognition technique known as genetic algorithm k-nearest neighbors (GA/kNN) identified a pattern of gene expression that optimally discriminated between AIS and controls. In an independent validation cohort, the gene expression pattern was tested for its ability to discriminate between 39 AIS patients and each of two different control groups, one consisting of 30 neurologically asymptomatic controls, and the other consisting of 15 stroke mimics, with gene expression levels being assessed by qRT-PCR. Results: In the discovery cohort, GA/kNN identified ten transcripts (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B, and PLXDC2) whose coordinate pattern of expression correctly identified 98.4% of subjects (97.4% sensitive, 100% specific). In the validation cohort, the same 10 transcripts correctly identified 95.6% of subjects when comparing AIS patients to asymptomatic controls (92.3% sensitive, 100% specific), and 96.3% of subjects when comparing AIS patients to stroke mimics (97.4% specific, 93.3% sensitive). Conclusion: These results demonstrate that a highly accurate RNA-based companion diagnostic for AIS is plausible using a relatively small number of markers. The pattern of gene expression identified in this study shows strong diagnostic potential, and warrants further evaluation to determine true clinical efficacy.

Early and accurate diagnosis of stroke improves the probability of positive outcome. The objective of this study was to identify a pattern of gene expression in peripheral blood that could potentially be optimised to expedite the diagnosis of acute ischaemic stroke (AIS). A discovery cohort was recruited consisting of 39 AIS patients and 24 neurologically asymptomatic controls. Peripheral blood was sampled at emergency department admission, and genome-wide expression profiling was performed via microarray. A machine-learning technique known as genetic algorithm k-nearest neighbours (GA/kNN) was then used to identify a pattern of gene expression that could optimally discriminate between groups. This pattern of expression was then assessed via qRT-PCR in an independent validation cohort, where it was evaluated for its ability to discriminate between an additional 39 AIS patients and 30 neurologically asymptomatic controls, as well as 20 acute stroke mimics. GA/kNN identified 10 genes (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B and PLXDC2) whose coordinate pattern of expression was able to identify 98.4% of discovery cohort subjects correctly (97.4% sensitive, 100% specific). In the validation cohort, the expression levels of the same 10 genes were able to identify 95.6% of subjects correctly when comparing AIS patients to asymptomatic controls (92.3% sensitive, 100% specific), and 94.9% of subjects correctly when comparing AIS patients with stroke mimics (97.4% sensitive, 90.0% specific). The transcriptional pattern identified in this study shows strong diagnostic potential, and warrants further evaluation to determine its true clinical efficacy.

Compared to other megafauna managed in zoos and aquariums, the current state of welfare for the Nile hippopotamus (Hippopotamus amphibius) is poorly understood. Complex behavior and physiological characteristics make hippos a difficult species to manage. Thus, hippos in managed care are currently at risk for a decreased state of welfare. In an effort to assess and improve conditions for this species, a survey was administered to North American institutions housing Nile hippos. This assessment utilized a multiple-choice format and consisted of questions relating to group structure, behavior, and exhibit design, allowing for the creation of cross-institutional, welfare-based analysis. Responses were gathered from 85.29% of the institutions to which the survey was distributed. Despite recommendations for maintaining groups of at least five individuals (Forthman, 1998), only 34.25% of hippos in North America were housed in groups of three or more. The survey also highlighted that 39.29% of institutions secure their hippos in holding areas overnight, despite their highly active nocturnal propensities. A better understanding of hippo behavior and environmental preferences can be used to inform wellness-oriented management practices to achieve a state of "optimal welfare".

Background: Depression is a leading cause of disability post-stroke. Nearly a third of stroke victims suffer from depression after event occurrence. Post-stroke depression hinders physical rehabilitation, decreases quality of life, and has a negative effect on long-term survivability. Inflammatory processes post-ischemic stroke are likely associated with the development of depression. The neutrophil-lymphocyte ratio (NLR) is a routinely available marker of systemic inflammation and could serve as a prognostic tool at hospital admission for post-stroke depression. The goal of this project was to determine the relationship between admission NLR and depression 30 and 90 days post-stroke. Methods: 58 ischemic stroke patients were recruited from a regional primary stroke center and followed up to 90 days post stroke. NLR levels were drawn at Emergency Department admission and at 24 hours. The Quick Inventory for Depression Symptomology (QIDS) was used to measure depression symptoms at 24 hours, 30 days and 90 days post stroke. We scaled continuous variables by their standard deviation and used the Box-Cox or exponential transformation if the skew was greater than 0.5. An age-adjusted Pearson's correlation was utilized to assess bivariate relationships. Other methods used include Mann-Whitney-Wilcoxon test and Fisher's Exact test when appropriate to compare ischemic and non-stroke patients. Results: Adjustments for age were included due to weak to strong correlations with various measures of NLR and QIDS. There is a statistically significant correlation between the baseline NLR and baseline QIDS (correlation = -0.54, p-value=0.013) and QIDS at 30 days (correlation=-0.67, p-value=0.028). NLR at 24 hours has a statistically moderate correlation with QID at 30 days (correlation=0.39, p-value=0.055) and QIDS at 90 days (correlation=0.36, p-value=0.134). Conclusions: This preliminary study suggests that NLR at hospital admission could serve as a prognostic marker of post stroke depression at thirty days. Utilization of this marker in clinical practice for stroke care could identify high risk patients and result in earlier treatment of depression. Validation studies and preventative strategies will need to be explored in future studies.

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.

Background Supracondylar fractures of the humerus are common pediatric elbow injuries. Most displaced or angulated fractures are treated by closed reduction and percutaneous pinning, with either a crossed pin or lateral pin configuration. The purpose of this study was to conduct a systematic review to determine if there is an increased risk of iatrogenic nerve injury associated with the crossed pin configuration. Methods Relevant articles were identified by searching electronic databases and hand searching-related journal and conference proceedings. Within each trial, the risk of iatrogenic ulnar nerve injury was calculated for each pinning technique. For studies comparing crossed versus lateral pinning, the resulting trial-based differences in risk estimates were pooled using a random effects meta-analysis. A number needed to harm was determined using the pooled risk difference. Results Thirty-two trials consisting of 2639 patients were used in the pooled analysis. The pooled risk difference of iatrogenic ulnar nerve injury is 0.035 (95% confidence interval, 0.014-0.056), with a higher incidence of injury in the crossed pinning group. The weighed number needed to harm for the crossed pinning is 28 (95% confidence interval, 17-71). Conclusions The results of this review suggest that there is an iatrogenic ulnar nerve injury for every 28 patients treated with the crossed pinning compared with the lateral pinning. Further research is necessary to ensure that the optimal pinning technique is chosen to treat these factors. Level of evidence Level III.

This article attempts to define normal development throughout childhood and provide straightforward advice in the physical assessment of the child in this situation. It also attempts to outline the groups of conditions that lead to walking abnormalities and highlight the salient physical features and special investigations that are required to make these diagnoses with confidence.

Whilst most humeral fractures may be treated by closed methods, humeral nailing has gained popularity where a surgical option is indicated. Concern has been expressed regarding placement of proximal and distal locking screws whilst the efficiency of the ingenious intra-medullary locking device of the Seidel nail has also been questioned. The Marchetti–Vincenzi nail, which “locks” proximally with the spreading of intra-medullary pins and distally with a single screw inserted via the surgical wound, apparently avoids potential neurovascular and tendon injury. Prospectively recorded data was analysed in 19 “fresh” fractures, i.e. within 3 weeks of injury, and in 13 “late” fractures (total of 32 humeral fractures) treated with the Marchetti nail. All fresh fractures thus treated progressed to union, whilst in the late fracture group there were three non-unions all of whom were in osteoprotic females. Whilst we commend the use of the Marchetti humeral nail in fresh fractures, we have reservations about its use in “late” fractures particularly where the patient is female and osteoporotic.

Purpose of the study Using retrospective global reports, studies have found that middle-aged adults in the United States provide intermittent support to their aging parents and more frequent support to grown children. To date, studies have not examined support middle-aged adults provide to different generations on a daily basis. Daily support may include mundane everyday exchanges that may (or may not) affect well-being. Design and methods Middle-aged adults (N = 191, mean age 55.93) completed a general interview regarding family ties, followed by interviews each day for 7 days (N = 1,261 days). Daily interviews assessed support (e.g., advice, emotional, practical help) participants provided each grown child (n = 454) and aging parent (n = 253). Participants also reported daily mood. Results Most participants provided emotional support (80%), advice (87%), and practical help (69%) to a grown child and also provided emotional support (61%) and advice (61%) or practical help (43%) to a parent that week. Multilevel models confirmed generational differences; grown children were more likely to receive everyday support than parents. Providing support to grown children was associated with positive mood, whereas providing support to parents was associated with more negative mood. Implications Daily intergenerational support was more common than studies using global reports of support have found. Some daily support may be fleeting and not stand out in memory. The findings were consistent with the intergenerational stake hypothesis, which suggests middle-aged adults are more invested in their grown children than in their parents. Nonetheless, middle-aged adults were highly involved with aging parents.

Fractures of the foot and ankle are not commonly seen in children. However correct management is necessary to prevent potential complications such as long-term articular damage,growtharrest,andevenavascularnecrosis. This chapter summarises the main principles of management of the most important foot and ankle fractures, emphasizing indications for operative intervention where appropriate and summarising possible techniques.

Over 90% of intravenous heroin addicts (IVHAs) carry the hepatitis C virus (HCV). The other hepatitis viruses, A, B, D, and G are relatively unimportant in IVHAs compared to HCV although active hepatitis B may demonstrate a chronic, degenerative course identical to that of HCV. The clinical course of HCV and active hepatitis B may span three or more decades. It is helpful to classify patients as in the active, cirrhosis, or liver failure stages. Only in the active, early stage are the liver enzymes, ALT and AST, likely to be elevated. It is this stage that will most likely respond to antiviral therapy. HCV has so many extra-hepatic manifestations including immune suppression, collagen diseases, and possibly lymphoma and leukemia that the disease is best termed HCV syndrome rather than simple hepatitis.

Conventional methods of imaging in the investigation of developmental dysplasia of the hip all have disadvantages, either in definition or in exposure to radiation. We describe a new open-configuration MR scanner which is unique in that it allows anaesthesia and access to the patient within the imaging volume for surgical procedures and application of casts. We performed 13 scans in eight anaesthetised infants. Dynamic imaging revealed two dislocated hips which were then visualised during reduction. Hip spicas were applied without removing the patient from the scanner. In one hip, an adductor tenotomy was carried out. In all patients, stressing the hips during dynamic imaging allowed an assessment of stability. This was particularly useful in two hips in which an analysis of stability in different positions facilitated the planning of femoral osteotomies. This method of imaging provides new and important information. It has great potential in the investigation of developmental dysplasia of the hip and, with ultrasound, may allow management without the need for radiography.

Peripheral conversion of gender steroid precursors has been implicated in playing a role in bone turnover in postmenopausal women. It has been reported that aromatase cytochrome P450 (P450arom) is present in primary bone and bone marrow (BM), and that P450arom mRNA has been identified in cultured BM and osteoblast-like cell lines. However, there are no reports that P450arom transcripts have been detected in skeletal tissue that has not been cultured. We therefore elected to test for the presence of P450arom mRNA in primary human bone and BM in normal and fractured necks of femora using the reverse transcription-polymerase chain reaction method. Although the RNA extracted from these tissues was of good quality as demonstrated by the expression of transcripts for interleukin-6, P450arom transcripts failed to be detected in normal primary cortical bone and fatty BM containing trabecular bone. However, P450arom transcripts were detected in the latter when they were cultured. Transcripts for P450arom were also detected in total RNA extracted from six fractured necks of femora and semiquantitative PCR demonstrated that P450arom mRNA was present in similar abundance in the same amount of RNA analyzed from buttock adipose tissue and fractured bone/BM. P450arom mRNA expression was also detected in cultured peripheral blood leukocytes, suggesting that this might be the source of the enzyme. In these cultures no correlation was detected between the expression of P450arom mRNA and cell proliferation. PCR failure was excluded in cases when P450arom transcripts failed to be detected in bone/BM by coamplifying RNA from human and rat brain mRNA, known to express P450arom mRNA, using primers that detect both P450arom mRNA from both species. These products were analyzed by Southern blot using oligonucleotide probes, which label either human or rat P450arom cDNA. The blots confirmed the absence of P450arom in nonfractured human bone and BM and preclude PCR failure. Our results indicate that P450arom mRNA is not detected in either normal human bone or BM, but can be induced in this microenvironment under pathological conditions. We propose that tissue grown in vitro is analogous to a wound and this explains why P450arom transcripts were detected in cultured normal skeletal tissue, whereas they failed to be detected in primary normal bone and BM.

Cocaine abuse in methadone maintenance patients has emerged as a significant clinical problem. To determine if raising the daily methadone dosage is an effective way to eliminate cocaine abuse, 74 methadone maintenance patients maintained at daily dosages between 30 and 80 mg and who chronically abused cocaine were studied by a standard protocol. A total of 21 (28.4%) subjects ceased cocaine abuse when their methadone dosage was progressively raised to a maximal daily dose of 160 mg. Cocaine abuse appeared to accelerate elimination of methadone, since inadequate methadone serum concentrations (below 100 ng/ml) were found in 48 of 67 (71.6%) subjects tested 24 hours after a 100 mg oral methadone dose. Although cocaine abuse in methadone maintenance patients may respond to raising the daily methadone dosage, alternative treatments for cocaine abuse in methadone maintenance patients must be identified since cocaine abuse may lower serum methadone concentrations.

This open-label study was done to determine which of several recommended agents and rationales may be effective for outpatient detoxification of cocaine dependence. A total of 324 cocaine-dependent persons were sequentially assigned to subgroups of 8-23 subjects and detoxified with 20 different treatment agents. Subjects who received each treatment agent were compared to a control group of 18 subjects who received only placebo and amino acids. Fourteen of the 20 agents (70%) appeared inappropriate for outpatient cocaine detoxification because they demonstrated intolerable side effects, a first-week drop-out rate over 40%, or failed to reduce urine cocaine metabolite concentrations. Cocaine use appeared to increase with bromocriptine mesylate, levodopa, and phenmetrazine hydrochloride, since mean cocaine urine concentration increased during treatment. Although no agent was statistically superior in performance to the placebo (control) group on any evaluation criterion, amantadine hydrochloride, bupropion h...

Individuals with diabetic retinopathy (DR) represent a high-risk group who would benefit from intensive metabolic control and risk factor management. This brief report examines quality of care among diabetic patients attending a tertiary retinal clinic.A cross-sectional survey, notes review, and slit-lamp examination was conducted in 139 diabetic patients attending a specialist retinal clinic to assess the quality of comprehensive diabetes care. DR was graded according to the Early Treatment Diabetic Retinopathy Study scale.The prevalence of non-proliferative DR (NPDR) and proliferative DR (PDR) was 39.6 and 35.2%, respectively. The prevalence of microalbuminuria in patients with no DR, NPDR and PDR was 32, 54.1 and 68.8%, respectively. Glycaemic control was suboptimal (mean HbA(1c) 8.0 +/- 1.8%) and 15.8% were current smokers. Drugs affecting the renin-angiotensin system were used by only 61.9% of patients with both DR and microalbuminuria, and aspirin by only 35.3%.These data suggest that diabetes care in this high-risk population with established microvascular complications was suboptimal. Specialist clinics dealing with diabetic complications may be a setting where quality improvement strategies to reduce morbidity and mortality should be focused.