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Background: Approximately, 10% of people report a penicillin allergy; however, more than 90% can safely undergo delabeling after a detailed history, oral challenge, or other investigations such as penicillin skin testing (PST). Although PST is the gold standard, the results can be heterogeneous, and awaiting specialist assessment may take an inordinate amount of time. Therefore, oral provocation challenge has become acceptable for individuals with low-risk penicillin allergy histories. There also appears to be an association with increased prevalence of adverse drug reaction reporting in female individuals, which may translate to penicillin allergy prevalence; however, the evidence has not been assessed through a sex and gender lens. This systematic review will identify and synthesize the findings from studies that report measures of effectiveness and safety of interventions aimed at delabeling penicillin allergies in low-risk individuals. Information related to sex and gender will be extracted, where available, to understand potential differences in allergy reporting and patient outcomes., Methods: The Cochrane Handbook for Systematic Reviews of Interventions and the Centre for Review and Dissemination's Guidance for Undertaking Reviews in Health Care will be used as frameworks for conducting this systematic review. The literature search will be conducted by a medical librarian (B. M. M.) and will consist of a search strategy to identify and retrieve published studies that meet our inclusion criteria. Studies that require penicillin skin testing (PST) as a step prior to other interventions will be excluded. Integrated knowledge translation involving co-design was carried out for this systematic review protocol creation. Data extraction will be conducted at four levels: (1) study level, (2) patient level, (3) intervention level, and (4) outcome level. A narrative descriptive synthesis of results and risk of bias of all included studies will be provided, and, if relevant, a meta-analysis will be performed., Discussion: The dissemination of findings from this knowledge synthesis to various stakeholders is intended to inform on options for evidence-based interventions to aid in delabeling penicillin allergies in individuals with a low risk of experiencing a hypersensitivity reaction. Detailed reporting on the characteristics of delabeling interventions as well as the effectiveness of similar interventions will benefit policy makers considering the implementation of a penicillin allergy delabeling protocol. Additionally, findings from this systematic review will report on the current evidence regarding the role of sex and gender in both the prevalence and outcomes associated with the presence of penicillin allergies., Systematic Review Registration: PROSPERO CRD42022336457., (© 2024. The Author(s).)

Peripheral edema is a prevalent condition affecting patients dealing with an assortment of health conditions, such as congestive heart failure (CHF), liver disease, venous insufficiency, and postoperative surgical complications. Edema can present in a variety of ways, ranging from mild localized symptoms to severely debilitating forms that impact patients' daily lives. Despite the vast number of publications addressing the underlying causes of peripheral edema, there seems to be an absence of literature that presents the effectiveness and compliance of current management techniques. This paper aims to condense the current literature on the effectiveness and compliance of current edema management approaches across various common etiologies, with the intention of identifying alternative therapies that could enhance the quality of care for patients with chronic lower extremity edema. Several promising new therapies such as exogenous calf muscle stimulation, leg raise exercises, high-dose albumin injections, and device-based negative pressure lymph drainage (NPLD), deviate from the current established standard of care. This scoping review revealed diverse treatment methods tailored to the specific underlying etiology of edema. The use of diuretics and vasodilators has shown benefits in treating CHF-induced edema but failed to alleviate and prevent the recurrence of edema in hospitalized and recently discharged patients. Albumin injections have emerged as a potential alternative treatment for edema due to liver disease, addressing hypoalbuminemia symptoms caused by liver failure. Patients with vascular causes of edema are efficaciously treated conservatively with compression stockings, although patient adherence remains a hurdle. For postoperative edema, device-based NPLD appears promising, with potential benefits over elastic bandage wraps and kinesiology taping., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Smith et al.)

Harmful algal bloom (HAB) toxins consumed by marine predators through fish prey can be lethal but studies on the resulting population consequences are lacking. Over the past approximately 20 years there have been large regional declines in some harbour seal populations around Scotland. Analyses of excreta (faeces and urine from live and dead seals and faecal samples from seal haulout sites) suggest widespread exposure to toxins through the ingestion of contaminated prey. A risk assessment model, incorporating concentrations of the two major HAB toxins found in seal prey around Scotland (domoic acid (DA), and saxitoxins (STX)), the seasonal persistence of the toxins in the fish and the foraging patterns of harbour seals were used to estimate the proportion of adults and juveniles likely to have ingested doses above various estimated toxicity thresholds. The results were highly dependent on toxin type, persistence, and foraging regime as well as age class, all of which affected the proportion of exposed animals exceeding toxicity thresholds. In this preliminary model STX exposure was unlikely to result in mortalities. Modelled DA exposure resulted in doses above an estimated lethal threshold of 1900 µg/kg body mass affecting up to 3.8 % of exposed juveniles and 5.3 % of exposed adults. Given the uncertainty in the model parameters and the limitations of the data these conclusions should be treated with caution, but they indicate that DA remains a potential factor involved in the regional declines of harbour seals. Similar risks may be experienced by other top predators, including small cetaceans and seabirds that feed on similar prey in Scottish waters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Participating in physical activity benefits health, yet a majority of children remain inactive. The Daily Mile™ (TDM) originated in Scotland in 2012 with the aim of increasing primary school children's physical fitness. Despite being a practically feasible and popular initiative, it remains unclear the extent to which schools implement TDM, and whether TDM core principles are adhered to (i.e., run or jog at least 3-days per week). In Northern Ireland it is unknown how many schools regularly participate in TDM, and whether there is an association between TDM participation with school type, school location, size, total number of children attending the school, school deprivation level, and/or motivation as measured by the COM-B model (Capabilities, Opportunities, Motivation model of behaviour). Therefore, this study aimed to quantify the uptake of TDM in Northern Ireland, assess whether schools are following the core principles, and analyse if there is an association between aforesaid demographic factors and TDM participation., Methods: An online cross-sectional survey was sent to all primary and special education schools in Northern Ireland with the support of the Education Authority for Northern Ireland and the Public Health Agency for Northern Ireland. The survey was completed by the school principal or teacher, and was available from 31st August until 16th December 2022. Survey results were linked with the 2021/2022 Northern Ireland School Census Data and Northern Ireland Multiple Deprivation Measure 2017. Quantitative and qualitative questions were included in the survey to assess participation and implementation of TDM., Results: The survey received 609 school responses. After data cleaning, and removal of duplicates from schools a sample of 358 primary schools (45%) and 19 special education schools (47.5%) was analysed. Over half (54.7%) of primary schools and 36.8% of special education schools reported taking part in TDM. More special education needs schools reported taking part in their own version of an 'active mile' rather than TDM formally, and qualitative findings showed TDM was not perceived as appropriate for many children in special educational settings. There was wide variation in adherence to TDM core principles. A multivariate binary logistic regression model was fitted to the data, but it was not statistically significant (χ2(17) = 22.689, p = .160). However, univariate effects showed that increasing levels on COM-B (Capability) was associated with increased likelihood of TDM participation (OR = 2.506), and Catholic Maintained schools were almost twice as likely as Controlled schools to be delivering TDM (OR = 1.919). There was no association found between deprivation and TDM uptake., Conclusion: Encouragingly over 50% of schools in Northern Ireland reported taking part in TDM. However, despite being a low-cost and practically feasible physical activity initiative, further intervention work with sound research methodology is needed to promote adherence to TDM core principles to maximise benefits to children's health. Furthermore, concerted efforts are required to adjust TDM so that it is inclusive for all educational settings, and children's abilities., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors are members of The Daily Mile Network Northern Ireland. We can confirm that our membership of the Daily Mile Network Northern Ireland does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Breslin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Maternal mental health problems are experienced frequently in the perinatal period and can be up to twice as common in women from low- and middle-income countries. The terms used to describe mental illness symptoms and the factors that contribute to developing these symptoms are affected by culture and context. Based on 14 focus group discussions held with pregnant women, health professionals and cultural leaders, this qualitative study aimed to understand women's experiences of mental distress during the perinatal period in The Gambia. To do this it aimed to 1) identify the most commonly used idioms of distress, 2) identify the factors believed to affect women's perinatal mental health and 3) explore the role of existing cultural practices, including musical practices, that were identified as locally significant in supporting maternal and mental health. Sondomoo tenkung baliyaa (Mandinka) and xel bu dalut (Wolof) were identified as the most commonly used idioms of distress which roughly translate to lack of a steady mind/heart. Using thematic analysis, six themes (Poverty of the healthcare system, Shifting cultural context, Economic factors, Social factors, Spiritual factors, and Cultural practices involving music) were identified to describe the factors that shape women's experience of mental health during the perinatal period. Lack of economic resources, the prevailing poverty of the health system, an unsupportive husband and spiritual attack by evil spirits or witches were common reasons given for a woman experiencing maternal mental distress. Various existing cultural practices involving music, such as fertility societies, naming ceremonies and community music-making, were recognised as valuable for supporting women's mental health during the perinatal period. This work emphasises that initiatives to support perinatal mental health should be grounded in an understanding of local community cultural practices, knowledge, and experiences., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sanfilippo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pulmonary vasodilator therapy in Fontan patients can improve exercise tolerance. We aimed to assess the potential for non-invasive testing of acute vasodilator response using four-dimensional (D) flow MRI during oxygen inhalation., Materials and Methods: Six patients with well-functioning Fontan circulations were prospectively recruited and underwent cardiac MRI. Ventricular anatomical imaging and 4D Flow MRI were acquired at baseline and during inhalation of oxygen. Data were compared with six age-matched healthy volunteers with 4D Flow MRI scans acquired at baseline., Results: All six patients tolerated the MRI scan well. The dominant ventricle had a left ventricular morphology in all cases. On 4D Flow MRI assessment, two patients (Patients 2 and 6) showed improved cardiac filling with improved preload during oxygen administration, increased mitral inflow, increased maximum E-wave kinetic energy, and decreased systolic peak kinetic energy. Patient 1 showed improved preload only. Patient 5 showed no change, and patient 3 had equivocal results. Patient 4, however, showed a decrease in preload and cardiac filling/function with oxygen., Discussion: Using oxygen as a pulmonary vasodilator to assess increased pulmonary venous return as a marker for positive acute vasodilator response would provide pre-treatment assessment in a more physiological state - the awake patient. This proof-of-concept study showed that it is well tolerated and has shown changes in some stable patients with a Fontan circulation.

Objectives: It is important to be able to detect symptoms of common mental disorders (CMDs) in pregnant women. However, the expression of these disorders can differ across cultures and depend on the specific scale used. This study aimed to (a) compare Gambian pregnant women's responses to the Edinburgh Postnatal Depression Scale (EPDS) and Self-reporting Questionnaire (SRQ-20) and (b) compare responses to the EPDS in pregnant women in The Gambia and UK., Design: This cross-sectional comparison study investigates Gambian EPDS and SRQ-20 scores through correlation between the two scales, score distributions, proportion of women with high levels of symptoms, and descriptive item analysis. Comparisons between the UK and Gambian EPDS scores were made by investigating score distributions, proportion of women with high levels of symptoms, and descriptive item analysis., Setting: This study took place in The Gambia, West Africa and London, UK., Participants: 221 pregnant women from The Gambia completed both the SRQ-20 and the EPDS; 368 pregnant women from the UK completed the EPDS., Results: Gambian participants' EPDS and SRQ-20 scores were significantly moderately correlated (r s =0.6, p<0.001), had different distributions, 54% overall agreement, and different proportions of women identified as having high levels of symptoms (SRQ-20=42% vs EPDS=5% using highest cut-off score). UK participants had higher EPDS scores (M=6.5, 95% CI (6.1 to 6.9)) than Gambian participants (M=4.4, 95% CI (3.9 to 4.9)) (p<0.001, 95% CIs (-3.0 to -1.0), Cliff's delta = -0.3)., Conclusions: The differences in scores from Gambian pregnant women to the EPDS and SRQ-20 and the different EPDS responses between pregnant women in the UK and The Gambia further emphasise how methods and understanding around measuring perinatal mental health symptoms developed in Western countries need to be applied with care in other cultures.Cite Now., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: A minority of children in the United Kingdom meet the recommended physical activity guidelines. One initiative which has been introduced to try and increase the physical activity levels of school children is The Daily Mile™ (TDM). The aim of this review was to determine the effect of TDM on children's physical activity levels, physical health, mental health, wellbeing, academic performance and cognitive function., Methods: Six databases were systematically searched from TDM's inception (2012) to 30th June 2022. Studies were included if they involved school-aged children (aged 4-12 years), taking part in TDM and measured at least one pre-defined outcome., Results: Thirteen studies were included from the 123 studies retrieved. Longer-term participation in TDM was found to increase moderate-to-vigorous physical activity and physical fitness. None of the studies reported a significant change in Body Mass Index or academic performance. An acute bout of TDM was not found to improve cognitive function, however one good-quality study reported that longer-term participation in TDM increased visual spatial working memory. There was evidence from one fair-quality design study that TDM can improve mental health in the short term. There were no significant effects on wellbeing, however scores on self-perceptions improved mainly for children with low baseline self-perceptions., Conclusion: There is evidence to show that TDM can increase physical activity and physical fitness. However, higher-quality research, with adequate participant randomisation and longer-term, post-intervention follow-up is needed to ensure that any changes accurately reflect the components of TDM and are sustained beyond an intervention time frame. Policy recommendations of TDM increasing PA levels in the short term are supported by the evidence in this review. However, long-term improvement on mental health, wellbeing, academic performance and cognitive function requires further good-to excellent quality research. Promisingly, several protocol articles that include randomised controlled trials with long term follow-up have been published. These higher-quality design studies may provide a stronger evidence-base on the effects of TDM on children's health and should underpin future recommendations in public health policy., Systematic Review Registration: PROSPERO CRD42022340303., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors are members of The Daily Mile Network Northern Ireland. We can confirm that our membership of the Daily Mile Network Northern Ireland does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Breslin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Microduplication of the LCR22-A to LCR22-D region on chromosome 22q11.2 is a recurrent copy number variant found in clinical populations undergoing chromosomal microarray, and at lower frequency in controls. Often inherited, there is limited data on intellectual (IQ) and psychological functioning, particularly in those individuals ascertained through a family member rather than because of neurodevelopmental disorders. To investigate the range of cognitive-behavioral phenotypes associated with 22q11.2 duplication, we studied both probands and their non-proband carrier relatives. Twenty-two individuals with 22q11.2 duplication (10 probands, 12 non-proband carriers) were prospectively assessed with a battery of neuropsychological tests, physical examination, and medical record review. Assessment measures with standardized norms included IQ, academic, adaptive, psychiatric, behavioral, and social functioning. IQ and academic skills were within the average range, with a trend toward lower scores in probands versus non-probands. Adaptive skills were within age expectations. Prevalence of attention deficits (probands only) and anxiety (both groups) was high compared with norms. The prevalence of autism spectrum disorder was relatively low (5% of total sample). Assessment of both probands and non-probands with 22q11.2 duplication suggests that the phenotypic spectrum with respect to neurodevelopment overlaps significantly with the general population. IQ and academic abilities are in the average range for most of the individuals with 22q11.2 duplication in our study, regardless of ascertainment as a proband or non-proband relative. Symptoms of attention deficit and anxiety were identified, which require further study. Results of this study further clarify the phenotype of individuals with 22q11.2 duplication, and provides important information for genetic counseling regarding this recurrent copy number variant., (© 2022 Wiley Periodicals LLC.)

Introduction: Dialectical behaviour therapy (DBT) is a well-known intervention for treating borderline personality disorder, and has been increasingly adapted for other disorders. Standard DBT consists of four treatment modes, delivered over a year. Adaptations to DBT include changes to modes of delivery, treatment length, and skills modules taught to clients, or incorporating interventions from other evidence-based therapies. There is a need to synthesise existing evidence on DBT so that stakeholders-clinicians, researchers and policymakers-can understand how it has been provided for various psychiatric conditions, and whether it has been effective., Methods and Analysis: This study proposes a scoping review conducted according to Arksey and O'Malley's (2005) procedures, to map and summarise the literature on DBT interventions for treating a range of psychiatric concerns. Electronic databases (ie, the Cochrane Central Register of Controlled Trials, PubMed, PsycINFO, SCOPUS, EBSCOhost and ProQuest Dissertations and Theses), conference proceedings and the US National Institutes of Health Ongoing Trial Register will be searched for intervention studies that involve a control or comparison group, and that report quantitative data on pre/post-measures for psychiatric symptom severity. The initial search was conducted on 18 September 2020, and data charting has not commenced. An update will be performed in September 2022, pending this protocol's publication. Data charting will collect individual studies' characteristics, methodology and reported findings. Outcomes will be reported by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for Scoping Reviews., Ethics and Dissemination: No ethical approval is required for this study. The goal of dissemination is to keep DBT stakeholders abreast on latest updates in clinical applications of DBT. Findings from this research are intended to inform a more specific topic of study (eg, a meta-analysis), to further aid in the development of DBT interventions for psychiatric populations., Registration Details: The study protocol was pre-registered with the Open Science Framework on 24 August 2021 (https://osf.io/vx6gw)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Seasonal windows of opportunity are intervals within a year that provide improved prospects for growth, survival, or reproduction. However, few studies have sufficient temporal resolution to examine how multiple factors combine to constrain the seasonal timing and extent of developmental opportunities. Here, we document seasonal changes in milkweed ( Asclepias fascicularis )-monarch ( Danaus plexippus ) interactions with high resolution throughout the last three breeding seasons prior to a precipitous single-year decline in the western monarch population. Our results show early- and late-season windows of opportunity for monarch recruitment that were constrained by different combinations of factors. Early-season windows of opportunity were characterized by high egg densities and low survival on a select subset of host plants, consistent with the hypothesis that early-spring migrant female monarchs select earlier-emerging plants to balance a seasonal trade-off between increasing host plant quantity and decreasing host plant quality. Late-season windows of opportunity were coincident with the initiation of host plant senescence, and caterpillar success was negatively correlated with heatwave exposure, consistent with the hypothesis that late-season windows were constrained by plant defense traits and thermal stress. Throughout this study, climatic and microclimatic variations played a foundational role in the timing and success of monarch developmental windows by affecting bottom-up, top-down, and abiotic limitations. More exposed microclimates were associated with higher developmental success during cooler conditions, and more shaded microclimates were associated with higher developmental success during warmer conditions, suggesting that habitat heterogeneity could buffer the effects of climatic variation. Together, these findings show an important dimension of seasonal change in milkweed-monarch interactions and illustrate how different biotic and abiotic factors can limit the developmental success of monarchs across the breeding season. These results also suggest the potential for seasonal sequences of favorable or unfavorable conditions across the breeding range to strongly affect monarch population dynamics., Competing Interests: The authors' contributions are described according to ANSI/NISO standard Contributor Roles Taxonomy (CRediT) in the Supporting Information. The authors declare that they have no conflicts of interest., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Up to 40% of dementias may be preventable via risk factor modification. This inference has motivated the development of lifestyle interventions for reducing cognitive decline. Typically delivered to older adults face-to-face, the COVID-19 pandemic has necessitated their adaptation for remote delivery. We systematically reviewed randomized controlled trials of remotely delivered lifestyle interventions (≥4 weeks duration and delivered >50% remotely), for adults aged ≥ 60 without dementia, examining effects on objective cognitive measures. Comparators were active (face-to-face or remote) or passive. Ten studies (n = 2967) comprising multidomain (k = 4), physical activity (k = 3) or psychosocial (k = 3) remote interventions were included. Data were synthesized using robust variance estimation meta-analysis. The pooled estimate comparing the effect of remote interventions versus comparators on cognition was not significant (g=-0.02; 95%CI [-0.14, 0.09]; p = .66); subgroup analyses by type of intervention or comparator also yielded non-significant effects. Most studies had low risk of bias. Current evidence to support remote lifestyle interventions is limited. Included studies were conducted pre-pandemic, and evaluated individual, rather than group interventions. Future studies may exploit the greater digital connectivity of older people since the pandemic. Group formats, more frequently efficacious than individual interventions in face-to-face dementia prevention trials, may be a rational approach for future remote trials., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: Human milk oligosaccharides (HMOs) impact the intestinal microbiota by increasing beneficial bacteria in infants and adults, and are safe and well tolerated in these age groups. Effects on intestinal microbiota, safety, and digestive tolerance in children have not been, however, assessed. The aims of this trial were to evaluate if HMOs are able to specifically modulate the intestinal microbiota in children, and to assess safety and digestive tolerance., Methods: In this randomized, double-blinded, placebo-controlled trial, 75 children with overweight (including obesity) ages 6 to 12 years were randomized to receive 2'-fucosyllactose (2'FL), a mix of 2'FL and lacto-N-neotetraose (Mix), or a glucose placebo orally administrated once per day for 8 weeks., Results: The relative abundance of bifidobacteria increased significantly after 4 (P < 0.001) and 8 (P = 0.025) weeks of intervention in the 2'FL-group and after 4 weeks (P = 0.033) in the Mix-group, whereas no change was observed in the placebo group. Compared with placebo, the 2'FL-group had a significant increase in bifidobacteria abundance after 4 weeks (P < 0.001) and 8 weeks (P = 0.010) and the Mix-group showed a tendency to increased bifidobacteria abundance after 4 (P = 0.071) and 8 weeks (P = 0.071). Bifidobacterium adolescentis drove the bifidogenic effect in the 2 groups. Biochemical markers indicated no safety concerns, and the products did not induce digestive tolerance issues as assessed by Gastrointestinal Symptoms Rating Scale and Bristol Stool Form Scale., Conclusions: Both 2'FL and the Mix beneficially modulate intestinal microbiota by increasing bifidobacteria. Furthermore, supplementation with either 2'FL alone or a Mix is safe and well tolerated in children., Competing Interests: L.K.V., I.D.A., and B.M. were employed at Glycom A/S, Denmark. The remaining authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Clostridioides difficile (formerly Clostridium difficile ) infection (CDI) is one of the most common hospital-acquired infections, which is often triggered by a dysbiosed indigenous gut microbiota (e.g., upon antibiotic therapy). Symptoms can be as severe as life-threatening colitis. The current study assessed the antipathogenic potential of human milk oligosaccharides (HMOs), i.e., 2'-O-fucosyllactose (2'FL), lacto-N-neotetraose (LNnT), and a combination thereof (MIX), against C. difficile ATCC 9689 using in vitro gut models that allowed the evaluation of both direct and, upon microbiota modulation, indirect effects. During a first 48 h fecal batch study, dysbiosis and CDI were induced by dilution of the fecal inoculum. For each of the three donors tested, C. difficile levels strongly decreased (with >4 log CFU/mL) upon treatment with 2'FL, LNnT and MIX versus untreated blanks, coinciding with increased acetate/ Bifidobacteriaceae levels. Interindividual differences among donors at an intermediate time point suggested that the antimicrobial effect was microbiota-mediated rather than being a direct effect of the HMOs. During a subsequent 11 week study with the Pathogut TM model (specific application of the Simulator of the Human Intestinal Microbial Ecosystem (SHIME ® )), dysbiosis and CDI were induced by clindamycin (CLI) treatment. Vancomycin (VNC) treatment cured CDI, but the further dysbiosis of the indigenous microbiota likely contributed to CDI recurrence. Upon co-supplementation with VNC, both 2'FL and MIX boosted microbial activity (acetate and to lesser extent propionate/butyrate). Moreover, 2'FL avoided CDI recurrence, potentially because of increased secondary bile acid production. Overall, while not elucidating the exact antipathogenic mechanisms-of-action, the current study highlights the potential of HMOs to combat CDI recurrence, help the gut microbial community recover after antibiotic treatment, and hence counteract the adverse effects of antibiotic therapies.

Harmful algal bloom events are increasing in a number of water bodies around the world with significant economic impacts on the aquaculture, fishing and tourism industries. As well as their potential impacts on human health, toxin exposure from harmful algal blooms (HABs) has resulted in widespread morbidity and mortality in marine life, including top marine predators. There is therefore a need for an improved understanding of the trophic transfer, and persistence of toxins in marine food webs. For the first time, the concentrations of two toxin groups of commercial and environmental importance, domoic acid (DA) and saxitoxin (including Paralytic Shellfish Toxin (PST) analogues), were measured in the viscera of 40 different fish species caught in Scotland between February and November, 2012 to 2019. Overall, fish had higher concentrations of DA compared to PSTs, with a peak in the summer / autumn months. Whole fish concentrations were highest in pelagic species including Atlantic mackerel and herring, key forage fish for marine predators including seals, cetaceans and seabirds. The highest DA concentrations were measured along the east coast of Scotland and in Orkney. PSTs showed highest concentrations in early summer, consistent with phytoplankton bloom timings. The detection of multiple toxins in such a range of demersal, pelagic and benthic fish prey species suggests that both the fish, and by extension, piscivorous marine predators, experience multiple routes of toxin exposure. Risk assessment models to understand the impacts of exposure to HAB toxins on marine predators therefore need to consider how chronic, low-dose exposure to multiple toxins, as well as acute exposure during a bloom, could lead to potential long-term health effects ultimately contributing to mortalities. The potential synergistic, neurotoxic and physiological effects of long-term exposure to multiple toxins require investigation in order to appropriately assess the risks of HAB toxins to fish as well as their predators., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Long-acting injectable (LAI) antipsychotic medications are used to optimise treatment outcomes in schizophrenia. Guaranteed medication delivery increases the responsibility of prescribers to monitor and manage adverse effects., Methods: In the context of a quality improvement programme conducted by the Prescribing Observatory for Mental Health, a clinical audit addressed documented side-effect monitoring in patients prescribed continuing LAI antipsychotic medication under the care of United Kingdom adult mental health services., Results: A total of 62 mental health services submitted data on 5169 patients prescribed LAI antipsychotic medication for more than a year. An assessment of side effects had been documented in the past year in 2304 (45%) cases. Post hoc analysis showed that extrapyramidal side effects were more likely to have been assessed and found to be present in those patients prescribed LAI haloperidol, flupentixol or zuclopenthixol. There was little other targeting of assessments to the known side effects profiles of individual LAI antipsychotic medications, but when dysphoria had been assessed it was most commonly found with LAI haloperidol treatment and when weight gain, sexual and prolactin-related side effects had been assessed, they were more often identified with LAI paliperidone., Conclusion: The data suggest a relatively low frequency of side-effect assessments, largely untargeted. This is likely to result in many adverse effects going unrecognised and unmanaged, thus failing to tackle their potential to confound mental state assessment and adversely affect physical health and adherence. Patients receiving LAI antipsychotic medication have regular contact with a healthcare professional who administers the medication, which provides an opportunity to potentially remedy this situation., Competing Interests: Conflict of interest statement: CP and BM have nothing to declare. TJC reported honoraria and travel support from Sanofi, Otsuka and Janssen. TREB reported participation in scientific advisory boards for Lundbeck, Newron Pharmaceuticals and Gedeon Richter/Recordati and receipt of an honorarium for a lecture from Janssen., (© The Author(s), 2021.)

Introduction: Treatment options for irritable bowel syndrome (IBS) are limited, causing many patients to remain symptomatic. This study assessed the potential of human milk oligosaccharides (HMOs) to normalize bowel habits. Secondary outcomes included IBS severity and health-related quality of life., Methods: This multicenter, open-label trial recruited patients with IBS from 17 sites across the United States. Patients received daily orally administrated 5-g intervention of the HMOs 2'-fucosyllactose and lacto-N-neotetraose in a 4:1 mix. Bowel habits, IBS symptoms, and quality of life were assessed at baseline and every 4 weeks during the 12-week intervention., Results: A total of 317 patients (70.7% women; mean age of 44.0 years, range 18-93 years) received the trial product, and 245 patients completed the trial according to protocol. Patients had a significant improvement from baseline to 12 weeks in total percentage of bowel movements with abnormal stool consistency (mean and [95% confidence interval]: 90.7 [88.9-92.9] vs 57.2% [53.9-60.5], P < 0.0001), overall IBS Symptom Severity Score (323 [314-332] vs 144 [133-155], P < 0.0001) and health-rela,ted quality of life (50.4 [48.0-52.8] vs 74.6 [72.3-76.9], P < 0.0001). Improvement was similar across IBS subtypes. Symptoms improved most in the first 4 weeks of intervention. The most common side effects were mild gastrointestinal symptoms such as flatulence, abdominal pain and discomfort, and distension., Discussion: Supplementation with 2 selected HMOs improves IBS symptoms and quality of life without substantial side effects. These promising results suggest that this novel approach to IBS should be confirmed in a randomized, placebo-controlled trial.

Objectives: Examine the feasibility of a Community Health Intervention through Musical Engagement (CHIME) in The Gambia to reduce common mental disorder (CMD) symptoms in pregnant women., Design: Feasibility trial testing a randomised stepped-wedge cluster design., Setting: Four local antenatal clinics., Participants: Women who were 14-24 weeks pregnant and spoke Mandinka or Wolof were recruited into the intervention (n=50) or control group (n=74)., Intervention: Music-based psychosocial support sessions designed and delivered by all-female fertility societies. Sessions lasted 1 hour and were held weekly for 6 weeks. Delivered to groups of women with no preselection. Sessions were designed to lift mood, build social connection and provide health messaging through participatory music making. The control group received standard antenatal care., Outcomes: Demographic, feasibility, acceptability outcomes and the appropriateness of the study design were assessed. Translated measurement tools (Self-Reporting Questionnaire (SRQ-20); Edinburgh Postnatal Depression Scale (EPDS)) were used to assess CMD symptoms at baseline, post-intervention and 4-week follow-up., Results: All clinics and 82% of women approached consented to take part. A 33% attrition rate across all time points was observed. 72% in the intervention group attended at least three sessions. Audio and video analysis confirmed fidelity of the intervention and a thematic analysis of participant interviews demonstrated acceptability and positive evaluation. Results showed a potential beneficial effect with a reduction of 2.13 points (95% CI (0.89 to 3.38), p<0.01, n=99) on the SRQ-20 and 1.98 points (95% CI (1.06 to 2.90), p<0.01, n=99) on the EPDS at the post-intervention time point for the intervention group compared with standard care., Conclusion: Results demonstrate that CHIME is acceptable and feasible in The Gambia. To our knowledge, CHIME is the first example of a music-based psychosocial intervention to be applied to perinatal mental health in a low- and middle-income country context., Trial Registration Number: Pan African Clinical Trials Registry (PACTR201901917619299)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Human milk oligosaccharides safely and beneficially impact bifidobacteria abundance in healthy adults, while their effects in patients with irritable bowel syndrome (IBS) are unknown. Hence, we aimed to determine the dose of 4:1 mix of 2'-O-fucosyllactose and Lacto-N-neotetraose (2'FL/LNnT) that increases fecal bifidobacteria abundance without aggravating overall gastrointestinal symptoms in IBS patients in a randomized, double-blind, controlled study. Additionally, the impact of 2'FL/LNnT on the fecal bacterial profile was assessed., Methods: Irritable bowel syndrome patients diagnosed according to the Rome IV criteria received placebo (glucose), or 5 g or 10 g 2'FL/LNnT for 4 weeks followed by a four-week follow-up period. Gastrointestinal Symptom Rating Scale-IBS was used to assess gastrointestinal symptom severity; fecal microbiota composition was evaluated by GA-map™ Dysbiosis Test., Results: Of the included 60 patients, two (one placebo and one 10 g) discontinued prematurely. Fecal bifidobacteria abundance was increased at week 4, but not at week 8, in the 10 g group compared to the other groups. Severity of overall or individual gastrointestinal symptoms did not differ between the groups at week 4 or 8, and no symptom deterioration was seen in any of the groups. The 10 g dose influenced overall fecal microbiota composition, and responders-defined as bifidobacteria increase ≥50%-could be discriminated from non-responders based on fecal microbiota modulation., Conclusions: The 10 g dose of 2'FL/LNnT induced an increase in the beneficial Bifidobacterium spp. without aggravating gastrointestinal symptoms in patients with IBS. This approach may be worthwhile to modulate gut microbiota of IBS patients toward a healthier profile., (© 2020 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Human milk oligosaccharides (HMOs) shape the gut microbiota in infants by selectively stimulating the growth of bifidobacteria. Here, we investigated the impact of HMOs on adult gut microbiota and gut barrier function using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME ® ), Caco2 cell lines, and human intestinal gut organoid-on-chips. We showed that fermentation of 2'-O-fucosyllactose (2'FL), lacto-N-neotetraose (LNnT), and combinations thereof (MIX) led to an increase of bifidobacteria, accompanied by an increase of short chain fatty acid (SCFA), in particular butyrate with 2'FL. A significant reduction in paracellular permeability of FITC-dextran probe was observed using Caco2 cell monolayers with fermented 2'FL and MIX, which was accompanied by an increase in claudin-8 gene expression as shown by qPCR, and a reduction in IL-6 as determined by multiplex ELISA. Using gut-on-chips generated from human organoids derived from proximal, transverse, and distal colon biopsies (Colon Intestine Chips), we showed that claudin-5 was significantly upregulated across all three gut-on-chips following treatment with fermented 2'FL under microfluidic conditions. Taken together, these data show that, in addition to their bifidogenic activity, HMOs have the capacity to modulate immune function and the gut barrier, supporting the potential of HMOs to provide health benefits in adults., Competing Interests: The authors declare no conflict of interest. L.K.V. and B.M.C. participated in the design of the study, the interpretation of the data, and the writing of the manuscript but did not participate in the collection and analyses of data and encouraged publication of the study.

Background: Research suggests that spinal manipulation may effect motion. Less clear is whether this effect is limited to localized responses or may involve generalizable changes. Objective : To determine whether Mid-thoracic manipulation (MTM) would result in a significant change in the lower extremity passive straight leg raise (PSLR) range of motion immediately and after 1 week. Methods : Twenty-three healthy subjects were randomly assigned in a double-blinded study. An experimental group received MTM and a control group received a sham intervention. PSLR measurements were taken prior to, immediately after, and one week after the intervention. Results : Mixed model repeated measure analysis of variance was used to determine that there was a significant interaction between MTM and time ( F (2, 21) = 3.84, p  < 0.05). Post hoc tests revealed a significant difference between the pretest to immediate posttest values ( p  < 0.05, SE = 1.47). PSLR in the MTM group increased 10.3° while the sham group increased 1.9°. Difference was non-significant between pretest and 1-week follow-up ( p  = 0.129, SE = 2.46). Conclusions : MTM may immediately increase lower extremity passive range of motion, but the effect was lost by the 1-week follow-up. This supports evolving research suggesting that spinal manipulation may have a generalized but transient physiological effect.

The thermal stabilization of blue phases is a subject that has been of scientific and technological interest since their discovery. Meanwhile, carbonaceous nanomaterials such as C60 fullerenes, carbon nanotubes and graphene have generated interdisciplinary interest spanning across solid-state physics, organic chemistry, colloids, all the way to soft matter physics. Herein, the stabilization of liquid crystal blue phases by doping with C60, single-walled carbon nanotubes and graphene oxide is described. All three types of particles are found to extend the combined temperature range of blue phases I and II by a factor of ∼5. Furthermore, mixtures of pairs of different materials, and all three types are shown to stabilize the blue phases. The temperature range of the blue phases is shown to grow at the expense of the cholesteric phase. This leads to a blue phase-cholesteric-smecticA phase triple-point in all cases except that of doping with carbon nanotubes. The mechanisms of this thermal stabilization are discussed in light of theoretical descriptions for other established systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Post-traumatic headache is common after pediatric traumatic brain injury and affects thousands of children every year, but little is known about how headache affects recovery after traumatic brain injury in other symptom domains. We aimed to determine the association between headache and other common symptoms after pediatric traumatic brain injury and explore whether subjective complaints of headache are associated with objective deficits on specialized neurocognitive testing. We conducted a retrospective cohort study of children ages 3-19 years following traumatic brain injury with a completed Sports Concussion Assessment Tool (SCAT) questionnaire. Post-traumatic headache was defined by a score more than 2 on the SCAT question for headache and define headache groups for comparison. In our cohort, we analyzed data from the Delis-Kaplan Executive Function System and the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II). Headache was reported in 40 (33%) patients presenting for post-traumatic brain injury care among 121 pediatric traumatic brain injury patients and did not differ by injury severity. Median total SCAT symptom score in the headache group was 5-fold higher compared to patients without headache (median 45.5 vs 9; P < .001). Significantly lower-scaled scores in color naming, matrix reasoning, letter sequencing, and letter switching were also found in the headache group (all P ≤ .03). Our study shows that headache, as reported by patients on the SCAT, is associated with higher symptom scores in all other symptom domains, including sleep, mood, sensory, and cognitive. Headache was also associated with worse objective neurocognitive measures and may identify patients who could benefit from specialized follow-up care and management.

Background: Perinatal mental health problems affect up to one in five women worldwide. Mental health problems in the perinatal period are a particular challenge in low- and middle-income countries (LMICs) where they can be at least twice as frequent as in higher-income countries. It is thus of high priority to develop new low-cost, low-resource, non-stigmatising and culturally appropriate approaches to reduce symptoms of anxiety and depression perinatally, for the benefit of both mother and child. Music-centred approaches may be particularly useful in The Gambia since a range of musical practices that specifically engage pregnant women and new mothers already exist., Methods: This protocol is for a study to examine the feasibility of undertaking a stepped wedge trial to test how a Community Health Intervention through Musical Engagement (CHIME) could be beneficial in alleviating perinatal mental distress in The Gambia. In this study, we plan to recruit 120 pregnant women ( n  = 60 intervention, n  = 60 control) at four antenatal clinics over two 6-week stepped sequences. Women in the intervention will participate in weekly group-singing sessions, led by local Kanyeleng singing groups, for 6 weeks. The control group will receive standard care. We will assess symptoms of anxiety and depression using the Edinburgh Postnatal Depression Scale (EPDS) and the Self-Reporting Questionnaire (SRQ-20). The feasibility of the design will be assessed through recruitment, retention and attrition rates of participants, clinics' adherence to the schedule and completeness of data by site. Qualitative interviews and video and audio recordings will be used to evaluate the acceptability of the intervention., Discussion: This feasibility trial will allow us to determine whether a larger trial with the same intervention and target group is feasible and acceptable in The Gambia., Trial Registration: Retrospectively registered (24/01/2019) with Pan African Clinical Trials Registry (PACTR): PACTR201901917619299., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Study Objective: To assess the efficacy and safety of dexmedetomidine as an adjunct to general anesthesia for craniotomy., Design: A meta-analysis after systematically searching PubMed, Medline, EMBASE, and Cochrane library for randomized trials (RCTs). Relative risk (RR) and weighted mean difference (WMD) were calculated using random-effects meta-analysis., Setting: Perioperative setting., Patients: Twenty-two RCTs (1348 patients) with craniotomy under general anesthesia were included., Interventions: Dexmedetomidine as an adjunct to general anesthesia versus placebo or other anesthetics., Measurements: Primary outcomes included procedure success and postoperative pain; Secondary outcomes included cardiac adverse events, postoperative nausea and vomiting (PONV) and other clinically important outcomes., Main Results: Dexmedetomidine vs. Placebo: High to moderate quality evidence suggested that dexmedetomidine reduced postoperative pain (WMD -0.25 cm, 95%CI -0.43 to -0.07 cm on a 10 cm visual analogue scale), postoperative nausea and vomiting (PONV, RR 0.57, 95%CI 0.39 to 0.84), hypertension (RR 0.37, 95%CI 0.22 to 0.61) and tachycardia (RR 0.32, 95%CI 0.12 to 0.85) with no significant increase of hypotension and bradycardia. Moderate quality evidence suggested no significant difference in procedural success. Dexmedetomidine vs. Active Comparators (including remifentanil, fentanyl, or propofol): Moderate quality evidence showed no difference in procedural success and postoperative pain., Conclusions: Dexmedetomidine as an adjunct to general anesthesia shows small benefits in reduction of pain, PONV, and maintains more stable hemodynamics with comparable effects on procedural success versus placebo. Very limited evidence explored comparative effects between dexmedetomidine and active controls. Further evidence is required to evaluate patient-important outcomes and optimal dosing strategies, particularly versus active comparators., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Classifying movement behaviour of marine predators in relation to anthropogenic activity and environmental conditions is important to guide marine conservation. We studied the relationship between grey seal (Halichoerus grypus) behaviour and environmental variability in the southwestern Baltic Sea where seal-fishery conflicts are increasing. We used multiple environmental covariates and proximity to active fishing nets within a multivariate hidden Markov model (HMM) to quantify changes in movement behaviour of grey seals while at sea. Dive depth, dive duration, surface duration, horizontal displacement, and turning angle were used to identify travelling, resting and foraging states. The likelihood of seals foraging increased in deeper, colder, more saline waters, which are sites with increased primary productivity and possibly prey densities. Proximity to active fishing net also had a pronounced effect on state occupancy. The probability of seals foraging was highest <5 km from active fishing nets (51%) and decreased as distance to nets increased. However, seals used sites <5 km from active fishing nets only 3% of their time at sea highlighting an important temporal dimension in seal-fishery interactions. By coupling high-resolution oceanographic, fisheries, and grey seal movement data, our study provides a scientific basis for designing management strategies that satisfy ecological and socioeconomic demands on marine ecosystems.

Killer whales ( Orcinus orca ) are among the most highly polychlorinated biphenyl (PCB)-contaminated mammals in the world, raising concern about the health consequences of current PCB exposures. Using an individual-based model framework and globally available data on PCB concentrations in killer whale tissues, we show that PCB-mediated effects on reproduction and immune function threaten the long-term viability of >50% of the world's killer whale populations. PCB-mediated effects over the coming 100 years predicted that killer whale populations near industrialized regions, and those feeding at high trophic levels regardless of location, are at high risk of population collapse. Despite a near-global ban of PCBs more than 30 years ago, the world's killer whales illustrate the troubling persistence of this chemical class., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

This report is part of a larger project examining associative interference as a function of the nature of the interfering and target associations. Lick suppression experiments with rats assessed the effects of context shifts on proactive outcome interference by latent inhibition (LI) and Pavlovian conditioned inhibition (CI) treatments on subsequently trained Pavlovian conditioned excitation treatment. LI and CI were trained in Context A during Phase 1, and then excitation treatment was administered in Context B during Phase 2, followed by tests for conditioned excitation in Contexts A, B, or C. Experiment 1 preliminarily established our LI and CI treatments and resulted in equally retarded acquisition of behavioral control when the target cue was subsequently trained as a conditioned excitor and tested in Context A. However, only CI treatment caused the target to pass a summation test for inhibition. Centrally, Experiment 2 consisted of LI and CI treatments in Context A followed by excitatory training in Context B. Testing found low excitatory control by both LI and CI cues in Context A relative to strong excitatory control in Context B, but CI treatment transferred to Context C more strongly than LI treatment. Experiment 3 determined that LI treatment failed to transfer to Context C even when the number of LI trials was greatly increased. Thus, first-learned LI appears to be relatively context specific, whereas first-learned CI generalizes to a neutral context. These observations add to existing evidence that LI and CI treatments result in different types of learning that diverge sharply in transfer to a novel test context.

Purpose: To perform a narrative review of the current trials examining the use of perioperative ultrasound to diagnose common issues related to the heart, lungs, stomach, and airway., Method: A review of the current literature was conducted in June 2017 on all trials involving ultrasound, including both surface and transesophageal ultrasound, in the perioperative period. The search included the terms 'ultrasonography', 'perioperative care', 'point-of-care', and 'bedside'. Trials were limited to human subjects with no language or time restrictions being applied. The results were then collected and a narrative review was completed with the available information., Results: In total 1,176 reports of original investigation or systematic reviews were collected and reviewed. Of those 1,176 reports and reviews, a total of 80 original articles met the inclusion criteria for this review. Topics were broadly defined based on common themes emerging from the literature including cardiac disease, lung pathology (pneumothorax, pleural effusion, pulmonary edema, and pulmonary consolidation), volume and contents of the stomach, confirmation of endotracheal tube position, confirmation of lung isolation, and the application of ultrasound for guiding cricothyroidotomy. Where possible, the sensitivity and specificity of the trials are presented. Few trials reported on patient outcomes, although several discussed provider outcomes such as a change in anesthesia practice. In addition, trials reporting outcomes, although few in number, were included., Conclusion: Perioperative point-of-care ultrasound is a useful method for the diagnosis of many important perioperative conditions. The impact of this diagnostic approach on patient outcomes however remains to be determined.

Background: Health plans are moving away from a volume-driven payment structure toward value-driven and risk-based contracts. There is very limited information on commercial payers' perspectives on coverage of medication management services (MMS) in value-based alternative payment models. While some health plans have experience with Medicare Part D Medication Therapy Management (MTM) programs, this experience does not promote the integration of pharmacists as health care team members., Objectives: The study objectives were to: (1) understand the evaluation process that health plan executives would use to determine benefit coverage for pharmacist-provided MMS in value-based health plans, (2) identify the facilitators and barriers that affect pharmacist-provided MTM services at the community pharmacy level, and (3) propose strategies for pharmacist-provided MMS in value-based health plans., Methods: This study used qualitative research methods that involved structured key informant interviews with commercial health plan executives and focus groups with community pharmacists who had experience providing MTM services., Results: Health plan executives agreed conceptually that MMS could be a valuable program and recognized its potential. However, the most substantial barriers that health plan executives expressed were funding MMS in today's fee-for-service payment models; lack of physician infrastructure to implement and manage MMS; and difficulty in collecting timely, accurate data to execute and assess MMS programs. Community pharmacists identified the most serious barrier to altering health outcomes through MTM as the current lack of integration of MTM with a coordinated health care team. MTM services are conducted as a separate program by pharmacists who do not have access to patient health records, are time-constrained, and poorly incentivized., Conclusions: The findings can inform the development of successful strategies for pharmacist-provided MMS that align with emerging value-based health plans and alternative provider payment models. Current MTM program barriers and facilitators are identified that could be addressed in future Part D MTM program policy changes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The hearing sensitivity of 18 free-ranging and 10 captive harbour seals (Phoca vitulina) to aerial sounds was measured in the presence of typical environmental noise through auditory brainstem response measurements. A focus was put on the comparative hearing sensitivity at low frequencies. Low- and mid-frequency thresholds appeared to be elevated in both captive and free-ranging seals, but this is likely due to masking effects and limitations of the methodology used. The data also showed individual variability in hearing sensitivity with probable age-related hearing loss found in two old harbour seals. These results suggest that the acoustic sensitivity of free-ranging animals was not negatively affected by the soundscape they experienced in the wild., Competing Interests: Compliance with ethical standards Ethical statement Hearing measurements on wild animals were conducted under Home Office Animals (Scientific Procedures) Act licence number 60/4009. All measurements on captive animals were part of a routine animal health assessment conducted by the zoo veterinarians. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. Conflict of interest The authors declare that they have no conflict of interest. Informed consent Informed consent was obtained from all individual participants included in the study.

The gut microbiota has been established as an important player influencing many aspects of human physiology. Breast milk, the first diet for an infant, contains human milk oligosaccharides (HMO) that shape the infant's gut microbiota by selectively stimulating the growth of specific bacteria, especially bifidobacteria. In addition to their bifidogenic activity, the ability of HMO to modulate immune function and the gut barrier makes them prime candidates to restore a beneficial microbiota in dysbiotic adults and provide health benefits. We conducted a parallel, double-blind, randomised, placebo-controlled, HMO-supplementation study in 100 healthy, adult volunteers, consuming chemically produced 2'-O-fucosyllactose (2'FL) and/or lacto-N-neotetraose (LNnT) at various daily doses and mixes or placebo for 2 weeks. All participants completed the study without premature discontinuation. Supplementation of 2'FL and LNnT at daily doses up to 20 g was shown to be safe and well tolerated, as assessed using the gastrointestinal symptoms rating scale. 16S rRNA sequencing analysis showed that HMO supplementation specifically modified the adult gut microbiota with the primary impact being substantial increases in relative abundance of Actinobacteria and Bifidobacterium in particular and a reduction in relative abundance of Firmicutes and Proteobacteria. This study provides the first set of data on safety, tolerance and impact of HMO on the adult gut microbiota. Collectively, the results from this study show that supplementing the diet with HMO is a valuable strategy to shape the human gut microbiota and specifically promote the growth of beneficial bifidobacteria.

Objective: To determine whether an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) at 28 weeks' gestation, in the absence of fetal growth restriction (FGR) and prematurity, is associated with adverse neurocognitive outcome in children aged 12 years., Methods: Prospective cohort study, comparing children with a normal fetal UAD PI (<90th centile) (n=110) and those with an elevated PI (≥90th centile) (n=40). UAD was performed at 28, 32 and 34 weeks gestation. At 12 years of age, all children were assessed under standardised conditions at Queen's University, Belfast, UK to determine cognitive and behavioural outcomes using the British Ability Score-II and Achenbach Child Behavioural Checklist Parent Rated Version under standardised conditions. Regression analysis was performed, controlling for confounders such as gender, socioeconomic status and age at assessment., Results: The mean age of follow-up was 12.4 years (±0.5 SD) with 44% of children male (n=63). When UAD was assessed at 28 weeks, the elevated fetal UAD group had lower scores in cognitive assessments of information processing and memory. Parameters included (1) recall of objects immediate verbal (p=0.002), (2) delayed verbal (p=0.008) and (3) recall of objects immediate spatial (p=0.0016). There were no significant differences between the Doppler groups at 32 or 34 weeks' gestation., Conclusions: An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with lower scores of declarative memory in children aged 12 years. A potential explanation for this is an element of placental insufficiency in the presence of the appropriately grown fetus, which affects the development of the fetal hippocampus and information processing and memory long-term. These findings, however, had no impact on overall academic ability, mental processing and reasoning or overall behavioural function., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Self-injurious behavior (SIB) is associated with several neurologic and psychiatric syndromes but rarely with focal lesions. Two patients with lesions of the right temporo-parietal junction presented to psychiatric inpatient services with SIB in the absence of notable neurologic deficits or suicidal ideation. Right temporo-parietal lesions may be associated with disturbances of agency and body ownership, both of which may facilitate SIB. Misoplegia, or hatred of a limb, may be associated with SIB and has been reported without hemiplegia with a right temporo-parietal lesion. Further study is warranted to improve our understanding of the mechanisms underlying SIB.

Purpose: Point-of-care ultrasound (POCU) is an evolving field in anesthesia. Therefore a systematic review of common diagnoses made by POCU during non-cardiac surgery was conducted. The information obtained from the review may be used to develop POCU curricula for the perioperative setting during non-cardiac surgery., Source: A systematic review was conducted for perioperative use of transthoracic /transesophageal echocardiography (TTE/TEE) in high-risk patients or in other patients experiencing periods of hemodynamic instability. The diagnoses included segmental wall motion abnormalities (SWMAs), low left ventricular ejection fraction (LVEF), hypovolemia, air embolism, cardiac/aortic thrombus, pulmonary embolus (PE), aortic valve disease, mitral valve disease, tricuspid valve disease, right ventricular (RV) failure, pericardial disease, and patent foramen ovale., Principal Findings: Three hundred twenty-one studies were found using our search terms, and thirteen studies were retained that met our inclusion criteria for review. The studies included 968 patients analyzed as either preoperative exams in high-risk patients (n = 568) or intraoperative exams during times of hemodynamic compromise/cardiac arrest (n = 400). The most common diagnoses in the preoperative exam group were low ejection fraction (25.4%), aortic valve disease (24.4%), mitral valve disease (20.0%), RV failure (6.6%), and hypovolemia (6.3%). In the intraoperative exam group, the most common diagnoses were hypovolemia (33.2%), low ejection fraction (20.5%), RV failure (13.1%), SWMAs (10.1%), and PE (5.8%)., Conclusion: In this systematic review examining the use of TTE or TEE in non-cardiac surgery, the most frequent diagnoses were valvulopathy, low LVEF, hypovolemia, PE, SWMAs, and RV failure. This information should be used to inform evidence-based curricula for POCU in anesthesiology.

Offshore construction and survey techniques can produce pulsed sounds with a high sound pressure level. In coastal waters, the areas in which they are produced are often also used by seals, potentially resulting in auditory damage or behavioral avoidance. Here, we describe a study on harbor seals during a wind farm installation off southeast England. The study used GPS/global system for mobile communication tags on 23 harbor seals that provided distribution and activity data; the closest range of individual seals to piling varied from 6.65 to 46.1 km. Furthermore, the maximum predicted received levels (RLs) at individual seals varied between 146.9 and 169.4 dB re 1 μPa peak to peak.

A recent increase in euglycemic diabetic ketoacidosis (euDKA)-a metabolic state with plasma bicarbonate exceeding 10 mEq/L and blood glucose levels lower than 300 mg/dL-has caught regulators and providers by surprise. It's been more than 40 years since the British Medical Journal expanded the "panorama of diabetic metabolic upsets" with an article on euDKA. Although still rare, the occurrence of euDKA is becoming slightly more common. Unlike the more widely known diabetic ketoacidosis, this condition is devoid of blood glucose elevation. Over two years, the Food and Drug Administration (FDA) Adverse Event Reporting System database linked 73 episodes of euDKA to the use of one of the newest drug classes used in diabetes, the SGLT-2 inhibitors. Subsequently, FDA issued a warning in May 2015 regarding this class of medications. FDA's continued investigation led to a labeling change for this class in December 2015, describing increased risk of euDKA. Health care providers, patients, and caregivers need to increase vigilance, as this seemingly silent complication can be fatal.

Background: Free ranging foraging animals can vary their searching intensity in response to the profitability of the environment by modifying their movements. Marine diving animals forage in a three dimensional space and searching intensity can be varied in both the horizontal and vertical planes. Therefore understanding the relationship between the allocation of searching effort in these two spaces can provide a better understanding of searching strategies and a more robust identification of foraging behaviour from the multitude of foraging indices (FIs) available. We investigated the movement of a widespread marine coastal predator, the harbour seal (Phoca vitulina), and compared two sets of foraging indices reflecting searching intensity respectively in the horizontal plane (displacement speed, extensive vs. intensive movement types, residence time) and in the vertical dimension (time at the bottom of a dive). We then tested how several factors (dive depth, direction of the trip with respect to haul-out site, different predatory tactics, the presence of factors confounding the detection of foraging, and temporal resolution of the data) affected their relationships., Results: Overall the indices only showed a very weak positive correlation across the two spaces. However controlling for various factors strengthened the relationships. Resting at sea, a behaviour intrinsically static in the horizontal plane, was found to be strongly negatively related to the time spent at the bottom of the dives, indirectly weakening the relationship between horizontal and vertical foraging indices. Predatory tactic (benthic vs. pelagic) was found to directly affect the relationship. In benthic (as opposed to pelagic) foraging a stronger positive relationship was found between vertical and horizontal indices., Conclusions: Our results indicated that movement responses, leading to an intensification of search, are similar in the two spaces (positive relationship), but additional factors need to be taken into account for this relationship to emerge. Foraging indices measuring residence in the horizontal plane tend to be inflated by resting events at sea, while vertical indices tend to distinguish mainly between periods of activity and inactivity, or of benthic and pelagic foraging. The simultaneous consideration of horizontal and vertical movements, as well as topographic information, allows additional behavioural states to be inferred, providing greater insight into the interpretation of foraging activity.

Aims and Objectives: To identify the barriers critical care nurses experience to relative involvement in intensive care unit patient care., Background: Previous studies have discussed the experiences of relatives visiting an intensive care unit, the needs of relatives in the intensive care environment, critical care nurse and relative interaction, intensive care unit visiting policies and the benefits of including relatives in patient care. The barriers that critical care nurses experience to relative involvement in patient care have received minimal exploration., Design: Critical care nurses were recruited for a mixed methods study. An explanatory mixed method design was used, with two phases. Phase 1 was Quantitative and Phase 2 was Qualitative., Methods: Data collection occurred over five months in 2012-2013. Phase 1 used an online questionnaire (n = 70), and semi-structured interviews (n = 6) were conducted in Phase 2. Phase 1 participants were 70 critical care nurses working in Australian intensive care units and six critical care nurses were recruited from a single Sydney intensive care unit for Phase 2. Through sequential data collection, Phase 1 results formed the development of Phase 2 interview questions., Results: Participants reported various barriers to relative involvement in critically ill patient care. Factors related to the intensive care unit patient, the intensive care unit relative, the critical care nurse and the intensive care environment contributed to difficulties encompassing relative involvement., Conclusions: This study has identified that when considering relative involvement in patient care, critical care nurses take on a paternalistic role. The barriers experienced to relative involvement result in the individual critical care nurse deciding to include or exclude relatives from patient care., Relevance to Clinical Practice: Knowledge of the barriers to relative involvement in critically ill patient care may provide a basis for improving discussion on this topic and may assist intensive care units to implement strategies to reduce barriers., (© 2015 John Wiley & Sons Ltd.)

Background: Pyoderma gangrenosum (PG) is a skin condition characterized by necrotic ulcers and most commonly occurs on the legs in association with inflammatory bowel disease and rheumatoid arthritis; however, PG rarely involves the head and neck, and very rarely causes nasal septal perforation., Objective: Here, we describe a case report of PG causing nasal septal perforation in a 71-year-old male with truncal lesions in the absence of either inflammatory bowel disease or autoimmune arthritis., Methods: Case report with histologic description., Results: Histology from nasal mucosal biopsies showed chronic inflammation and reactive change without evidence of malignancy. Together with serologic and nonserologic testing, as well as clinical evaluation, we were able to rule out other causes of septal perforation including Wegener's granulomatosis, lymphoma, and vasculitis, and concluded that the cause of nasal septal perforation was most likely PG., Conclusion: Septal perforation etiology should include a complete history and physical to evaluate for systemic etiologies, including rare ones such as PG.

Introduction: Laryngeal clefts (LC) are congenital malformations of the upper aerodigestive tract that can cause dysphagia, aspiration, and subsequent pulmonary complications. This investigation assessed the outcomes of multidisciplinary evaluation and surgical management of type I and II LC (LC1-2) at a tertiary children's hospital., Materials and Methods: A retrospective chart review was used to identify patients who underwent repair of LC1-2 by a single surgeon., Results: Twenty-five patients who underwent surgical management for LC1-2 were identified. Twenty patients with LC-1 and 5 with LC-2 were included. Most common presentations were aspiration on modified barium swallow (MBS) (76%) and recurrent pulmonary infections (60%). Gastroesophageal reflux disease (GERD) was a concurrent co-morbidity in 68%. Of the 19 patients who presented with preoperative aspiration on MBS, 52.6% had evidence of improvement on their first MBS. This improved to 78.9% at the time of their most recent MBS (10 with resolution of aspiration, 5 with improved tolerance of consistencies). Two patients failed to improve from surgical repair and two had worsened aspiration on most recent MBS., Conclusion: Endoscopic repair of laryngeal clefts is a well-tolerated procedure. Concurrent GERD and positive bronchoalveolar lavage (BAL) cultures are common and require management prior to definitive repair. Given the multidimensional nature of swallowing disorders and aspiration, a comprehensive team approach in the evaluation, management, and surveillance of these patients is a valuable complement to surgical repair since not all aspiration may resolve., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We examined self-reported complementary and alternative medicine (CAM) use among a largely indigent population with epilepsy. Overall CAM use was 70%, with the most frequently reported complementary and alternative medicines (CAMs) being medical marijuana (33%), prayer/spirituality (31%), meditation (19%), vitamins (19%), and stress management (16%). Forty-four percent of patients reported improved seizure control with CAMs. Stress management accounted for perceived seizure reduction in 74%, followed by marijuana (54%), prayer (49%), and yoga (42%). Among the most commonly used and helpful CAMs, stress management was not associated with specific demographic or clinical variables; marijuana use was significantly associated with lower age (users=35.2±10 years vs. nonusers=41.6±12; p<0.01) and lower income (under $15,000 40% use vs. 14% over $15,000; p<0.05); and prayer was significantly associated with female gender (male=21% vs. female=45%; p<0.01) and Black ethnicity (Black=55% vs. Hispanic=30% vs. White=23%; p<0.05). Taken together, our study was notable for the high rate of CAM utilization in a largely indigent population, with high rates of perceived efficacy among several CAM modalities., (Copyright © 2014 Elsevier Inc. All rights reserved.)