Parenteral Fish-Oil Lipid Emulsions in the Prevention of Severe Retinopathy of Prematurity: A Systematic Review and Meta-Analysis.

Objective Omega-3 fatty acids are vital for brain and retinal maturation. It is not clear if early use of ω-3 fatty acids in the form of fish-oil lipid emulsions (FLEs) prevents retinopathy of prematurity (ROP) in preterm infants. The aim of this meta-analysis is to evaluate whether early administration of parenteral FLEs reduces ROP requiring laser therapy or severe ROP ≥stage 3 in preterm infants. Methods A literature search was performed to identify studies comparing parenteral FLEs with soybean-based lipid emulsions (SLEs) in preventing ROP. The main outcome was incidence of severe ROP or ROP requiring laser therapy. Results Studies met the inclusion criteria (four RCTs and two observational studies). The pooled relative risk of ROP requiring laser therapy or severe ROP ≥ stage 3 in FLEs group was 0.47 [95% CI: 0.24-0.90] and 0.40 [95% CI: 0.22-0.76] in RCTs and observational studies, respectively. FLEs also reduced cholestasis; however, other secondary outcomes of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), sepsis, intraventricular hemorrhage (IVH), and mortality were similar. Conclusion The use of FLEs may reduce the incidence of severe ROP or need for laser therapy in preterm infants. A large multicenter RCT is required to confirm this.

A Systematic Review of Psychiatric, Psychological, and Behavioural Outcomes following Mild Traumatic Brain Injury in Children and Adolescents.

BACKGROUND: Evidence regarding longer-term psychiatric, psychological, and behavioural outcomes (for example, anxiety, mood disorders, depression, and attention disorders) following mild traumatic brain injury (mTBI) in children and adolescents has not been previously synthesized. OBJECTIVE: To conduct a systematic review of the available evidence examining psychiatric, psychological, and behavioural outcomes following mTBI in children and adolescents. MATERIALS AND METHODS: Nine electronic databases were systematically searched from 1980 to August 2014. Studies selected met the following criteria: original data; study design was a randomized controlled trial, quasi-experimental design, cohort or historical cohort study, case-control study, or cross-sectional study; exposure included mTBI (including concussion); population included children and adolescents (<19 years) at the time of mTBI, as well as a comparison group (for example, healthy children, children with orthopaedic injuries); and included psychiatric, psychological, or behavioural outcomes (for example, anxiety, mood disorders, depression, attention disorders). Two authors independently assessed the quality and level of evidence with the Downs and Black (DB) criteria and Oxford Centre of Evidence-Based Medicine (OCEBM) model, respectively, for each manuscript. RESULTS: Of 9472 studies identified in the initial search, 30 were included and scored. Heterogeneity in methodology and injury definition precluded meta-analyses. The median methodological quality for all 30 studies, based on the DB criteria, was 15/33 (range 6 to 19). The highest level of evidence demonstrated by all reviewed studies was level 2b based on OCEBM criteria, with the majority (28/30 studies) classified at this level. Based on the literature included in this systematic review, psychological and psychiatric problems in children with a history of mTBI were found to be more prevalent when mTBI is associated with hospitalization, when assessment occurs earlier in the recovery period (that is, resolves over time), when there are multiple previous mTBIs, in individuals with preexisting psychiatric illness, when outcomes are based on retrospective recall, and when the comparison group is noninjured healthy children (as opposed to children with injuries not involving the head). CONCLUSIONS: Overall, few rigorous prospective studies have examined psychological, behavioural, and psychiatric outcomes following mTBI. In the absence of true reports of preinjury problems and when ideally comparing mild TBI to non-TBI injured controls, there is little evidence to suggest that psychological, behavioural, and/or psychiatric problems persist beyond the acute and subacute period following an mTBI in children and adolescents.

Clinical Presentation of Patients With Tension Pneumothorax: A Systematic Review.

OBJECTIVE: To determine whether the reported clinical presentation of tension pneumothorax differs between patients who are breathing unassisted versus receiving assisted ventilation. BACKGROUND: Animal studies suggest that the pathophysiology and physical signs of tension pneumothorax differ by subject ventilatory status. METHODS: We searched electronic databases through to October 15, 2013 for observational studies and case reports/series reporting clinical manifestations of tension pneumothorax. Two physicians independently extracted clinical manifestations reported at diagnosis. RESULTS: We identified 5 cohort studies (n = 310 patients) and 156 case series/reports of 183 cases of tension pneumothorax (n = 86 breathing unassisted, n = 97 receiving assisted ventilation). Hypoxia was reported among 43 (50.0%) cases of tension pneumothorax who were breathing unassisted versus 89 (91.8%) receiving assisted ventilation (P < 0.001). Pulmonary dysfunction progressed to respiratory arrest in 9.3% of cases breathing unassisted. As compared to cases who were breathing unassisted, the adjusted odds of hypotension and cardiac arrest were 12.6 (95% confidence interval, 5.8-27.5) and 17.7 (95% confidence interval, 4.0-78.4) times higher among cases receiving assisted ventilation. One cohort study reported that none of the patients with tension pneumothorax who were breathing unassisted versus 39.6% of those receiving assisted ventilation presented without an arterial pulse. In contrast to cases breathing unassisted, the majority (70.4%) of those receiving assisted ventilation who experienced hypotension or cardiac arrest developed these signs within minutes of clinical presentation. DISCUSSION: The reported clinical presentation of tension pneumothorax depends on the ventilatory status of the patient. This may have implications for improving the diagnosis and treatment of this life-threatening disorder.

Inflammatory mediators in intra-abdominal sepsis or injury - a scoping review.

INTRODUCTION: Inflammatory and protein mediators (cytokine, chemokine, acute phase proteins) play an important, but still not completely understood, role in the morbidity and mortality of intra-abdominal sepsis/injury. We therefore systematically reviewed preclinical and clinical studies of mediators in intra-abdominal sepsis/injury in order to evaluate their ability to: (1) function as diagnostic/prognostic biomarkers; (2) serve as therapeutic targets; and (3) illuminate the pathogenesis mechanisms of sepsis or injury-related organ dysfunction. METHODS: We searched MEDLINE, PubMed, EMBASE and the Cochrane Library. Two investigators independently reviewed all identified abstracts and selected articles for full-text review. We included original studies assessing mediators in intra-abdominal sepsis/injury. RESULTS: Among 2437 citations, we selected 182 studies in the scoping review, including 79 preclinical and 103 clinical studies. Serum procalcitonin and C-reactive protein appear to be useful to rule out infection or monitor therapy; however, the diagnostic and prognostic value of mediators for complications/outcomes of sepsis or injury remains to be established. Peritoneal mediator levels are substantially higher than systemic levels after intra-abdominal infection/trauma. Common limitations of current studies included small sample sizes and lack of uniformity in study design and outcome measures. To date, targeted therapies against mediators remain experimental. CONCLUSIONS: Whereas preclinical data suggests mediators play a critical role in intra-abdominal sepsis or injury, there is no consensus on the clinical use of mediators in diagnosing or managing intra-abdominal sepsis or injury. Measurement of peritoneal mediators should be further investigated as a more sensitive determinant of intra-abdominal inflammatory response. High-quality clinical trials are needed to better understand the role of inflammatory mediators.

The evolution of pharmaceutical care for drug misusers.

BACKGROUND: In the last 20 years, pharmaceutical care has evolved as a modus operandi for community pharmacy. This article tracks the development of pharmaceutical care for drug misusers since 1995 and considers the implications for pharmacy engagement with the wider care team. OBJECTIVE: To survey current community pharmacy service provision for drug misusers, past training and future training needs and compare with data from previous years (1995, 2000 and 2006). METHOD: A cross-sectional postal questionnaire of pharmacy managers in Scotland (n = 1246), and telephone interviews with non-respondents. Results were compared with previous surveys. RESULTS: The response rate was 70% (873) including 13.2% (164) by telephone. More pharmacies dispensed methadone in 2014 (88.5%) than previously, a significant increase across all time points (1995, 2000 and 2006) (P < 0.001). Most pharmacies (88.1%) had some drug misusers registered for the minor ailment scheme. In 2014, 43.4% of pharmacists always reported a drug misuser's non-attendance for opiate replacement treatment (ORT) to the prescriber (36.6% in 2006). If patient intoxication was suspected, medication was always withheld by 47.9% (27.5% in 2006). Pharmacists undertaking training in drug misuse and blood-borne diseases increased significantly since 1995, to 78.6% and 48.7%, respectively, in 2014 (P < 0.001). The preferred topic for future training was communication/engagement with other services. CONCLUSION: Pharmaceutical care for drug misusers has evolved from ORT supply to a more clinical approach. Pharmacists actively monitored ORT patients, managed their minor ailments and increasingly engaged with the wider care team.

Arginine supplementation in prevention of necrotizing enterocolitis in the premature infant: an updated systematic review.

BACKGROUND: Hypoxic-ischemic injury is thought to play a significant role in necrotizing enterocolitis (NEC). Nitric Oxide (NO) is the principal inhibitory neurotransmitter in the gut and is involved in regulation of mucosal blood flow and maintenance of mucosal integrity. NO is synthesized from L-arginine by NO synthases. Our primary objective was to determine the effectiveness of supplemental L-arginine versus placebo in prevention of NEC in preterm infants ≤ 34 weeks gestational age by systematic review of published randomized controlled trials (RCTs). METHODS: This review included RCTs in which L-arginine was administered as a supplement to neonates to prevent NEC. Searches were conducted in OVID MEDLINE, EMBASE, PubMed, and CINAHL from their dates of inception to July, 2014. Inclusion criteria were informed parental consent, neonates born at ≤ 34 weeks gestation, and birth weight ≤ 1500 g. Exclusion criteria included neonates with severe congenital anomalies and inborn errors of metabolism. Incidence of NEC was the primary outcome measure. Whole data were analyzed by RevMan 5.1 (Update Software, Oxford, UK). Outcome data were analyzed to determine risk ratios, number needed to treat, confidence intervals, and test for overall effect. RESULTS: Two trials including 425 neonates were eligible for this review. Of these, 235 neonates were included in the study. L-arginine had a 59% reduction in the incidence of stage II and III NEC (RR 0.41, 95% CI 0.20 to 0.85, NNT = 9) compared with placebo (P = 0.02). A similar finding was identified for all stages of NEC (60% reduction, RR 0.40, 95% CI 0.23 to 0.69, NNT = 5) (P = 0.001). At age 3 yrs, there was no significant difference between the 2 groups in terms of any neurodevelopmental disability (RR 0.65; 95% CI 0.23-1.83, P = 0.41). CONCLUSIONS: L-arginine supplementation appears to be protective in prevention of NEC in preterm infants and without any significant impact on neurodevelopmental outcomes at 36 months of corrected age. With the addition of the results of one more study to the literature, an intriguing role for L-arginine supplementation continues to gain support. However, large multi-centre RCTs are needed before this can become common practice.

Single cell atlas of Xenoturbella bocki highlights limited cell-type complexity.

Phylogenetic analyses over the last two decades have united a few small, and previously orphan clades, the nematodermatids, acoels and xenoturbelids, into the phylum Xenacoelomorpha. Some phylogenetic analyses support a sister relationship between Xenacoelomorpha and Ambulacraria (Xenambulacraria), while others suggest that Xenacoelomorpha may be sister to the rest of the Bilateria (Nephrozoa). An understanding of the cell type complements of Xenacoelomorphs is essential to assessing these alternatives as well as to our broader understanding of bilaterian cell type evolution. Employing whole organism single-cell RNA-seq in the marine xenacoelomorph worm Xenoturbella bocki, we show that Xenambulacrarian nerve nets share regulatory features and a peptidergic identity with those found in cnidarians and protostomes and more broadly share muscle and gland cell similarities with other metazoans. Taken together, these data are consistent with broad homologies of animal gland, muscle, and neurons as well as more specific affinities between Xenoturbella and acoel gut and epidermal tissues, consistent with the monophyly of Xenacoelomorpha.

Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis.

Efferocytic clearance of apoptotic cells in general, and T cells in particular, is required for tissue and immune homeostasis. Transmembrane mucins are extended glycoproteins highly expressed in the cell glycocalyx that function as a barrier to phagocytosis. Whether and how mucins may be regulated during cell death to facilitate efferocytic corpse clearance is not well understood. Here we show that normal and transformed human T cells express a subset of mucins which are rapidly and selectively removed from the cell surface during apoptosis. This process is mediated by the ADAM10 sheddase, the activity of which is associated with XKR8-catalyzed flipping of phosphatidylserine to the outer leaflet of the plasma membrane. Mucin clearance enhances uptake of apoptotic T cells by macrophages, confirming mucins as an enzymatically-modulatable barrier to efferocytosis. Together these findings demonstrate a glycocalyx regulatory pathway with implications for therapeutic intervention in the clearance of normal and transformed apoptotic T cells.

Insights into early animal evolution from the genome of the xenacoelomorph worm Xenoturbella bocki.

The evolutionary origins of Bilateria remain enigmatic. One of the more enduring proposals highlights similarities between a cnidarian-like planula larva and simple acoel-like flatworms. This idea is based in part on the view of the Xenacoelomorpha as an outgroup to all other bilaterians which are themselves designated the Nephrozoa (protostomes and deuterostomes). Genome data can provide important comparative data and help understand the evolution and biology of enigmatic species better. Here, we assemble and analyze the genome of the simple, marine xenacoelomorph Xenoturbella bocki, a key species for our understanding of early bilaterian evolution. Our highly contiguous genome assembly of X. bocki has a size of ~111 Mbp in 18 chromosome-like scaffolds, with repeat content and intron, exon, and intergenic space comparable to other bilaterian invertebrates. We find X. bocki to have a similar number of genes to other bilaterians and to have retained ancestral metazoan synteny. Key bilaterian signaling pathways are also largely complete and most bilaterian miRNAs are present. Overall, we conclude that X. bocki has a complex genome typical of bilaterians, which does not reflect the apparent simplicity of its body plan that has been so important to proposals that the Xenacoelomorpha are the simple sister group of the rest of the Bilateria.

Xenoturbella bocki is a small marine worm predominantly found on the seafloor of fjords along the west coast of Sweden. This simple organism's unusual evolutionary history has long intrigued zoologists as it is not clear how it is related to other animal groups. The worm may belong to one of the earliest branches of the animal kingdom, which would explain its simple body. On the other hand, it could be related to a more complex group, the deuterostomes, which includes a wide range of animals, from mammals and birds to sea urchins and starfish. Understanding X. bocki's evolution could provide valuable insights into how bilaterians evolved as a whole. Unlike its close relatives, the acoelomorphs, X. bocki evolves more slowly, which makes it simpler to study its genome. As a result, it serves as a starting point for investigating the evolutionary processes and genetics underpinning the broader group of bilaterians. To better understand the evolution of X. bocki's simple body, Schiffer et al. asked whether its genome is simpler or differs in other ways from that of more complex bilaterian organisms. Sequencing the entire X. bocki genome revealed that it has a similar number of genes to that of other animals and includes the genes required for complex biochemical pathways. Reconstructing the worm's chromosomes ­ the structures that house genetic information ­ showed that the X. bocki genes are also distributed in a manner similar to those in other animals. The findings suggest that, despite its simple body plan, X. bocki has a complex genome that is typical of bilaterians. This challenges the idea that X. bocki belongs to a more primitive, simplified sister group to Bilateria and provides a starting point for further studies of how this simple worm evolved.

Growth and development of captive Geocrinia rosea (Myobatrachidae): a rare species analogue.

Using Geocrinia rosea as an analogue of the two threatened frog species, G. alba and G. vitellina, techniques were developed which contribute to an ex situ rearing program. We tested the effect of two levels of enclosure complexity on metamorph growth, and tested the effect of different substrate types on the success of egg clutch hatching and the subsequent development and growth of metamorph frogs. We found that the simplest enclosure was associated with the highest growth rates and better bone density of metamorphs, while a low pH sphagnum peat substrate was the better substrate for egg clutch survival and subsequent growth of metamorphs. Success of the program was highlighted by the rearing of second-generation frogs. These recommendations have now been applied to the captive management of the two endangered Geocrinia species.

The status of accreditation in primary care.

BACKGROUND: One method utilised to improve the quality of health care is accreditation. Although accreditation has been extensively used in the acute care sector, its presence in primary care is limited and so is our understanding of its nature, uptake and associated outcomes. Because acute care and primary care environments are vastly different, our understanding of acute care accreditation cannot simply be translated to primary care. AIM: The purpose of this paper was to explore the current state of primary care accreditation. METHODS: An extensive search was completed examining peer-reviewed and grey literature. In addition, interviews with key stakeholders involved in primary care accreditation were undertaken. RESULTS: From the 501 reviewed abstracts, 62 papers were used in this review in addition to 72 sources from grey literature. Eight interviews were also held with key informants. CONCLUSIONS: In this review of the available literature of accreditation within primary care, it was found that accreditation in this sector is generally non-government funded and voluntary with some countries offering financial incentives. It was evident that there is a dearth of research on the nature and uptake of accreditation in this sector, along with how accreditation affects outcomes of care, whether it is an effective method to improve quality, perceptions of care, healthcare utilisation and costs. These findings imply that further research is required to examine the possible impact accreditation may have on health care within primary care.

Risk Scores for Clinical Risk Stratification of Emergency Department Patients With Chest Pain but No Acute Myocardial Infarction: A Systematic Review.

BACKGROUND: Chest pain is a common cause for emergency department (ED) presentations. After myocardial infarction (MI) has been ruled out by means of electrocardiography and troponin testing, decisions around anatomic or functional testing may be informed by clinical risk scores. We conducted a systematic review to synthesize evidence of the prognostic performance of chest pain risk scores among ED patients who have had MI ruled out by means of a high-sensitivity troponin assay. METHODS: We queried multiple databases from inception to May 17, 2022. We included studies that quantified risk of 30-day major adverse cardiac events (MACE), at different cutoffs of clinical risk scores, among adult patients who had MI ruled out by means of a high-sensitivity troponin assay. Prognostic performance of each score was synthesized and described, but meta-analysis was not possible. RESULTS: Six studies met inclusion criteria. Short-term MACE risk among patients who had MI ruled out by means of high-sensitivity cardiac troponin assays was very low. The HEART score, with a cutoff of 3 or less, predicted a very low risk of MACE among the greatest proportion of patients. Other scores had lower sensitivity or classified fewer patients as low risk. CONCLUSIONS: The HEART score with a cutoff value of 3 or less accurately identified the greatest number of patients at low risk of 30-day MACE. However, MACE risk among patients who have MI ruled out by means of high-sensitivity troponin testing is sufficiently low that clinical risk stratification or noninvasive testing may be of little additional value in identifying patients with coronary disease.

Methods for determination of optimal positive end-expiratory pressure: a protocol for a scoping review.

INTRODUCTION: Titrated application of positive end-expiratory pressure (PEEP) is an important part of any mechanical ventilation strategy. However, the method by which the optimal PEEP is determined and titrated varies widely. Methods for determining optimal PEEP have been assessed using a variety of different study designs and patient populations. We will conduct a scoping review to systematically identify all methods for determining optimal PEEP, and to identify the patient populations, outcomes measured and study designs used for each method. The goal will be to identify gaps in the optimal PEEP literature and identify areas where there may be an opportunity to further systematically synthesise and meta-analyse existing literature. METHODS AND ANALYSIS: Using scoping review methodology, we will generate a comprehensive search strategy based on inclusion and exclusion criteria generated using the population, concept, context framework. Five different databases will be searched (MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus). Three investigators will independently screen titles and abstracts, and two investigators will independently complete full-text review and data extraction. Included citations will be categorised in terms of PEEP method, study design, patient population and outcomes measured. The methods for PEEP titration will be described in detail, including strengths and limitations. ETHICS AND DISSEMINATION: Given this is a synthesis of existing literature, ethics approval is not required. The results will be disseminated to stakeholders via presentation at local, regional and national levels, as well as publication in a high-impact critical care journal. There is also the potential to impact local clinical care protocols and inform broader clinical practice guidelines undertaken by societies.

Non-invasive assessment of stress in captive numbats, Myrmecobius fasciatus (Mammalia: Marsupialia), using faecal cortisol measurement.

Annual patterns of faecal cortisol metabolite (FCM) secretion were examined in six captive numbats (Myrmecobius fasciatus). The use of enzyme-immunoassay for the measurement of FCM in the numbat faeces was validated using an adrenocorticotropic hormone (ACTH) challenge and the resultant FCM measurements represent the first description of adrenal endocrinology in this species. Total overall, baseline and peak FCM mean concentrations varied according to individual, but not gender. For males, mean baseline and overall FCM secretion was higher in spring in summer (compared to winter and autumn) and was elevated during the breeding season. For females, mean baseline FCM secretion did not differ by season or breeding season, but mean overall FCM secretion was elevated during the breeding season. Thus, male (but not female) numbats display an annual change in FCM secretion that is strongly linked to their seasonal pattern of reproduction. Significant FCM elevations (n=178) were observed in response to 20 different stressors, with these stressors being allocated to one of six categories: ANIM, ENVIRO, HAND, HEALTH, MAN and UNK. The mean proportion of positive responses to each category varied according to category, season and breeding season, but did not vary by individual or gender. ANIM and HEALTH stressors elicited a higher response rate than all other categories and an increase in the number of ANIM, ENVIRO, and HEALTH stressors were observed during the breeding season. Although there were multiple stressors within the captive environment that the numbats reacted to, this did not translate into a welfare issue.

Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials.

OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury. DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles. STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury. DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results. DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure. CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.

Rehabilitation therapies in Rett syndrome across the lifespan: A scoping review of human and animal studies.

PURPOSE: To perform a scoping review of the evidence for therapeutic interventions to manage functional impairments associated with Rett syndrome (RTT) throughout the lifespan. METHODS: MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL, Scopus and Index to Chiropractic Literature were searched systematically up to December 2019. Two investigators independently reviewed all search results and extracted those that met the inclusion criteria. Human and animal model studies pertaining to therapies that increase functional ability or treat RTT-associated symptoms in all age groups were included. Relevant studies were grouped into intervention categories and rated using the Oxford Centre of Evidence Based Medicine Levels of Evidence. Demographics of participants, interventions, and outcomes were summarized. RESULTS: Ninety-one articles representing 88 studies met the inclusion criteria, of which 80 were human clinical studies and eight were studies using animal models. Study designs were primarily case series and only six studies involved participants above the age of 40. CONCLUSION: A small number of rigorously studied rehabilitation interventions have been published. Published studies aim to address a wide variety of functional impairments. Research regarding implementation of therapies for older patients with RTT is lacking and requires further exploration.

Malignancy risk of hyperfunctioning thyroid nodules compared with non-toxic nodules: systematic review and a meta-analysis.

BACKGROUND: Hyperfunctioning or hot nodules are thought to be rarely malignant. As such, current guidelines recommend that hot nodules be excluded from further malignancy risk stratification. The objective of this systematic review and meta-analysis is to compare the malignancy risk in hot nodules and non-toxic nodules in observational studies. METHODS: Ovid MEDLINE Daily and Ovid MEDLINE, EMBASE, Scopus, and Web of Science databases were searched. Observational studies which met all of the following were included: (1) use thyroid scintigraphy for nodule assessment, (2) inclusion of both hyperfunctioning and non-functioning nodules based on scintigraphy, (3) available postoperative histopathologic nodule results, (4) published up to November 12, 2020 in either English or French. The following data was extracted: malignancy outcomes include malignancy rate, mapping of the carcinoma within the hot nodule, inclusion of microcarcinomas, and presence of gene mutations. RESULTS: Among the seven included studies, overall incidence of malignancy in all hot thyroid nodules ranged from 5 to 100% in comparison with non-toxic nodules, 3.8-46%. Odds of malignancy were also compared between hot and non-toxic thyroid nodules, separated into solitary nodules, multiple nodules and combination of the two. Pooled odds ratio (OR) of solitary thyroid nodules revealed a single hot nodule OR of 0.38 (95% confidence interval (CI) 0.25, 0.59), toxic multinodular goiter OR of 0.51 (95% CI 0.34, 0.75), and a combined hot nodule OR of 0.45 (95% CI 0.31, 0.65). The odds of malignancy are reduced by 55% in hot nodules; however, the incidence was not zero. CONCLUSIONS: Odds of malignancy of hot nodules is reduced compared with non-toxic nodules; however, the incidence of malignancy reported in hot nodules was higher than expected. These findings highlight the need for further studies into the malignancy risk of hot nodules.

T cell-mediated biliary epithelial-to-mesenchymal transition in liver allograft rejection.

Loss of bile duct epithelium is characteristic of early chronic rejection following liver transplantation. Recent studies have suggested that intrahepatic biliary epithelial cells can transform into myofibroblasts. This study examines the induction and molecular regulation of this transition during allograft rejection. Immortalized human cholangiocytes were stimulated with either transforming growth factor beta1 (TGFbeta1) or a T cell line, and they were examined for morphological, proteomic, and functional features. Posttransplant liver biopsy sections were also examined. Treatment of cholangiocytes with TGFbeta1 or TGFbeta-presenting T cells induced a bipolar morphology, reduced expression of E-cadherin and zona occludens 1 (ZO-1), and increased vimentin, fibronectin, matrix metalloproteinase 2 (MMP-2), MMP-9, and S100 calcium binding protein A4 (S100A4); treated cells invaded a model basement membrane. Chemokines induced T cell penetration of 3-dimensional, cultured bile duct-like structures and bile ducts in liver biopsy sections. A spatial association was observed between duct-infiltrating T cells and cholangiocyte expression of mesenchymal markers, including S100A4. Inhibition of S100A4 expression in vitro blocked TGFbeta1-mediated loss of E-cadherin and ZO-1 but did not reduce induction of fibronectin, MMP-2, or MMP-9. This study demonstrates the potential for T cells to induce an intrahepatic biliary epithelial-to-mesenchymal cell transition during chronic rejection. Furthermore, S100A4 expression by cholangiocytes was identified as a crucial regulator of this transition.