Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.

Combat-related peripheral nerve injuries.

Active-duty service members (ADSM) and military Veterans represent a population with increased occupational risk for nerve injuries sustained both during training operations and wartime. Mechanisms of war-related nerve injuries have evolved over time, from the musket ball-related traumas described by S.W. Mitchell to complex blast injuries and toxic exposures sustained during Middle East conflicts in the 21st century. Commonly encountered nerve injury etiologies in this population currently include compression, direct trauma, nutritional deficits, traumatic limb amputation, toxic chemical exposures, or blast-related injuries. Expeditious identification and comprehensive, interdisciplinary treatment of combat-associated neuropathies, as well as prevention of these injuries whenever possible is critical to reduce chronic morbidity and disability for service members and to maintain a well-prepared military. However, diagnosis of a combat-associated nerve injury may be particularly challenging due to comorbid battlefield injuries or delayed presentation of neuropathy from military toxic exposures. Advances in imaging for nerve injury, including MRI and ultrasound, provide useful tools to compliment EMG in establishing a diagnosis of combat-associated nerve injury, particularly in the setting of anatomic disruption or edema. Surgical techniques can improve pain control or restoration of function. In all cases, comprehensive interdisciplinary rehabilitation provides the best framework for optimization of recovery. Further work is needed to prevent combat-associated nerve injuries and promote nerve recovery following injury.

How etiological beliefs contribute to the structure of depression symptom networks.

OBJECTIVES: Each person possesses a unique view surrounding depressive symptomology and etiology that is shaped by idiosyncratic experiences. However, the influence that subjective etiological beliefs regarding a person's depressive symptoms have on actual symptom presentation and organization is seldom considered. METHODS: The current study employed network analytic techniques to examine how subjective views surrounding the cause of depressive symptoms altered actual symptom presentation networks. Additionally, the interaction between depressive symptoms and various etiological beliefs was examined. RESULTS: The results revealed that characterological beliefs, representing the idea that depression is caused by an internal sense of self, are strongly connected to a negative view of self, as well as a saddened mood. Additionally, the characterological beliefs node exhibited the greatest node predictability in its respective network, as well as in an omnibus network consisting of all depression symptoms and potential etiological beliefs. Whereas an achievement-based view of depression has a strong connection with concentration difficulties, a physical view of depression tends to form strong connections with physically based depressive symptoms. CONCLUSION: Subjective views regarding the cause of depression have the potential to influence symptom presentation and organization within a network, which may influence a person's willingness to engage in treatment or specific treatment preferences.

Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK.

The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with the time to first cell division, the relative scale of the effector cell response, and the graded expression of activation-associated proteins like IRF4. To regulate T cell activation programming, the TCR and the TCR proximal interleukin-2-inducible T cell kinase (ITK) simultaneously trigger many biochemically separate signaling cascades. T cells lacking ITK exhibit selective impairments in effector T cell responses after activation, but under the strongest signaling conditions, ITK activity is dispensable. To gain insight into whether TCR signal strength and ITK activity tune observed graded gene expression through the unequal activation of distinct signaling pathways, we examined Erk1/2 phosphorylation or nuclear factor of activated T cells (NFAT) and nuclear factor (NF)-κB translocation in naïve OT-I CD8+ cell nuclei. We observed the consistent digital activation of NFAT1 and Erk1/2, but NF-κB displayed dynamic, graded activation in response to variation in TCR signal strength, tunable by treatment with an ITK inhibitor. Inhibitor-treated cells showed the dampened induction of AP-1 factors Fos and Fosb, NF-κB response gene transcripts, and survival factor Il2 transcripts. ATAC sequencing analysis also revealed that genomic regions most sensitive to ITK inhibition were enriched for NF-κB and AP-1 motifs. Specific inhibition of NF-κB during peptide stimulation tuned the expression of early gene products like c-Fos. Together, these data indicate a key role for ITK in orchestrating the optimal activation of separate TCR downstream pathways, specifically aiding NF-κB activation. More broadly, we revealed a mechanism by which variations in TCR signal strength can produce patterns of graded gene expression in activated T cells.

Providing insights into health data science education through artificial intelligence.

BACKGROUND: Health Data Science (HDS) is a novel interdisciplinary field that integrates biological, clinical, and computational sciences with the aim of analysing clinical and biological data through the utilisation of computational methods. Training healthcare specialists who are knowledgeable in both health and data sciences is highly required, important, and challenging. Therefore, it is essential to analyse students' learning experiences through artificial intelligence techniques in order to provide both teachers and learners with insights about effective learning strategies and to improve existing HDS course designs. METHODS: We applied artificial intelligence methods to uncover learning tactics and strategies employed by students in an HDS massive open online course with over 3,000 students enrolled. We also used statistical tests to explore students' engagement with different resources (such as reading materials and lecture videos) and their level of engagement with various HDS topics. RESULTS: We found that students in HDS employed four learning tactics, such as actively connecting new information to their prior knowledge, taking assessments and practising programming to evaluate their understanding, collaborating with their classmates, and repeating information to memorise. Based on the employed tactics, we also found three types of learning strategies, including low engagement (Surface learners), moderate engagement (Strategic learners), and high engagement (Deep learners), which are in line with well-known educational theories. The results indicate that successful students allocate more time to practical topics, such as projects and discussions, make connections among concepts, and employ peer learning. CONCLUSIONS: We applied artificial intelligence techniques to provide new insights into HDS education. Based on the findings, we provide pedagogical suggestions not only for course designers but also for teachers and learners that have the potential to improve the learning experience of HDS students.

Integrating plant physiology into simulation of fire behavior and effects.

Wildfires are a global crisis, but current fire models fail to capture vegetation response to changing climate. With drought and elevated temperature increasing the importance of vegetation dynamics to fire behavior, and the advent of next generation models capable of capturing increasingly complex physical processes, we provide a renewed focus on representation of woody vegetation in fire models. Currently, the most advanced representations of fire behavior and biophysical fire effects are found in distinct classes of fine-scale models and do not capture variation in live fuel (i.e. living plant) properties. We demonstrate that plant water and carbon dynamics, which influence combustion and heat transfer into the plant and often dictate plant survival, provide the mechanistic linkage between fire behavior and effects. Our conceptual framework linking remotely sensed estimates of plant water and carbon to fine-scale models of fire behavior and effects could be a critical first step toward improving the fidelity of the coarse scale models that are now relied upon for global fire forecasting. This process-based approach will be essential to capturing the influence of physiological responses to drought and warming on live fuel conditions, strengthening the science needed to guide fire managers in an uncertain future.

Can restoration of fire-dependent ecosystems reduce ticks and tick-borne disease prevalence in the eastern United States?

Over the past century, fire suppression has facilitated broad ecological changes in the composition, structure, and function of fire-dependent landscapes throughout the eastern US, which are in decline. These changes have likely contributed mechanistically to the enhancement of habitat conditions that favor pathogen-carrying tick species, key wildlife hosts of ticks, and interactions that have fostered pathogen transmission among them and to humans. While the long-running paradigm for limiting human exposure to tick-borne diseases focuses responsibility on individual prevention, the continued expansion of medically important tick populations, increased incidence of tick-borne disease in humans, and emergence of novel tick-borne diseases highlights the need for additional approaches to stem this public health challenge. Another approach that has the potential to be a cost-effective and widely applied but that remains largely overlooked is the use of prescribed fire to ecologically restore degraded landscapes that favor ticks and pathogen transmission. We examine the ecological role of fire and its effects on ticks within the eastern United States, especially examining the life cycles of forest-dwelling ticks, shifts in regional-scale fire use over the past century, and the concept that frequent fire may have helped moderate tick populations and pathogen transmission prior to the so-called fire-suppression era that has characterized the past century. We explore mechanisms of how fire and ecological restoration can reduce ticks, the potential for incorporating the mechanisms into the broader strategy for managing ticks, and the challenges, limitations, and research needs of prescribed burning for tick reduction.

Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength.

TCR signal strength is critical for CD8+ T cell clonal expansion after Ag stimulation. Levels of the transcription factor IRF4 control the magnitude of this process through the induction of genes involved in proliferation and glycolytic metabolism. The signaling mechanism connecting graded TCR signaling to the generation of varying amounts of IRF4 is not well understood. In this study, we show that Ag potency regulates the kinetics but not the magnitude of NFAT1 activation in single mouse CD8+ T cells. Consequently, T cells that transduce weaker TCR signals exhibit a marked delay in Irf4 mRNA induction, resulting in decreased overall IRF4 expression in individual cells and increased heterogeneity within the clonal population. We further show that the activity of the tyrosine kinase ITK acts as a signaling catalyst that accelerates the rate of the cellular response to TCR stimulation, controlling the time to onset of Irf4 gene transcription. These findings provide insight into the function of ITK in TCR signal transduction that ultimately regulates IRF4 expression levels in response to variations in TCR signal strength.

The Post-GWAS Era: From Association to Function.

During the past 12 years, genome-wide association studies (GWASs) have uncovered thousands of genetic variants that influence risk for complex human traits and diseases. Yet functional studies aimed at delineating the causal genetic variants and biological mechanisms underlying the observed statistical associations with disease risk have lagged. In this review, we highlight key advances in the field of functional genomics that may facilitate the derivation of biological meaning post-GWAS. We highlight the evidence suggesting that causal variants underlying disease risk often function through regulatory effects on the expression of target genes and that these expression effects might be modest and cell-type specific. We moreover discuss specific studies as proof-of-principle examples for current statistical, bioinformatic, and empirical bench-based approaches to downstream elucidation of GWAS-identified disease risk loci.

A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin Architecture and Gene Expression.

Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain. Furthermore, increases in the amount of TMEM106B resulted in increases in abnormal lysosomal phenotypes and cell toxicity in both immortalized cell lines and neurons. We then combined fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, that differentially recruits CTCF in lymphoblastoid cell lines and human brain to influence CTCF-mediated long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWASs to frontotemporal lobar degeneration, nominating a causal variant and causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk of neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in CTCF-binding sites found in brain-relevant tissues, implicating CTCF-mediated gene regulation in risk of neurodegeneration more generally.

Circulating tumour cell enumeration does not correlate with Miller-Payne grade in a cohort of breast cancer patients undergoing neoadjuvant chemotherapy.

PURPOSE: The association between pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC) for breast cancer and Circulating Tumour Cells (CTCs) is not clear. The aim of this study was to assess whether CTC enumeration could be used to predict pathological response to NAC in breast cancer as measured by the Miller-Payne grading system. METHODS: Twenty-six patients were recruited, and blood samples were taken pre- and post-NAC. CTCs were isolated using the ScreenCell device and stained using a modified Giemsa stain. CTCs were enumerated by 2 pathologists and classified as single CTCs, doublets, clusters/microemboli and correlated with the pathological response as measured by the Miller-Payne grading system. χ2 or ANOVA was performed in SPSS 24.0 statistics software for associations. RESULTS: 89% of patients had invasive ductal carcinoma (IDC) and 11% invasive lobular carcinoma (ILC). At baseline 85% of patients had CTCs present, median 7 (0-161) CTCs per 3 ml of whole blood. Post-chemotherapy, 58% had an increase in CTCs. This did not correlate with the Miller-Payne grade of response. No significant association was identified between the number of CTCs and clinical characteristics; however, we did observe a correlation between pre-treatment CTC counts and body mass index, p < 0.05. CONCLUSIONS: Patients with a complete response to NAC still had CTCs present, suggesting enumeration is not sufficient to aid surgery stratification. Additional characterisation and larger studies are needed to further characterise CTCs isolated pre- and post-chemotherapy. Long-term follow-up of these patients will determine the significance of CTCs in NAC breast cancer patients.

Transthoracic echocardiographic findings in patients admitted with SARS-CoV-2 infection.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients commonly have elevated troponin and D-dimer levels, but limited imaging exists to support most likely etiologies in efforts to avoid staff exposure. The purpose of this study was to report transthoracic echocardiographic (TTE) findings in SARS-CoV-2 patients with correlating troponin and D-dimer levels. METHODS: We identified 66 SARS-CoV-2 patients (mean age 60 ± 15.7 years) admitted within a large, eight-hospital healthcare system over a 6-week period with a TTE performed. TTE readers were blinded to laboratory data with intra-observer and inter-observer analysis assessed. RESULTS: Sixty-six of 1780 SARS-CoV-2 patients were included and represented a high-risk population as 38 (57.6%) were ICU-admitted, 47 (71.2%) had elevated D-dimer, 41 (62.1%) had elevated troponin, and 25 (37.9%) died. Right ventricular (RV) dilation was present in 49 (74.2%) patients. The incidence and average D-dimer elevation was similar between moderate/severe vs. mild/no RV dilation (69.6% vs 67.6%, P = 1.0; 3736 ± 2986 vs 4141 ± 3351 ng/mL, P = .679). Increased left ventricular (LV) wall thickness was present in 46 (69.7%) with similar incidence of elevated troponin and average troponin levels compared to normal wall thickness (66.7% vs 52.4%, P = .231; 0.88 ± 1.9 vs 1.36 ± 2.4 ng/mL, P = .772). LV dilation was rare (n = 6, 9.1%), as was newly reduced LV ejection fraction (n = 2, 3.0%). CONCLUSION: TTE in SARS-CoV-2 patients is scarce, technically difficult, and reserved for high-risk patients. RV dilation is common in SARS-CoV-2 but does not correlate with elevated D-dimer levels. Increased LV wall thickness is common, while newly reduced LV ejection fraction is rare, and neither correlates with troponin levels.

Nanopore whole genome sequencing and partitioned phylogenetic analysis supports a new salmonid alphavirus genotype (SAV7).

Salmon pancreas disease virus, more commonly known as salmonid alphavirus (SAV), is a single-stranded positive sense RNA virus and the causative agent of pancreas disease and sleeping disease in salmonids. In this study, a unique strain of SAV previously isolated from ballan wrasse was subjected to whole genome sequencing using nanopore sequencing. In order to accurately examine the evolutionary history of this strain in comparison to other SAV strains, a partitioned phylogenetic analysis was performed to account for variation in the rate of evolution for both individual genes and codon positions. Partitioning the genome alignments almost doubled the observed branch lengths in the phylogenetic tree when compared to the more common approach of applying one model of substitution across the genome and significantly increased the statistical fit of the best-fitting models of nucleotide substitution. Based on the genomic data, a valid case can be made for the viral strain examined in this study to be considered a new SAV genotype. In addition, this study adds to a growing number of studies in which SAV has been found to infect non-salmonid fish, and as such we have suggested that the viral species name be amended to the more inclusive 'piscine alphavirus'.

IgH isotype-specific B cell receptor expression influences B cell fate.

Ig heavy chain (IgH) isotypes (e.g., IgM, IgG, and IgE) are generated as secreted/soluble antibodies (sIg) or as membrane-bound (mIg) B cell receptors (BCRs) through alternative RNA splicing. IgH isotype dictates soluble antibody function, but how mIg isotype influences B cell behavior is not well defined. We examined IgH isotype-specific BCR function by analyzing naturally switched B cells from wild-type mice, as well as by engineering polyclonal Ighγ1/γ1 and Ighε/ε mice, which initially produce IgG1 or IgE from their respective native genomic configurations. We found that B cells from wild-type mice, as well as Ighγ1/γ1 and Ighε/ε mice, produce transcripts that generate IgM, IgG1, and IgE in an alternative splice form bias hierarchy, regardless of cell stage. In this regard, we found that mIgµ > mIgγ1 > mIgε, and that these BCR expression differences influence respective developmental fitness. Restrained B cell development from Ighγ1/γ1 and Ighε/ε mice was proportional to sIg/mIg ratios and was rescued by enforced expression of the respective mIgs. In addition, artificially enhancing BCR signal strength permitted IgE+ memory B cells-which essentially do not exist under normal conditions-to provide long-lived memory function, suggesting that quantitative BCR signal weakness contributes to restraint of IgE B cell responses. Our results indicate that IgH isotype-specific mIg/BCR dosage may play a larger role in B cell fate than previously anticipated.

Pediatric Toxic Shock Syndrome After a 7% Burn: A Case Study and Systematic Literature Review.

INTRODUCTION: Toxic shock syndrome (TSS) is a life-threatening condition, which occurs in children after sustaining a burn. Often diagnosed retrospectively, many patients may not receive optimal treatment.The primary objective of this study was to evaluate a severe and complex case of TSS at our unit and subsequently conduct a Preferred Reporting for Systematic Reviews and Meta-Analyses-compliant systematic literature review, to identify cases of postthermal injury TSS and evaluate their presentation and management. CASE REPORT: A 9-year-old boy with Down syndrome presented with a 7% total body surface area scald to his back and posterior head. Four days after discharge, he developed a fever. The following day, he deteriorated, becoming stridulous and unresponsive. A working diagnosis of TSS was made. The patient's intensive care stay was arduous with multiple complications, including 2 cardiac arrests. METHODS: A Preferred Reporting for Systematic Reviews and Meta-Analyses-compliant systematic literature review was conducted. MEDLINE, PubMed, and Web of Science were searched using key terms "burns, thermal injury, scalds, paediatric, child, infant, neonate, toxic shock syndrome" to identify cases. Two authors independently checked each study against inclusion criteria. RESULTS: The systematic literature search yielded 9 articles, identifying 40 cases. Ages ranged between 9 months and 8 years. The mean number of days' postburn patients presented with symptoms of TSS was 2.5 days (1-7 days). The most common presenting symptoms were fever (75%), rash (70%), and diarrhea, and/or vomiting (52.5%). Intravenous immunoglobulins were administered in 11 (27.5%) cases. DISCUSSION: We have highlighted a case where a possible delayed diagnosis along with the immunodeficiency seen in Down syndrome may have impacted the severity of TSS. The literature review highlighted that a significant proportion of patients do not meet diagnostic criteria. CONCLUSIONS: It is fundamental that appropriate diagnostic and management guidelines are developed. Furthermore, this case highlights the importance of educating patient's carers and health professionals of key symptoms to be wary of postburn.

Microbial colonization influences early B-lineage development in the gut lamina propria.

The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH µ and IgL (Igκ or Igλ) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Igκ V(D)J recombination that replaces the initial VκJκ exon with one that generates a new specificity. This 'receptor editing' process, which can also lead to Igλ V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different Vκ repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Igλ-expressing versus Igκ-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.

Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery.

BACKGROUND: Surgery has been used as part of breast cancer treatment for centuries; however any surgical procedure has the potential risk of infection. Infection rates for surgical treatment of breast cancer are documented at between 3% and 15%, higher than average for a clean surgical procedure. Pre- and perioperative antibiotics have been found to be useful in lowering infection rates in other surgical groups, yet there is no consensus on the use of prophylactic antibiotics for breast cancer surgery. This is an update of a Cochrane Review first published in 2005 and last updated in 2014. OBJECTIVES: To determine the effects of prophylactic (pre- or perioperative) antibiotics on the incidence of surgical site infection (SSI) after breast cancer surgery. SEARCH METHODS: For this fourth update, in August 2018 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase; and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We included randomised controlled trials of pre- and perioperative antibiotics for patients undergoing surgery for breast cancer. Primary outcomes were rates of surgical site infection (SSI) and adverse reactions. DATA COLLECTION AND ANALYSIS: Three review authors independently examined the title and abstracts of all studies identified by the search strategy, then assessed study quality and extracted data from those that met the inclusion criteria. We contacted study authors to obtain missing information. We evaluated the certainty of evidence using the GRADE approach. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: A total of 11 randomised controlled trials (2867 participants) were included in the review. No new studies were identified in this update. All studies included breast cancer patients and were based in the hospital setting. Ten studies evaluated preoperative antibiotic compared with no antibiotic or placebo. One study evaluated perioperative antibiotic compared with placebo or no antibiotic. Pooling of the results demonstrated that prophylactic antibiotics administered preoperatively probably reduce the incidence of SSI for patients undergoing breast cancer surgery without reconstruction (pooled risk ratio (RR) 0.67, 95% confidence interval (CI) 0.53 to 0.85; moderate certainty evidence). Anticipated absolute effects were calculated for the outcome incidence of SSI; 105 per 1000 for the none or placebo group and 71 per 1000 (95% CI 56 to 89) for the preoperative antibiotic prophylaxis group. Analysis of the single study comparing perioperative antibiotic with no antibiotic was inconclusive for incidence of SSI (RR 0.11, 95% CI 0.01 to 1.95; very low certainty evidence). No studies presented separate data for patients who underwent reconstructive surgery at the time of removal of the breast tumour.Secondary outcomes were not consistently included in the studies investigating preoperative antibiotic prophylaxis. It is very uncertain whether there is a difference in incidence of adverse events between the treatment and no treatment or placebo groups (10 studies, 2818 participants); very low certainty evidence downgraded one level for serious risk of bias, one level for serious inconsistency and one level for serious imprecision. It is unclear whether there is a difference in time to onset of infection between the treatment and no treatment or placebo groups (4 studies, 1450 participants); low certainty evidence downgraded one level for serious risk of bias and one level for serious inconsistency. It is unclear whether there is a difference in rates of readmission to hospital between the treatment and placebo groups (3 studies, 784 participants); low certainty evidence downgraded one level for serious inconsistency and one level for serious risk of bias. It is unclear whether there is a difference in cost of care between the treatment and no treatment or placebo groups (2 studies, 510 participants); low certainty evidence downgraded one level for serious risk of bias and one level for serious inconsistency. No analysable secondary outcome data were reported for the single study evaluating perioperative antibiotics. AUTHORS' CONCLUSIONS: Prophylactic antibiotics administered preoperatively probably reduce the risk of SSI in patients undergoing surgery for breast cancer. However, it is very uncertain whether there is an effect on incidence of adverse events. Furthermore, the effects on time to onset of infection, readmission to hospital and cost of care remain unclear. Further studies are required to establish the best protocols for clinical practice.

Genetic diversity among geographically distant isolates of Neoparamoeba perurans.

The present study explored the use of 2 common genetic markers, the mitochondrial cytochrome oxidase I (COI) and the ribosomal internal transcribed spacer (ITS) to infer the relationship between geographically distant isolates of the protozoan gill parasite Neoparamoeba perurans, the agent responsible for amoebic gill disease in farmed Atlantic salmon worldwide. Present data confirmed that the ITS marker is suitable for Neoparamoeba species discrimination; however, it is not recommended as a population marker due to the presence of multiple copies of ITS within both N. perurans clonal and polycultures. On the other hand, in the partial COI gene analysed here, a low variability was observed, with 8 haplotypes recovered from N. perurans samples collected from Europe (Ireland, Norway, Scotland) and Tasmania (Australia). In Europe, the COI haplotypes which have more recently been detected in aquaculture are different to the haplotypes associated with the original gill disease emergence in Ireland in 1997 and Norway in 2006. The presence of unique COI haplotypes in different continents suggests the presence of multiple distinct reservoirs of the pathogen in both Europe and Tasmania. Isolates from additional geographical locations are required to fully understand the origins and routes for the spread of N. perurans worldwide.