Somatic structural variants undoubtedly play important roles in driving tumourigenesis. This is evident despite the substantial technical challenges that remain in accurately detecting structural variants and their breakpoints in tumours and in spite of our incomplete understanding of the impact of structural variants on cellular function. Developments in these areas of research contribute to the ongoing discovery of structural variation with a clear impact on the evolution of the tumour and on the clinical importance to the patient. Recent large whole genome sequencing studies have reinforced our impression of each tumour as a unique combination of mutations but paradoxically have also discovered similar genome-wide patterns of single-nucleotide and structural variation between tumours. Statistical methods have been developed to deconvolute mutation patterns, or signatures, that recur across samples, providing information about the mutagens and repair processes that may be active in a given tumour. These signatures can guide treatment by, for example, highlighting vulnerabilities in a particular tumour to a particular chemotherapy. Thus, although the complete reconstruction of the full evolutionary trajectory of a tumour genome remains currently out of reach, valuable data are already emerging to improve the treatment of cancer. These alterations usually include somatic structural variants (SVs) which are large-scale changes to the genome, ranging from 50 nucleotides to many megabases in length2. SVs can occur as a result of improper DNA double-strand break (DSB) repair3 and are traditionally classified into five different types: insertions, deletions, duplications, inversions, and translocations2. Although all tumours accumulate both somatic single-nucleotide variant (SNV) mutations and SVs, certain tumour types such as high-grade serous ovarian cancer (HGSOC) and invasive breast cancer4 are dominated by SVs. Furthermore, in HGSOC5 and pancreatic neuroendocrine tumours6, there is good evidence for SVs playing prominent roles in driving tumourigenesis. Various sequencing strategies, particularly whole genome sequencing (WGS), can be used to identify structural variation in tumours by comparing the pattern of structural variation in tumour tissue with that observed in normal cells7. A range of computational tools are then used to detect these variants from sequencing data, but detection algorithms perform very differently in identifying particular SV classes, and none of the existing tools are effective in detecting all SVs on their own8. Copy number alteration (CNA) detection in cancer samples has been reviewed extensively11 because of its important role in tumourigenesis13. For example, it has been suggested that HLA allele loss in 40% of non-small cell lung cancers enables immune escape14. The detection of CNA is a more tractable problem than the detection of many other SVs, as CNAs can be inferred purely on the basis of changes in read depth over a region. Regions with lower read depth suggest loss of genetic material, whereas regions of higher read depth suggest gain. Aside from detecting copy number changes, analyses of SVs in the past have focused on investigating simpler rearrangements of known cancer genes or identifying fusion genes19; however, the focus is now shifting to considering more complex events and SVs as part of broader, genome-wide patterns of mutation20. Our present knowledge of structural aberrations is clearly far from complete, such that although aneuploidy is well studied23, large-scale phenomena such as whole genome doubling have only recently been discovered to be a common event in many cancers and to have important implications for clinical prognoses24.Tumours arise when normal cells accumulate enough genetic alterations to affect normal regulatory control systems27. It also seems that SVs with breakpoints in the main body of a gene may often be associated with increased expression of the gene but that SVs with breakpoints within 50 kb upstream or downstream of a gene are correlated with decreased expression25. Similarly, it has been observed that amplified regions of the genome are enriched for oncogenes but that deleted regions are enriched for tumour suppressors1. However, SVs may alter the expression of genes through various mechanisms, and multiple SVs may occur at the same locus, so the impact of a particular SV on nearby genes is often difficult to predict25. SVs have long been known to result in the formation of functional fusion genes by translocations1. For example, the BCR1-ABL fusion gene is formed by a t translocation which leads to increased tyrosine kinase activity, uncontrolled proliferation, and ultimately chronic myeloid leukaemia (CML). This type of gene fusion can be targeted with kinase inhibitors, resulting in an effective treatment for CML. Rearrangements can also reposition regulatory elements such as enhancers next to oncogenes, which has been observed in Burkitt’s lymphoma and results in increased expression of theMYC oncogene25. Recent studies have suggested that enhancer adoption by oncogenes following the disruption of regulatory domains is fairly common in tumourigenesis, occurring at rates comparable to those of recurrent in-frame gene fusions28, although the domain architectures themselves may simply be prone to higher rates of mutation29. Finally, there appear to be SVs with breakpoints that do not have direct effects on either genes or regulatory elements and yet their presence is associated with patient survival rates1. Beyond gene expression, the effects of SVs are not well studied, but notably modest correlations have been reported between the extent of tumour duplications and deletions involving a gene and the levels of the protein it encodes30. In summary, although simpler SVs may tend to have intuitive effects on gene expression , it is generally not straightforward to interpret the functional effects of a given SV within a given tumour.Even when an SV is associated with patient survival, it is challenging to uncover the underlying mechanism . It is known that SVs can alter the expression of oncogenes or tumour suppressor genes and that these changes in expression may directly contribute to tumourigenesisin situ hybridisation techniques31. Modern high-throughput sequencing technologies are capable of detecting a wider variety of structural variation at much higher resolution. The most widely used sequencing technologies generate billions of short reads about 100 nucleotides in length from sequencing libraries8. The short lengths of the reads, sequencing platform error rates, and the sequencing libraries used can all present challenges for SV detection. Some reads map ambiguously to many different regions in the reference genome, which makes it difficult to determine the true location of the corresponding SV. This is particularly true of reads in repetitive regions8. Smaller library insert sizes enable the precise identification of small SVs such as insertions and deletions; however, smaller insert sizes will cover only short stretches of sequence, making it hard to cover large SVs2. Contrastingly, larger insert sizes allow the identification of large SVs but may have insufficient coverage to determine the location of breakpoints at base-pair resolution. Given the high cost of conducting sequencing experiments using multiple library sizes, it is important to use the appropriate strategy for the biological hypothesis under study. Chimeric reads are artificial sequences formed during the amplification step of polymerase chain reaction (PCR) and can also result in artefacts during analysis. The effect of chimeric reads on SV prediction can be mitigated by using multiple libraries per sample and filtering out novel sequences that are in only one library; however, this comes with the risk of filtering out low-frequency SVs2. Alternatively, there are tools such as ChimeraChecker32 and ChimeraSlayer33 which are designed to remove chimeric reads. Finally, the genomic context of the sequence also impacts SV calling. Regions that are poorly characterised in the reference genome such as pericentromeric and telomeric regions present a challenge to the identification of SVs. In addition, repetitive or GC-rich regions are often problematic for confident read mapping, which can be overcome by sequencing technologies generating longer reads2.Historically, chromosomal aberrations were detected by using microscopy and traditional karyotyping methods, which then were improved with the development of fluorescent34. PacBio35 and Oxford Nanopore36 sequencing platforms both produce long reads that can be used for SV detection. The resultant reads from these technologies average about 10 kb in length and some read lengths recorded up to 100 kb for PacBio and 1 Mb for Oxford Nanopore. However, these technologies are more expensive than standard Illumina short-read sequencing and have higher error rates. An alternative approach is to use a technology based on linked short reads, such as the platforms developed by 10X Genomics37. This enables the identification of large SVs at a lower cost than for the long-read technologies; however, sequencing coverage can be relatively sparse, limiting the resolution of locally repetitive sequences34. Although they are established, these technologies are currently not widely used in cancer genomics and the majority of SV detection in tumours for the moment is still carried out on the basis of short-read sequencing data.Several long-range technologies have been developed to try to address these challenges2. Anomalously mapped reads fall into one of three categories: discordant reads, soft-clipped reads, and one-end-anchored reads. Discordant reads can be used in the direct discovery of SVs and are mapped to either different chromosomes (providing evidence for translocations) or incorrect strands (suggesting inversions) or are in incorrect orientation (suggesting duplications) or are an incorrect distance apart (indicating the presence of an insertion or deletion). Detecting SVs from discordant reads is more effective for the detection of larger SV events, as they are unable to estimate breakpoint locations precisely and small SVs may have insufficient discordant read coverage to be detectable8. Soft-clipped and one-end-anchored reads can be used for indirect SV discovery. Soft-clipped reads are only partially mapped, and one-end-anchored reads have only one read of the pair mapped. In both cases, split-read mapping is needed to successfully map both ends of the SV. These categories of anomaly are better for detecting smaller events such as small insertions and deletions, as they are able to estimate the breakpoints at a higher resolution.Most SV detection algorithms or “callers” identify SVs from paired-end sequencing reads that are anomalously mapped. Anomalous reads can be used to predict candidate SV loci because reads that do not contain an SV breakpoint are expected to map concordantly2: first, by clustering discordant reads that support the same type of SV together ; second, by using split-read mapping to map the other end of indirectly discovered SVs  or to refine the estimate of the breakpoint location in directly discovered SVs ; and, third, by usingde novo contig assembly to stitch together short reads to make a longer segment that can be mapped back to the reference and improve the ability to locate breakpoints . Some callers use combinations of all of these techniques, in addition to assessing changes in read depth, in order to improve their detection sensitivity .In practice, SV callers use one or more types of anomalous reads to predict candidate SV loci in the following wayshttps://www.synapse.org/#!Synapse:syn312572/wiki/) was launched in 2013, aiming to benchmark somatic SNV and SV predictions from a wide variety of algorithms using simulated and real tumour-normal WGS pairs. The project revealed widespread biases in caller predictions and recommended the use of consensus calls made by multiple callers for both SNV and SV prediction43. More detailed accounts of the SV callers’ performance showed that several algorithms  could achieve high precision after stringent filtering of SV calls and substantial overlaps in the breakpoints called between them44. Unfortunately, SV calling is a rapidly evolving field, and there is no ongoing attempt to comprehensively benchmark algorithms as they appear or are updated. In spite of this, multiple comparative reviews of the most popular SV detection tools and algorithms have emerged46. The ensemble approach to both SNV and SV calling explored in the DREAM Challenge has since become thede facto standard operating procedure in the field, as reflected in the recent re-analyses of large TCGA47 and ICGC48 tumour sequencing studies. The choice of algorithms employed in such an ensemble is often influenced by practical considerations, such as computational demands and run times, but should also consider the shared assumptions and biases between tools49. Because any ensemble is expected to generate false-positive and false-negative results, there is also a requirement for validation by orthogonal data for SVs of particular interest, and long-read sequencing technologies may often be useful in this respect50.Assessing the accuracy of SV callers has proven to be challenging. The International Cancer Genome Consortium–The Cancer Genome Atlas (ICGC-TCGA) DREAM SMC-DNA Challenge (51. The three main DSB repair mechanisms are homologous recombination (HR), non-homologous end joining (NHEJ), and replication-based mechanisms52. HR is the most common DNA repair mechanism3 and is accurate as long as there is a homologous sequence to use as a repair template. However, in tumour genomes, there are few overlapping sequences at the breakpoints54, so generally HR is not possible and the error-prone NHEJ is implemented instead. NHEJ requires no homology and sometimes can generate short segments of microhomology or small insertions at the breakpoints3. Replication-based mechanisms of DNA DSB repair such as microhomology-mediated break-induced repair (MMBIR) have also been described55. It is thought that in these cases the replication fork can stall and the polymerase can switch template sequence using microhomology to any nearby single-stranded DNA3. This can result in a range of complex structural rearrangements57. In tumour genomes, which are often HR deficient, these last two mechanisms of repair dominate3. A further mechanism behind structural variation in cancer is chromosome instability. This is defined as an increased rate of chromosomal change in comparison with normal cells. Nearly all cancer cells have some degree of chromosomal instability, but it is unclear whether this drives tumourigenesis or is a by-product of cancer evolution58. There is evidence to suggest that a background of chromosomal instability accelerates the rate of tumourigenesis aided by the acquisition of mutations that promote tolerance of instability 58. Furthermore, the role of recombination activating gene (RAG) and activation-induced cytidine deaminase (AID) in the diversification of immunoglobulin-encoding genes has been proposed as a driver of SVs in leukaemia. The RAG1 and RAG2 endonucleases introduce DSBs followed by the recombination of the immunoglobulin variable, diversity, and joining regions. AID deaminates cytosine residues in the immunoglobulin switch and variable regions, allowing somatic hypermutation. This genetic diversification of antibodies is activated in response to infectious or inflammatory stimuli and has been shown to contribute to the accumulation of somatic mutations necessary for clonal evolution in leukaemia60. The mechanisms underlying the generation of structural variation outlined above have been reviewed extensively elsewhere62.SVs arise when DNA DSBs are improperly repaired54. An alternative model was suggested by Stephenset al. to explain complex patterns of genomic rearrangement54. They suggest a catastrophe-like model where multiple SVs occur as a result of a single event54.The traditional model of cancer development involves the gradual sequential accumulation of mutations, which leads to gradual progression of normal tissue through increasingly disordered clinical and pathological stages until it becomes a malignant tumour66. Chromothripsis is characterised by tens to hundreds of genomic rearrangements across an extended chromosomal region. A region that has undergone chromothripsis shows the following hallmarks: oscillating copy number between usually two copy number states; the retention of heterozygosity in the regions with the higher copy number state; and clustering of SV breakpoints to a greater extent than would be expected given a background model of the regional propensity to rearrangement54. Chromothripsis appears to be present in 2% to 3% of all cancers and has a higher prevalence in bone cancers (25%)54. It has been reported to be associated with the presence ofTP53 mutations in tumours of diverse origins, including medulloblastomas, acute myeloid leukaemia, and pancreatic tumours73, suggesting a connection to general genome instability. Moreover, chromothripsis has been associated with poorer prognosis in neuroblastoma74, acute myeloid leukaemia73, multiple myeloma75, and malignant melanoma76. In contrast, it has been linked with longer progression-free survival in colorectal cancer77. This suggests that chromothripsis has the potential to be an informative biomarker in tumours but with implications that may differ by cancer type. A further complex pattern of structural rearrangements is chromoplexy80. This is characterised by chains of translocations and deletions that are interdependent. It differs from chromothripsis in that it involves fewer rearrangements per chain (3–40+) and the rearrangements can be spread across up to 10 chromosomes. It is thought that multiple chains of chromoplexy can be formed in successive cell cycles but that all of the SVs in each chain are likely to be formed by one event63. A further sign of chromoplexy is the presence of small deletions between fusion junctions of some translocation rearrangements known as “deletion bridges”79. Chromoplexy is largely copy number neutral and has a high prevalence in prostate cancers (88%)80.It is likely that such a model of mutation is behind complex patterns of genomic rearrangements found in cancer, such as chromothripsis and chromoplexyet al.81 used a large WGS breast cancer cohort20 to identify such regions that appear to harbour greater recurrent structural variation than expected given the genomic characteristics of the region. These characteristics included replication timing domains, gene-rich regions, background copy number, chromatin states, and repetitive sequences. Many of the rearrangement hotspots found were dominated by long (greater than 100 kb) tandem duplications. These hotspots often duplicated key driver genes and regulatory elements and were enriched for breast cancer susceptibility loci and tissue-specific super enhancers. Thus, based upon the functional regions included, some fraction of these hotspots may represent driver events under selection in tumours, but many hotspots may also be generated by mutational bias at these regions (such that they are more prone to mutation or less accessible to repair) mediated by their chromatin structure and replication timing81. Regardless of the relative roles of selection or other processes in their origins, as we discuss below, these patterns of recurrent structural mutation may be clinically informative.Rates of structural mutation vary across the genome, and there are some regions of the genome that are more susceptible to recurrent structural mutation than others. Glodzik83. Indeed, Cirielloet al.82 suggest that there is an inverse relationship between the burden of SNVs and CNAs across tumour types . Although it can be challenging to adjust for the inter-study differences highlighted below, it appears that certain  tumours possess high frequencies of SVs but that other tumour types such as bone cancers and chronic lymphocytic leukaemia do not. However, there are also noticeable differences in the frequencies of mutations reported between cohorts of the same tumour type, which may reflect differences in cellularity, sequencing depth, and the SV callers used across studies. These differences emphasise the challenges that exist in measuring the degree of structural variation across studies with multiple confounding factors. Nevertheless, the clinical utility of certain SVs is already established. Currently, clinically actionable SVs include gene fusions85 , oncogene amplifications , and tumour suppressor deletions . Mertenset al.85 discuss the impact of gene fusions in cancer and describe their utility as effective drug targets  and who are expected to respond to therapies exploiting defective repair, such as poly (ADP-ribose) polymerase (PARP) inhibitors95. The authors also demonstrated the success of HRDetect in predicting HR deficiency in ovarian and pancreatic tumours, suggesting broader potential for therapeutic stratification of patients. Another study has since validated these results, showing that HRDetect provides clinically relevant information independently ofBRCA1/2 mutation status and that high HRDetect scores identified patients with good responses to platinum-based chemotherapy96. However, the input to HRDetect relies on SV calls from a single SV caller. The incorporation of variant calls from additional callers to form consensus calls may be beneficial in ensuring the tool’s robustness. Beyond patient stratification, it has also been shown that SV mutational signatures can be used to predict overall survival in a cohort of HGSOC97. Finally, it has been shown that the burden of SVs and SNVs in a tumour is associated with the degree of infiltration by host immune cells98, linking the mutational state of a tumour to its tendency to elicit an immune response. At the cutting edge of cancer immunotherapy, efforts are under way to exploit such immunogenic tumour mutations and design individual anti-cancer vaccines, placing tumour genomics at the centre of oncology99.In the past, the analysis of somatic mutations in cancer has often focused on recurrent driver mutations located within the small fraction of the genome encoding proteins and thought to confer selective advantages to tumour cells100. The complete reconstruction of the evolutionary trajectory travelled by a tumour could provide new biomarkers for rapid diagnosis and effective treatment and ultimately allow us to predict cancer progression. This comprehensive understanding is currently out of reach and, given the challenges involved, may remain so in the near future101. However, in spite of our ignorance about the functional impacts of SVs and our modest success in detecting somatic mutations accurately, there are good reasons for optimism. Although we still lack the sample sizes required to detect all driver genes for most cancer types102, there have already been unexpected benefits in amassing WGS tumour cohorts, with the genome-wide patterns of damage seen in a tumour providing novel biomarkers and guiding treatment. The next decade will see an explosion in the available data and improvements in analysis, making genomics a routine component of medical practice in oncology.The last few decades have transformed our view of cancer to reveal each tumour as a largely unique constellation of SNV and SV mutations, and a tiny fraction of these mutations drive tumourigenesisAID, activation-induced cytidine deaminase; CML, chronic myeloid leukaemia; CNA, copy number alteration; DSB, double-strand break; HGSOC, high-grade serous ovarian cancer; HR, homologous recombination; ICGC, International Cancer Genome Consortium; NHEJ, non-homologous end joining; RAG, recombination activating gene; SNV, single-nucleotide variant; SV, structural variant; TCGA, The Cancer Genome Atlas; WGS, whole genome sequencinghttps://dcc.icgc.org/releases/current/Projects.The data used to generate


Guidance from economic evaluations on which implementation strategies represent the best return on investment will be critical to advancing the Triple Aim of health care: improving patient care and population health while minimizing per-capita cost. The results of traditional (quantitative) economic evaluations are limited by a remaining “qualitative residual” of contextual information and stakeholders perspectives, which cannot be captured by monetary values alone and is particularly prevalent in implementation science research. The emergence of qualitative methods for economic evaluation offers a promising solution.To maximize the contributions of economic evaluations to implementation science, we recommend that researchers embrace a mixed-methods research agenda that merges traditional quantitative approaches with innovative, contextually grounded qualitative methods. Such studies are exceedingly rare at present. To assist implementation scientists in making use of mixed methods in this research context, we present an adapted taxonomy of mixed-method studies relevant to economic evaluation. We then illustrate the application of mixed methods in a recently completed cost-effectiveness evaluation, making use of an adapted version of reporting standards for economic evaluations.By incorporating qualitative methods, implementation researchers can enrich their economic evaluations with detailed, context-specific information that tells the full story of the costs and impacts of implementation. We end by providing suggestions for building a research agenda in mixed-method economic evaluation, along with more resources and training to support investigators who wish to answer our call to action. In order to advance the three components of the Triple Aim in health care , there iTraditional methods of economic evaluation in health care see –8) compa compa8])These traditional methods are certainly informative to implementation efforts . However, the methods become more complex and challenging when extended to implementation research. Such extensions involve comparing the costs of different implementation strategies to the outcomes  resulting from those strategies. As shown in the equation below, which compares the incremental costs and outcomes of two different implementation strategies, both the intervention and implementation strategy chosen must be considered when evaluating economic impact:An additional challenge in economic evaluation is the “qualitative residual”  that oftRecognizing limitations to exclusive use of quantitative economic evaluations, an increasing number of scholars outside of implementation science have advocated for the incorporation of qualitative data into those evaluations –15. The Formal qualitative research occupies a small but growing place within the field of economics , 19. CerDespite their numerous strengths, we do not suggest that qualitative methods of economic evaluation should replace quantitative methods—which are well-established, rigorous, and have a long and impactful history of use. Instead, we recommend that implementation scientists begin to develop a research agenda around mixed-method economic evaluation. Mixed methods refer to a tradition that combines qualitative and quantitative data to address the same (or closely related) research questions , 23. ComUnfortunately, to date, virtually no research has combined quantitative and qualitative approaches in the economic evaluation of health services. We only located 165 results in a PubMed search on August 31, 2018, for the following terms: “ AND (“mixed method*” OR “mixed-method*”)) AND health.” A search with the same terms in EconLit returned only four results. Of the subset of these results that actually described an economic evaluation, most reported on a purely quantitative economic evaluation in the context of a larger mixed-method study . For examples, see Heller et al.’s  evaluatiGiven a limited primary empirical literature from which to draw, our recommendations for mixed-method economic evaluations instead come from conceptual and methodological literature related to these topics, as well as our own experience conducting qualitative and mixed-method research. That experience includes an economic evaluation, described in more detail later, which is currently undergoing peer review.structure , function , and process  of mixed methods within the study. Table Palinkas and colleagues  previousOur adapted taxonomy differs from the original in three key ways. First, because economic evaluation is ultimately focused on quant questions  and hypothesis testing, a mixed-method economic evaluation is best described as a “pure”  or “quant-dominant mixed” study . TherefoRecently, a subset of the present authors completed a cost-effectiveness evaluation of the implementation of Problematic Sexual Behavior–Cognitive-Behavioral Therapy (PSB-CBT) at six provider agencies nationwide . PSB-CBT is a community-based, group-format treatment that has demonstrated significant effects on problematic sexual behavior in youth ages 7 to 14 (see ). This sdevelopment function, connect-initiate process; see Table Our evaluation benefitted from the use of mixed methods in two key ways. First, we took a Qual ➔ QUAN approach  of these methods by presenting a recently completed study. Through incorporation of qualitative methods, implementation researchers can strengthen their economic evaluations with rich, contextually grounded stories that facilitate the interpretation (and actionability) of their results.What are the full economic costs and consequences of alternative implementation strategies and health services? These types of questions will extend traditional lines of economic evaluation research into the implementation science space. As in evaluation of other implementation outcomes, it will be critical to position findings within the contextual information and stakeholder perspectives provided by qualitative methods. Such information could be particularly valuable for understanding the economics of long-term sustainment of evidence-based practices following initial implementation, given the complex and dynamically changing factors involved.How do the economic costs and consequences of implementation vary as a function of systemic and contextual factors ? This could be an excellent opportunity for simulation modeling and systems science approaches to economic evaluation , in whicWhat are the major sources of uncertainty when estimating the economic impact of implementation efforts, and how should those sources be accounted for? For instance, in implementation studies, it may be unclear to what extent start-up costs  will recur in the future . Another source of complexity is what perspective the economic evaluation should take , given the numerous stakeholder perspectives often represented in implementation efforts . The various scenarios or values to be represented in a sensitivity analysis  can be dWhat is a reasonable return on investment for implementation and service outcomes; e.g., How much should we spend to increase fidelity to PSB-CBT (implementation outcome) or decrease average wait time to receive care (service outcome)? Such thresholds are not currently available in health economics literature , presenting challenges for implementation researchers . IncorpWhat are the best ways to address ethical issues introduced by using mixed methods in economic evaluations of implementation efforts? Inclusion of participant perspectives via qualitative methods certainly advances principles of justice and respect for persons , 21, butOf course, many challenges and unanswered questions remain in this area of research. We hope that other implementation researchers will use the proposed taxonomy and reporting standards to generate a more robust empirical research base. We also encourage those researchers to build on and modify the taxonomy and reporting standards; our example study had some notable limitations  that may have led to concomitant limitations in the tools that we have developed thus far. Rigorous engagement with the proposed research agenda by many experts—working across a variety of implementation strategies, settings, and target evidence-based practices—will be necessary to reach scientific consensus on best practices in mixed-method economic evaluation. Across these various research efforts, examples of questions that could advance implementation science  include:We close by acknowledging that our proposed agenda will require researchers to continue pushing the boundaries of the interdisciplinary team science approaches that are already common—yet remain challenging—in health services research , 26, 36.


Alcohol has sedative, as well as performance and memory-impairing effects. Several independent lines of research indicate that alcohol-induced sleepiness may contribute to the observed memory and performance impairment. Such a link would imply that alcohol consumption in combination with other drugs or conditions that enhance sleepiness could increase the risk for alcohol-related impairment. Alcohol is known to impair various aspects of cognitive functioning, including learning and memory . AlcoholA useful method of conceptualizing the way alcohol may affect memory is offered by This article reviews a wide range of research findings contributing to the hypothesis that alcohol’s direct sedative effects —in addition to its direct memory effects—contributes to alcohol’s amnestic  effects. Studies on both healthy, sleep-deprived people and on patients with sleep disorders and studies of the effects of sedative drugs provide the basis for this hypothesis. Studies separately assessing alcohol’s sedative and amnestic effects or simultaneously measuring alcohol’s sedative and performance-disruptive effects provide further support. The article also describes some of the neurotransmitter systems controlling sleep and wakefulness that are affected by alcohol and other sedative drugs and that may underlie the association of sedation and memory impairment. Finally, some important practical implications of the potential correlation between alcohol’s sedative and memory-impairing effects are discussed.Like hunger and thirst, sleepiness is considered a basic physiological drive state. It reflects the organism’s need or pressure for sleep. Like other physiological drive states, the level of sleepiness is difficult to assess. Despite a general tendency toward increasing sleepiness after sleep loss, most sleep deprivation studies find some inconsistencies in the subjects’ personal assessment of how sleepy they are .Research has shown that people’s ability to accurately judge their degree of sleepiness depends on several factors, such as internal point of reference, environmental demands, and time of day . For exaTo assess sleepiness or alertness or the sedative effects of drugs, such as alcohol, scientists have asked people to self-rate their sleepiness or have used standard laboratory tests of performance. However, for the reasons stated above, self-ratings of sleepiness or sedative drug effects may be inaccurate . SimilarA method to assess sleepiness objectively has been developed, however. This method conceptually is based on an observation originating in the 19th century that as sleep loss progresses over time, people increasingly experience uncontrollable brief naps or microsleeps . In the People with a high degree of sleepiness  fall asleep rapidly when given the opportunity to sleep. These people have a short latency on the MSLT. For example, limiting sleeping time by limiting time-in-bed (TIB) to 5 hours for several consecutive nights progressively decreases the subjects’ sleep latency over the test days . In peopThe MSLT also can measure the effects of stimulant and depressant drugs on sleepiness . StimulaA correlation between sleepiness and memory impairment already was observed in the last century when MSLT studies of patients with different sleep disorders have helped to confirm that sleepiness, which is the consequence of sleep loss or sleep fragmentation , is the intervening variable causing the memory impairment:Patients with sleep apnea syndrome stop breathing during their sleep and wake up to resume breathing, leading to sleep fragmentation. Standardized tests of neuropsychological functioning in these patients detect impairment on a range of cognitive functions, including memory . The extPatients with narcolepsy, a sleep disorder with unknown causes, suffer from excessive daytime sleepiness as documented by short MSLT latencies. Fifty percent of the patients have memory lapses, and 80 percent of the patients report episodes of automatic behavior  .Patients with chronic sleep restriction  complain about persistent daytime sleepiness and have reduced sleep latency on the MSLT . MerrionMemory development encompasses several processes, or phases, that occur when information is stored in the brain. One old and rather simplistic—but in this context, sufficient—model of memory processing distinguishes three phases of memory development . The firSleepiness can interfere with all three phases of memory development. Other studies found that the process of sleep onset or increasing sleepiness also disrupts memory consolidation. In a study by The correlation between sleepiness and memory impairment has been established not only in sleep deprivation studies and in patients with sleep disorders but also in studies of the effects of sedative drugs. Because alcohol also is a sedative drug, these studies may help elucidate the mechanisms of alcohol’s actions on the brain.Sedative drugs interact with several different neurotransmitterGamma-aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters and may promote sleep . Some seGABA agonists also have amnestic effects  that parGABA agonists can interfere with both the stimulus registration phase and the consolidation phase of memory development . The extAcetylcholine is a neurotransmitter that is important for maintaining wakefulness and for increasing the firing rate of nerve cells in the cortex. Drugs that are acetylcholine antagonists  have both sedative and memory-impairing effects, as do the GABA agonists . For exaA role of acetylcholine and acetylcholine antagonists in controlling memory functions is supported by the so-called cholinergic hypothesis of dementia. This hypothesis suggests that dementia is caused by the degeneration and dysfunction of cholinergic  neurons. Administration of acetylcholine antagonists would correspond to a cholinergic dysfunction.Histamine also is a neurotransmitter promoting wakefulness. Histamine antagonists, also called antihistamines, are used for symptomatic treatment of common colds, hay fever, and allergies and are the most common ingredients in over-the-counter sleep medications. Antihistamines that readily cross the blood-brain barrier at clinical doses also increase daytime sleepiness in a dose-dependent manner as measured both subjectively and objectively with the MSLT .Many studies assessing the effects of antihistamines on psychomotor performance detect impaired performance on the tests . The timThese examples show that drugs affecting various neurotransmitter systems can be associated with both sedative and amnestic effects. Some researchers have attempted to reverse the sedative and amnestic effects of a drug affecting one neurotransmitter system by using a drug affecting another neurotransmitter system . These sLaboratory studies evaluating alcohol’s stimulating and sedative effects have found a biphasic response by the test subjects . At low Other studies have focused on alcohol’s sedative effects throughout the descending phase of the BAC curve and beyond. Alcohol’s sedative effects as measured by the MSLT are dose dependent . With inAlcohol’s amnestic effects have been studied extensively. So far, no studies have established the correlation between alcohol’s sedative and amnestic effects by simultaneously assessing memory impairment and objective sleepiness . However, several studies provide indirect evidence for such a correlation.Researchers also have measured alcohol-induced memory impairment and self-rated sleepiness. Another strategy to establish a link between sleepiness and performance impairment—and, by inference, memory impairment—is to first manipulate subjects’ level of sleepiness by reducing or extending their TIB for one or more nights. The subjects then receive alcohol, and alcohol’s sedative and performance-disruptive effects are assessed , 1994a.Reducing TIB increases the level of sleepiness the following day; the increased sleepiness enhances the sedative and performance-disruptive effects of alcohol . For exaIn a similar experiment, simulated driving and psychomotor performance were assessed in subjects who received an alcohol dose of 0.6 gram per kilogram of body weight producing breath ethanol concentrations of 50 milligram-percent  and who had either 8 or 4 hours TIB a. SubjecIn contrast, longer TIB reduces the level of sleepiness  and leads to an attenuation of some of alcohol’s effects . SubjectAlcohol’s sedative and performance-disruptive effects can be attenuated by enhancing the basal level of alertness after alcohol consumption, for example, with daytime naps. Another study examined the capacity of a 60-minute nap to reverse the sedative and performance-disruptive effects of alcohol, a benzodiazepine, and an antihistamine . The effIt is important to note that performance in these studies was assessed using the divided attention and vigilance tasks and therefore did not directly measure memory impairment. Although a thorough evaluation of alcohol-induced sedation and amnesia is needed in the future, the available studies support the hypothesis of a correlation between sedative and amnestic alcohol effects for at least two reasons. First, the alcohol doses used in these studies produced sedation levels (as measured by MSLT) comparable with the levels achieved in some of the sedative drug studies that demonstrated amnestic drug effects. Second, the alcohol doses used to assess objectively measured sedation and performance disruption are comparable with those used in studies that demonstrated alcohol’s amnestic effects without objective measures of sedation levels.Alcohol affects some neurotransmitter systems in the same way that sedative drugs do. For example, alcohol facilitates GABA-mediated inhibition  and reduces the release of acetylcholine  . ConsequIndependent experiments have shown that alcohol causes memory impairment and that alcohol causes sedation. This article has reviewed information suggesting that the two effects may be linked, that is, that alcohol’s amnestic effects are related to its sedative effects. Evidence supporting this hypothesis comes from sleep deprivation studies in healthy people, studies of patients with sleep disorders, studies of drugs with sedative effects, and studies of the interaction between alcohol’s sedative and performance-disruptive effects. However, the sleepiness-memory hypothesis of alcohol effects has not yet been tested directly by manipulating levels of sleepiness and objectively measuring sedation and memory impairment.An association between alcohol’s sedative and amnestic effects could have practical implications for both research and clinical issues. For researchers, such an interaction could affect the design of experiments assessing alcohol’s amnestic or performance-disruptive effects. For example, researchers would need to control for, or at least document, the amount of sleep their subjects get before the experiment. Similarly, the time of day at which tests are performed could affect study results, given the normal variations in people’s sleepiness levels across the day. Inattention to these influences could distort study results and cause inconsistencies when comparing results between studies.From a clinical standpoint, the interaction between alcohol’s sedative and amnestic effects would imply that alcohol consumption combined with any condition or drug producing sleepiness could increase the risk for alcohol-induced memory impairment. For example, subgroups of the general population are known to be sleepier than average. People who shift their sleep schedule frequently  are much sleepier than are people with a regular nighttime sleep schedule. Older people, who experience more fragmented sleep and who are more likely to have undetected sleep disorders, are sleepier than are younger people. In these risk groups, lower alcohol doses than predicted could induce memory impairment. Younger people who periodically sleep less  similarly may experience memory problems after consuming alcohol in amounts they usually tolerate.In addition, drugs with sedative effects could lead to amnesia when combined with alcohol, even at doses normally considered safe. Benzodiazepines, which often are used for patients undergoing alcoholism treatment, could contribute to amnesia if the patients relapse. A brief report in the late 1980’s described three clinical cases of global amnesia  associated with the concurrent use of the benzodiazepine triazolam and alcohol . Many ov


Laparoscopy is widely utilised to diagnose and treat acute and chronic, gynaecological and general surgical conditions. It has only been in recent years that laparoscopy has become an acceptable surgical alternative to open surgery in pregnancy. To date there is little clinical guidance pertaining to laparoscopic surgery in pregnancy. This is why the BSGE commissioned this guideline. MEDLINE, EMBASE, CINAHL and the Cochrane library were searched up to February 2017 and evidence was collated and graded following the NICE-approved process. The conditions included in this guideline are laparoscopic management of acute appendicitis, acute gall bladder disease and symptomatic benign adnexal tumours in pregnancy.The intended audience for this guideline is obstetricians and gynaecologists in secondary and tertiary care, general surgeons and anaesthetists. However, only laparoscopists who have adequate laparoscopic skills and who perform complex laparoscopic surgery regularly should undertake laparoscopy in pregnant women, since much of the evidence stems from specialised centres. The scope of this guideline is the laparoscopic management of non-obstetric, abdominal conditions in pregnancy. Laparoscopy is widely utilised to diagnose and treat, acute and chronic, gynaecological and general surgical conditions. It is only in recent years that laparoscopy has become an acceptable surgical alternative to open surgery in pregnancy. To date there is little clinical guidance pertaining to laparoscopic surgery in pregnancy. This is why the British Society of Gynaecological Endoscopy (BSGE) commissioned this guideline using evidence grading as used by the Royal College of Obstetricians and Gynaecologists (RCOG)  with theThe conditions included in this guideline are acute appendicitis, acute gall bladder disease and symptomatic benign adnexal tumours in pregnancy. The intended audience for this guideline is obstetricians and gynaecologists in secondary and tertiary care, general surgeons and anaesthetists. However, only laparoscopists who have specialist laparoscopic skills and who perform complex laparoscopic surgery regularly should undertake laparoscopy in pregnant women.MEDLINE, EMBASE, CINAHL and the Cochrane library were searched for relevant articles. Literature searches were performed in MEDLINE (from 1950 to September 2015), EMBASE (from 1980 to September 2015), CINAHL (from 1981 to September 2015) and the Cochrane library. No restrictions were placed on the searches in an attempt to reduce selection bias. The databases were searched using the relevant MeSH terms and keywords.A subsequent update search ensured relevant papers were included up to February 2017.The main search terms were ‘laparoscopy’ and ‘pregnancy’, these were used with combinations of the following words and appropriate synonyms, depending upon the area of laparoscopy in pregnancy being examined; anaesthesia, appendicectomy, cholecystectomy, ovarian cysts, performance and safety of imaging.The results of the searches were systematically reviewed to identify relevant articles. The reference lists of selected papers were then searched to identify any additional articles not captured by the literature search. When a study, which was relevant to one of the other topic areas, was identified in a search, we cross-referenced to ensure that it was identified in the relevant search. Studies were included if they addressed the diagnosis and / or management of acute surgical conditions, such as acute appendicitis, acute cholecystitis and symptomatic benign adnexal tumours in pregnancy. Suspected ovarian malignancy, ectopic and heterotopic pregnancy were excluded  Guideline CG122, 2011 and the Where possible, recommendations were based on available evidence and the areas where evidence was lacking were annotated as ‘good practice points’. Further information about the assessment of evidence and the grading of recommendations may be found in appendix 1.What is the incidence of non-obstetrical emergencies in pregnancy?The incidence of acute, non-obstetric abdominal surgical emergencies in pregnancy is low.CClinicians should be aware of the possibility of appendicitis in pregnancy, but its incidence is lower than in the non-pregnant state.DHormonal changes may increase the ultrasound scan findings of gallstones and sludge in pregnancy. However, the risk of gallbladder disease appears to be reduced.DThe absolute numbers of torted and haemorrhagic ovarian cysts are low in pregnancy. Fertility treatment with GnRH analogues involving controlled ovarian stimulation appears to increase these risks.DNon-obstetric abdominal surgery during pregnancy is rare and occurs in 1–2/1000 pregnancies .Evidence level: 2+Two large cohort studies from the USA reported the incidence of appendicitis to be 1 in 1000 pregnancies , of those 39 women had received fertility treatment and nine had not. The relationship between ovarian enlargement and fertility treatment was not investigated .Evidence level: 3What are the specific concerns of ovarian cyst accidents, appendicitis and cholecystitis in pregnancy?Without appropriate surgical treatment, appendicitis and cholecystitis carry specific risks in pregnancy including generalised peritonitis and maternal sepsis resulting in miscarriage, preterm delivery and stillbirth. No data was identified regarding the effect of cyst accidents on pregnancy.DWhen comparing pregnant to non-pregnant women, a large retrospective cohort study showed a higher rate of pre-operative systemic infection (PSI) and systemic inflammatory response syndrome (SIRS) in pregnant women . For appNo studies were identified that compared the incidence of ovarian cyst complications in pregnant and in non-pregnant women in our search. For instance, there are no data on whether cyst accidents lead to more severe peritonitis or haemorrhage when a woman is pregnant. The risk of torsion appears to decrease with increasing gestation in a retrospective series of 107 fertility patients . After oEvidence level: 2-Pregnancy complications secondary to ovarian cysts include fetal loss and premature delivery.Is laparoscopy in pregnancy safe for mother and fetus?In comparison with open surgery, laparoscopy for adnexal and gallbladder disease has no increased risk for mother and fetus. Where appropriate surgical equipment and expertise is available, laparoscopy should be considered an appropriate surgical approach.B in a systematic review of 240 women .Two systematic reviews of non-randomised controlled trial (RCT) studies of laparoscopy for gallbladder disease reported good maternal and fetal safety. Adverse fetal outcomes =0.28-0.63, p<0.001), maternal complications , or intra-operative immediate post-operative surgery related complications  were all less frequent in laparoscopy than in laparotomy . In a noEvidence level: 2++However, the increased report of fetal loss was attributed to a single large study . No adveWhen comparing laparoscopic to open appendectomy, Balinskaite et al.  in a retMazze et al.  reviewedReedy et al.  looked aNo developmental or physical abnormalities were seen in children born to mothers who had laparoscopic surgery between 16 and 28 weeks’ gestation  . The folEvidence level: 2+What are the maternal benefits to laparoscopic compared to open surgery?Laparoscopic surgery is associated with faster recovery, shorter hospital stay and a trend to lower rate of wound infection for pregnant women.CCox et al.  using thEvidence level: 2+In a retrospective review of 2000 cases of open and laparoscopic appendicectomies in pregnancy from the NSQIP database, laparoscopy was associated with fewer wound infections (p=0.04), return to theatre, other infections, respiratory morbidity, venous thromboembolism (VTE), and blood transfusion (p=0.048), whilst open cases had more pre-operative systemic infections .Wilasrusmee et al.  conducteSince the publication of Wilasrusmee et al.  two compSegev et al.  comparedEvidence level: 2-What are the maternal risks from laparoscopy in pregnancy?General laparoscopic surgical risks such as haemorrhage and herniation at the port site also apply to laparoscopy during pregnancy.ADue to enlargement of the uterus and subsequent limitations to visual field and surgical access there is an increased risk of vascular and organ trauma, in particular uterine perforation, although this risk has not been quantified.DClinicians should counsel women about consequences of uterine perforation, which include subsequent uterine rupture, infections, preterm delivery, and laceration of the fetus or the placenta. The size of the perforation is likely to be of importance.✓Clinicians should be aware that there is increased risk of bleeding due to increased vascularity of uterus and adnexae, but this risk is currently not quantified.DA systematic review on cholecystectomy in pregnancy  gives a Evidence level: 1-There are only case reports on trauma to the uterus. Case series of less than five cases were not included in the guideline, with the exception of this section, where no other evidence was available. In one case the uterus was laparoscopically repaired after Veress needle and trocar injury. PROM occurred at 32 weeks. The child was well at 12 months . In a seA case report details the rupture of uterine varicocele at laparoscopic appendectomy at 33 weeks, followed by conversion to emergency caesarean section, with good maternal and neonatal outcome .Evidence level: 3No studies were identified which examined the maternal risks of anaesthesia for women undergoing laparoscopic surgery in pregnancy. Recommendations regarding the maternal anaesthetic risks for non-obstetric laparoscopic surgery in pregnancy have been extrapolated from both non-pregnant women having laparoscopy, and the delivery of anaesthesia in the pregnant population.What are the maternal anaesthetic risks of laparoscopy in pregnancy and how can these specific risks be safely managed?The pre-operative anaesthetic review should include relevant features related to the pregnancy such as gestation and pregnancy related co-morbidities as well as the routine anaesthesia history and examination.✓There should be early involvement of an obstetric anaesthetist, or at the very least consultation with an obstetric anaesthetist.✓Aspiration prophylaxis should be administered, and a strategy for airway management should be made. General anaesthesia and endotracheal intubation are essential, and the use of a laryngeal mask airway is not recommended.DCreation of the pneumoperitoneum should be gradual, as should alterations in maternal positioning.✓Pregnant woman undergoing non-obstetric surgery are at an added risk for venous thromboembolism. Their risk for venous thromboembolism should be stratified and prophylaxis considered as per the Royal College of Obstetricians and Gynaecologists Green-Top Guidance.DAn anaesthetic assessment should include a thorough evaluation of the patient, including timely pre-operative resuscitation if necessary. Aspiration prophylaxis should be administered as part of the premedication, and an early strategy for airway management should be formulated. A rapid sequence induction should be considered to minimise the risk of pulmonary aspiration.Establishment of pneumoperitoneum can be accompanied by marked changes in cardiovascular and respiratory physiology . AlteratEvidence level: 4Non-obstetric surgery during pregnancy is associated with an increased risk of venous thromboembolism (VTE). As a minimum, the RCOG classifies any surgical procedure as an intermediate risk, whereby pharmacological prophylaxis with low molecular weight heparin should be considered  can be used as a surrogate marker for arterial CO2.End-tidal CODNo primary studies were identified that selectively investigated the fetal anaesthetic risks of laparoscopic surgery separately from the risks of the surgical intervention. There are no primary studies that distinguish the effects of anaesthetic factors from surgical factors with regard to fetal risks.2), oxygenation, aorto-caval compression and increased intra-abdominal pressure.The risks of anaesthesia for the fetus of pregnant women undergoing non-obstetric laparoscopic surgery can broadly be divided into two. Firstly, the risks related to pharmacological agents used in anaesthesia and the risk of teratogenicity. Secondly, the risks related to a reduction in uteroplacental blood flow, secondary to changes in maternal mean arterial pressure, partial pressure of arterial carbon dioxide  experienced fewer maternal , fetal  and surgical  complications than other surgeons. Their patients also had a shorter length of stay  in a retrospective cohort study of 9714 predominantly laparoscopic surgeries (89% cholecystectomies) in pregnancy (p<0.0001) .The maternal benefits of laparoscopy  were not observed in cases of perforation of appendix or gallbladder . Timely Maternal and fetal outcomes are satisfactory in both open and laparoscopic interventions , therefoEvidence level: 2-At what gestation should laparoscopic surgery in pregnancy be performed?When deciding on the route of surgery clinicians should be aware that recent small series have shown good maternal and fetal outcomes for laparoscopic appendicectomy, cholecystectomy and adnexal surgery up to 34 weeks gestation, which extends historical recommendation to limit laparoscopic surgery to the second trimester.DAny surgery in pregnancy is associated with maternal and fetal risks. Non-urgent surgery should be postponed until after pregnancy.✓According to previous American College of Obstetrics and Gynecology (ACOG) committee opinion, the second trimester is the best time to carry out non-urgent laparoscopic surgery, because preterm contractions and miscarriage are least likely . FurtherEvidence level: 4A series of third trimester cases managed laparoscopically included five cholecystectomies, four appendicectomies, and two adnexal operations . One patEvidence level: 3Another observational study compared 117 laparoscopic operations  in the first trimester  with laparoscopic surgeries in the second and third trimesters  . No diffEvidence level: 2-Where should laparoscopic surgery in pregnancy be performed?Laparoscopic surgery in pregnancy should be carried out in settings where adequate time, laparoscopic expertise and monitoring facilities are available.✓After the age of fetal viability pregnant women undergoing laparoscopic surgery should be treated in a unit with adequate obstetric and neonatal facilities in case the immediate delivery of the baby is indicated.✓The studies which informed this guideline originated mainly from tertiary care units in developed countries and so the recommendations cannot be extrapolated to all settings.What interventions are needed when planning laparoscopic surgery in pregnancy?Fetal heart Doppler ultrasound monitoring may be done before and after surgery to confirm fetal wellbeing and reassure the mother. There is no need for routine intraoperative monitoring.DIf there is a risk of pre-term delivery antenatal corticosteroids for fetal lung maturation and magnesium sulphate for fetal neuro-protection should be administered dependent upon the gestation of the fetus.AAnti-D administration is not deemed necessary according to guidelines since aparoscopic surgery is not included in the list of potentially sensitising events.ARoutine tocolysis for women undergoing laparoscopic or open surgery in pregnancy is not recommended because it has not been shown to improve outcomes.BCaution needs to be exercised in steroid administration in maternal sepsis.✓In the past intraoperative fetal heart monitoring, especially with open surgery, was seen as mandatory. Newer large case series have shown good outcomes without routine intra-operative fetal heart monitoring during laparoscopy .Evidence level: 3A small quasi-experimental study showed no Doppler anomalies of the fetal heart or the maternal uterine arteries  during laparoscopic surgery on ovarian cysts using a routine laparoscopic approach with less than 12 mmHg pneumoperitoneum .Evidence level: 2+Intra-operative monitoring may be required only in selected cases and when emergency delivery of the fetus is being considered. According to ACOG the following items need to be present before considering fetal monitoring: fetal viability, technical feasibility for intraoperative electronic fetal monitoring, an obstetrician willing to intervene for fetal indications, maternal consent for Caesarean section (CS) (desirable) and feasibility to interrupt laparoscopic surgery for emergency CS . IntraopIf there is a risk of preterm delivery of a viable fetus, antenatal corticosteroids between 24±0 and 35±6 weeks and magnesium for fetal neuro protection should be used up to 33±6 in accordance with existing NICE guidance . Urgent A systematic review showed no difference in the preterm delivery rate between women who received prophylactic tocolysis and those who did not .Laparoscopic surgery is generally not considered a sensitising event and therefore routine administration of prophylactic anti D is not required .Evidence level: 2++The following section discusses intraoperative issues relating to laparoscopy in pregnancy. Specific conditions  will be discussed in Clinicians would be aware that intrauterine manipulation is contraindicated in pregnancy. Hence collaboration with the anaesthetic team  and experienced operating assistance is required.✓In order to improve surgical access without an intrauterine manipulator, alternative strategies include digital vaginal manipulation, planning the placement of surgical ports according to pathology and uterine size, tilting of the surgical table and consideration of thirty-degree laparoscope. Bearing in mind that uterine surface in pregnancy is more friable and can bleed more easily on contact even with blunt instruments, a ‘no touch’ approach should be adopted.How should the primary and secondary ports be placed?For generic entry techniques refer to the RCOG recommendations preventing entry-related gynaecological laparoscopic injuries for non-pregnant women . This seWhere should the primary port be placed in pregnancy?The location of the primary port will depend on the level of the uterine fundus.DThe uterine size should be determined by palpation or ultrasound.✓In the absence of RCTs clinicians should choose their primary port location including umbilical, supra-umbilical / sub-xiphoid and Palmers’ point (left upper quadrant in the mid- clavicular line) according to uterine size, location of pathology and operator experience.DIt has been suggested that in the late second and the third trimesters primary port sites could include 1-2cm below costal margin in the left  or right mid-clavicular line or 3-6 cm above the umbilicus in the midline.DInsertion of an orogastric tube for gastric decompression maybe helpful when Palmer’s point is used for access.✓No study was identified that randomised for location of the primary port, thus no recommendations can be made for one location over another.Researchers describe a variety of different locations for primary ports depending on gestational age .In order to avoid uterine perforation and restricting views from having the camera port too close to the uterus, it is recommended to adjust the port location according to the fundus . TherefoEvidence level: 3Should the Veress or Hasson technique be used for primary port placement?The Hasson technique has been reported inside or above the umbilicus in the midline.DWith either approach clinicians should be mindful of the possibility of uterine injury.DThe benefits of the Hasson technique may include reducing the risk of uterine trauma and spillage of contents of ovarian cysts.✓Clinicians should be aware that in experienced hands direct (gasless) entry may be an alternative, but there is insufficient information in late pregnancy to suggest this as a routine approach.✓Although there are no studies randomised for Hasson’s and Veress’ entry techniques, a number of authors have recorded case series using these approaches throughout all gestations for cholecystectomy , appendiChen et al.  reportedEvidence level: 3Where should secondary ports be placed?Secondary port placement will be dictated by uterine size, pathology and operative approach.DPre-surgical planning is paramount due to the challenges of accessing the pathology, given the limited degrees of freedom in laparoscopic surgery and the added obstacle of the size of the pregnant uterus. Ipsilateral port placement may circumvent this obstacle.✓A systematic search returned no randomised control trials, but authors of case series of appendicectomy , and choEvidence level: 3Secondary port placement should be considered on the same side  as the identified pathology as this technique prevents the surgeon from having to instrument across the pregnant uterus.Evidence level: 4What insufflation pressures and operative pressures should be used in laparoscopic surgery in pregnancy?An intraabdominal pressure of 20-25 mmHg should be used for gas insufflation before inserting the primary trocar .✓Clinicians should be aware that current evidence supports operating pressures of 12 mmHg.DCurrent recommendations on operating pressures in pregnancy are in keeping with recommendations for the non-pregnant state. There are no studies on insufflation pressure during port insertions in pregnancy. The recommendation for an insufflation pressure of 20-25 mmHg is extrapolated from the RCOG recommendation in non-pregnant women . Since tEvidence level: 4No adverse changes to feto-maternal perfusion or adverse pregnancy events were recorded at less than 12 mmHg pneumoperitoneum in a quasi- experimental setting using intraoperative Doppler studies . This waEvidence level: 3What diameter laparoscope is preferred for laparoscopic procedures during pregnancy?Both 5 and 10 mm diameter laparoscopes have been used in pregnancy and choice of diameter depends upon the surgical requirements and availability of equipment.✓The benefits of using a 10 mm diameter laparoscope include better quality of image and the possibility of removing a larger specimen through the camera port. The benefits of a smaller 5 mm laparoscope include the need for smaller incisions with better cosmesis and the ability to insert them through secondary ports to gain different views. Although numerous authors describe their use of 5 and 10 mm laparoscope, no data specifically comparing laparoscope diameter during pregnancy were identified.Evidence level: 4What degree of laparoscope is preferred for laparoscopic procedures during pregnancy?The choice of degree of laparoscope depends upon the preference of the surgeon and the surgical situation. Skilful use of a 30-degree laparoscope might improve the visual field in the presence of a large uterus.✓There are no studies evaluating the optimal degree of laparoscope that should be used in pregnancy.Evidence level: 4Traditionally, many gynaecologists use 0 degree and general surgeons more often use 30 degree laparoscopes. However, extrapolating from non-pregnant laparoscopic surgery on large fibroid uteri, a 30 degree scope can improve visibility in the pelvis in trained hands.Evidence level: 3What retrieval technique should be used to remove surgical specimens during laparoscopic surgery in pregnancy?The choice of extraction method for surgical specimens during laparoscopic surgery in pregnancy should be in accordance with the preference of the operating surgeon.DInfected and potentially dangerous specimens should be contained in a tissue bag.✓Consideration should be given to the use of a tissue bag to avoid peritoneal spill of cystic contents, bearing in mind the likely preoperative diagnosis. For example, care should be taken not to spill contents of dermoid cysts to avoid chemical peritonitis and spillage of potentially malignant cysts as clinical assessment cannot absolutely preclude malignancy .A systematic search identified 10 case series that mention techniques of tissue removal at laparoscopy during pregnancy between 5-34 weeks’ gestation . The indEvidence level: 3Bearing in mind the likely diagnosis of the specimen, consideration should be given to carrying out the dissection within the bag as well as using it for removal.No comparative data to guide preferred techniques for tissue extraction specimen were identified. There was no data on power morcellation, which should be discouraged in pregnancy due to the risk of uterine trauma.What energy modalities should be used during laparoscopic surgery in pregnancy?Ultrasound, bipolar and monopolar energy sources are safe to use during laparoscopy in pregnancy.DThe operating surgeon should choose energy modality based on his or her own preference. The surgeon should be mindful of the principles of safe electrosurgery in laparoscopy.✓No papers were available that investigated energy use during laparoscopic procedures in pregnant women as their main research question. There is no evidence that electrosurgery in a pregnant woman is harmful to the fetus or embryo. When monopolar energy is used it is recommended that the return plate should not be placed such that the uterus is between the electrode and the plate.Amniotic fluid, which is electrolyte rich, protects the fetus from concentration of current and there is no neuromuscular stimulation at the output frequency of electrosurgical generators. Whilst there is a discrepancy between advice from different manufacturers, published literature does not suggest increased risk of energy related complications with any type of energy devices including monopolar during pregnancy.Nine case series’ reported on the use of energy modalities but this was not the main topic under investigation . The ranEvidence level: 3Given the restricted access and visibility in laparoscopy in pregnancy the surgeon needs to respect electrosurgical principles to avoid trauma. General safety rules for monopolar diathermy apply .What wound closure techniques are recommended in pregnancy?The risk of hernia formation is 1-2% in incisions greater than 10 mm, therefore the fascia should be closed.DNo data were identified for port closure after laparoscopy in pregnancy. In non-pregnant women ports greater than 10 mm should be closed by formal sheath closure with a port closure system, such as Endoclose ® (with pneumoperitoneum maintained) or by using a J-needle, unless the Hasson entry technique has been used, in which case previously placed stay sutures are tied together. The risk of postoperative hernia formation is greater at the lateral port sites, especially taking into account the impact of the enlarging uterus on the abdominal wall stretch, which may further increase the risk of herniation. The skin can be closed by a variety of techniques e.g. subcuticular polyglactin and skin glue.Evidence level: 4Should an abdominal drain be inserted peri-operatively on completion of laparoscopic procedures in pregnancy?The operating surgeon should decide whether it is necessary to use a drain based on their preference and assessment of the individual case.DDrain placement has been only described in the context of laparoscopic appendicitis in pregnancy, not for cholecystectomy or adnexal surgery. Comparative data between routine placement , and selEvidence level: 3What maternal care and fetal monitoring should be offered post-operatively?The literature search did not return any studies that investigated fetal monitoring after surgery. Fetal heart Doppler ultrasound monitoring may be done after surgery to confirm fetal wellbeing and reassure the mother.Antibiotics should be used if there is an infective process. The choice of antibiotic should be based upon local anti-microbial guidance and drug safety in pregnancy.✓In the case of elective surgery for adnexal masses, antibiotics would not be routinely required.DGood analgesia, adequate rehydration to maintain euvolaemia and measures to prevent postoperative nausea and vomiting should be integrated into maternal postoperative care.✓In a prospective case series of adnexal cysts operated on electively in the first trimester in 12 women no routine antibiotics were given and there were no complications including infections .Evidence level: 3Is there a role for expectant management of appendicitis in pregnancy?In suspected appendicitis in pregnancy timely surgical intervention is preferable as delay may be associated with adverse maternal and fetal outcomes.CTwo large retrospective studies were identified comparing conservative to operative approach for suspected appendicitis in pregnancy. Abbasi et al.  reportedCheng et al.  investigEvidence level: 2+Tamir et al.  reportedShould the laparoscopic approach to appendicectomy be preferred over laparotomy in pregnancy?Whilst maternal outcomes are good, controversy exists regarding the association of laparoscopic appendicectomy and miscarriage. Further research is needed to distinguish between association and causality. In view of this, it is not possible to recommend one approach over the other and only experienced laparoscopists should carry out these procedures and outcomes should be monitored.CA systematic review of 11 non-randomised comparative studies of open (n=2816) and laparoscopic (n=599) cases for suspected appendicitis in pregnancy was identified . Most caEvidence level: 2++The adverse findings reported by Wilasrusmee et al.  were infEvidence level: 2-A small retrospective study was published after the systematic review by Wilasrusmee et al. . LaustseA large retrospective UK study on hospital data included 3061 appendicectomies . LaparosBoth studies have a large risk of a systematic distortion in measuring the true frequency of miscarriage due to laparoscopy because of the over-representation of first trimester pregnancies in the laparoscopy group.Evidence level: 2+Hence the risk of spontaneous miscarriage associated with appendicectomy during pregnancy should be interpreted with caution.Is there a role for expectant management of cholecystitis in pregnancy?A conservative approach to gallbladder disease  in pregnancy is associated with higher maternal morbidity than surgery.DClinicians should be vigilant about complications of gallbladder disease such as gallstone pancreatitis, since this may be associated with a high risk of fetal mortality.DIn pregnant women with biliary colic, supportive care will lead to resolution of symptoms in most cases. Complicated gallstone disease requires a more proactive approach.✓The search identified one systematic review of moderate quality , and a rDate et al.  systematEvidence level: 2-Should the laparoscopic approach to cholecystectomy be preferred over laparotomy in pregnancy?Laparoscopic cholecystectomy appears to be associated with better composite maternal and fetal outcomes than open approach, fewer surgical complications and shorter hospital stay.CThe search identified a systematic review comparing laparoscopic and open cholecystectomy in pregnancy . SedaghaEvidence level: 2++Should surgery for ovarian cysts be preferred over the conservative approach in pregnancy?Women with asymptomatic simple cysts may be managed conservatively in pregnancy provided that symptoms are absent or acceptable to the woman.DWomen with large, non-torted symptomatic cysts who wish to avoid surgery may be offered aspiration under ultrasound guidance during pregnancy, with definitive cystectomy after delivery if required.DThe risk of torsion of ovarian cysts requiring emergency surgery in pregnancy is low and, in most cases, surgery may be delayed until the woman becomes symptomatic, with good fetal outcomes.DA systematic search identified a retrospective series that observed the rate of torsion and malignancy by adnexal mass size in 470 women who underwent surgery for adnexal masses during all trimesters of pregnancy between 2002-2009 . Fifty-fEvidence level: 2-A systematic search identified four retrospective and two prospective case series that evaluated conservative management of ovarian cysts in pregnancy . No evidCondous et al.  followedZanetta et al.  followedCaspi et al.  followedEvidence level: 3Katz et al.  comparedEvidence level: 2-Majeed et al.  reportedEvidence level: 3Should the laparoscopic approach to ovarian cysts be preferred over the open approach in pregnancy?When surgery is indicated, laparoscopic cystectomy is associated with better maternal outcomes than laparotomy in the second trimester, with similarly good fetal outcomes.BGood maternal and fetal outcomes have also been reported for laparoscopic surgery for the first and third trimester, however the number of reported cases is small. More research is needed to prove the superiority of one approach over the other outside the second trimester. In the interim, choice of approach should be decided based on local circumstances and expertise.✓A Cochrane database review from 2013 did not identify any RCTs . A newerEvidence level: 2++In addition, three further retrospective studies  comparinEvidence level: 2-Cyst aspiration with or without concurrent cystectomy may be a safe alternative.DChung et al.  reportedKitade et al.  reports Guidance on ionising radiation in pregnancy can be found in Health Protections Agency & Royal College of Radiologists & College of Radiographers’ guidance . RecommeThe smallest possible dose of one of the most stable gadolinium contrast agents may be given to the pregnant mother if there is a very strong indication for enhanced MRI. No mutagenic and teratogenic effects have been described after maternal administration of gadolinium based on the limited data available . Webb etThere is mounting evidence that appendicitis, gallbladder disease and symptomatic adnexal cysts can be safely managed laparoscocpically in pregnancy. Most evidence is from specialist centers. Only adequately trained laparoscopists should carry out these procedures and adequate peri- operative preparations are paramount.Especially outside the second trimester most included papers are from small case series and more high-grade evidence is needed. Because it is difficult to perform RCTs for these conditions, creation and analysis of national large databases appears to be a way forward.


High protein diets have become popular for body weight maintenance and weight loss despite controversies regarding efficacy and safety. Although both weight gain and weight loss are determined by energy consumption and expenditure, data from rodent trials consistently demonstrate that the protein:carbohydrate ratio in high fat diets strongly influences body and fat mass gain per calorie eaten. Here, we review data from rodent trials examining how high protein diets may modulate energy metabolism and the mechanisms by which energy may be dissipated. We discuss the possible role of activating brown and so-called beige/BRITE adipocytes including non-canonical UCP1-independent thermogenesis and futile cycles, where two opposing metabolic pathways are operating simultaneously. We further review data on how the gut microbiota may affect energy expenditure. Results from human and rodent trials demonstrate that human trials are less consistent than rodent trials, where casein is used almost exclusively as the protein source. The lack of consistency in results from human trials may relate to the specific design of human trials, the possible distinct impact of different protein sources, and/or the differences in the efficiency of high protein diets to attenuate obesity development in lean subjects vs. promoting weight loss in obese subjects. This has in part been explained by the high satiating effect of high protein meals  and the ryanodine receptor . Cold-sensitive mice lacking UCP1 are not more obesity prone than wild type mice when fed a high fat diet and kept at 21°C  were found to characterize the gut in high protein fed mice  from 2012, where diets low and high in protein content were compared, concluded that high protein diets led to a greater weight reduction after 3 months than low protein diet (Santesso et al., Epidemiological studies indicate that whereas diets with dairy and vegetarian protein sources protect against obesity, diets with a high proportion of meat, in particular red meat, are associated with higher weight gain (Fogelholm et al., Inclusion of fatty fish, lean fish, or fish oil as part of an energy-restricted diet significantly increased weight loss in young overweight men (Thorsdottir et al., The ability of high protein diets using casein or whey as the protein source to prevent weight gain is well-documented in mouse studies. The accompanying reduced feed-efficiency may be related to an increased glucagon:insulin ratio, increased uncoupled respiration and/or ATP loss by futile cycling. To what extent the reduced feed-efficiency and increased energy expenditure are mediated via the gut microbiome is not yet known. Further, intake of high protein diets may lead to reduced insulin signaling in adipose tissue. Of note, these effects appear to be restricted to diets where casein or whey are used as protein sources and evidence that high fat high protein diets are able to induce weight loss in rodents is lacking.The effect of high protein diets on weight loss in humans is not conclusive. However, in line with the importance of the protein source in rodent studies, where obesity development is examined, epidemiological studies indicate that diets with dairy and vegetarian protein sources protect against, whereas diets with meat may promote obesity. However, when diets containing different protein sources are examined in combination with energy restriction, the protein source appears to be of little or no importance. Together, these data indicate that the dietary protein source is of greater importance in preventing weight gain than during weight reduction. It may be considered if dietary means for obesity prevention in lean persons may be different from dietary advices to obese subjects to achieve effective weight loss. Based on the different approaches in human and animal studies investigating dietary protein sources, we encourage to performing more studies in humans and animals focusing on weight gain, weight maintenance and weight loss with different dietary protein sources in order to determine the possible impact of protein source on obesity development and reversal. To what extent high protein intake in humans modulates energy expenditure via the gut microbiome, uncoupled respiration or other energy consuming futile cycles remains to be established.LM researched data and wrote the first draft. LSM, EF, JØ, and KK contributed with text, discussion of the content, illustrations, revised, and/or edited the manuscript before submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Rural communities are home to a disproportionate number of older adults, many of whom are living with a serious illness or providing care to a seriously ill family member or friend. For these individuals, hospice and palliative care services can provide much-needed biopsychosocial and spiritual support, leading to an enhanced quality of life. Technologically-mediated interventions hold promise as a strategy to bridge geographic distances between healthcare providers and rural elders; however, the effect of such interventions may be greater when they are designed in a manner congruent with rural culture and compatible with the technological infrastructure common in rural areas. Informed by lessons learned during a pilot study of a telehealth intervention in one Midwestern state (R21CA191165), this presentation includes a discussion of strategies to more effectively recruit, engage, and retain rural older adults into studies testing technologically-mediated interventions for hospice and palliative care patients and their families.


The advent of optogenetics has ushered in a new era in neuroscience where spatiotemporal control of neurons is possible through light application. These tools used to study neural circuits can also be used therapeutically to restore vision. In order to recapitulate the broad spectral and light sensitivities along with high temporal sensitivity found in human vision, researchers have identified and developed new optogenetic tools. There are two major kinds of optogenetic effectors employed in vision restoration: ion channels and G-protein coupled receptors (GPCRs). Ion channel based optogenetic therapies require high intensity light that can be unsafe at lower wavelengths, so work has been done to expand and red-shift the excitation spectra of these channels. Light activatable GPCRs are much more sensitive to light than their ion channel counterparts but are slower kinetically in terms of both activation and inactivation. This review article examines the latest optogenetic ion channel and GPCR candidates for vision restoration based on light and temporal sensitivity. In America, over 1,000,000 people are currently considered blind, with that number expected to double by 2030  with high temporal resolution  and light sensitivity  and has the largest activation spectrum of the ion channel based opsins tested thus far, ranging from 468 nm to 640 nm , which lowers the concentration of cGMP, closing cyclic nucleotide gated channels and hyperpolarizing the cell. When expressed in non-photoreceptor cells, rhodopsin has a similar light sensitivity to melanopsin of 1012 photons cm−2 s−1  and Müller cells, which have developed specialized mechanisms to deliver the incredibly photosensitive pigment to photoreceptors  experiments, in vivo assays demonstrated effective iterative activation of rhodopsin without the use of exogenous chromophore (Cehajic-Kapetanovic et al., cis and can aberrantly deliver it. Considering that photoreceptors contain approximately a thousand discs each with thousands of rhodopsin molecules (Nathans, cis (Walker et al., cis to melanopsin could potentially also deliver it to rhodopsin when expressed in ganglion or bipolar cells.What is impressive is that the rhodopsin protein is photosensitive at all. Many believed that rhodopsin outside a photoreceptor would be unable to attain its 11-Nathans, , the con11 photons cm−2 at 473 nm (Figure Recently, optically controlled GPCRs have been engineered by multiple groups (Airan et al., m Figure . In degem Figure , the ligThe goal of these ambitious projects is to cure blindness in humans. While transgenic animals are an invaluable laboratory tool, they are not applicable to humans. Viral transduction is currently the best method to constitutively express heterologous proteins in mammals. Other methods like electroporation have been shown to successfully deliver transgenes in mice (de Melo and Blackshaw, The current trend in many laboratories is to try and recapitulate the ON/OFF light response by infecting ON-bipolar cells with improved viral capsids and promoters Figure . The hypWhile this is an admirable goal, bipolar cells are one of the hardest cell types to infect in the retina (Dalkara et al., Instead of trying to restrict expression to bipolar cells, it might be more advantageous to use ubiquitous promoters that would allow expression in bipolar cells and other retinal cells to increase light sensitivity. This way some greater processing is preserved allowing for the generation of ON and OFF light responses, while generally increasing the light sensitivity of the retina as a whole.Bipolar cells direct the ON and OFF pathways in healthy tissue, but that does not mean that bipolar derived signal is the only way to generate ON and OFF signals. There are a variety of inhibitory optogenetic ion channels (Berndt et al., Recently, Berry et al.  improvedThe audacious goal of genetically restoring vision to the blind is now possible. Newly discovered and developed optogenetics have improved upon the original ChR2 studies. By red-shifting ion channels, researchers have made safer alternatives with broader spectrums. And new GPCRs are gaining speed to allow for the temporal precision required for high acuity vision. The new trend to use multiple effectors to generate diverse responses should be expanded further. Humans use three different cone opsins and one rod opsin to generate vivid visual perception. With so many optogenetics with diverse excitation spectra, combination therapies using multiple effectors producing excitatory and inhibitory responses at different wavelengths could generate the complex visual information comparable to responses naturally derived in healthy tissue. With new and innovative therapies constantly being developed, vision restoration is within sight.CB devised the review article. CB and JF wrote it.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Approaching from the left brachial artery is an important access route in endovascular therapy for complicated aortic and peripheral artery cases.Here, we report two cases of a poor access route from the left brachial artery because of asymptomatic axillary artery occlusion (AAO), despite no preoperative upper arm blood pressure laterality, a normal ankle brachial pressure index, and absence of occlusion of the subclavian artery on CT scan.Seventy-six-year-old female. We planned endovascular aneurysm repair (EVAR) for para-renal abdominal aortic aneurysm using the snorkel technique in the renal artery, but we failed to pass through the left subclavian artery when approaching from the left brachial artery because of AAO.Seventy-three-year-old female. We planned zone 2 thoracic endovascular aneurysm repair (TEVAR) for thoracic aortic aneurysm and embolization of the left subclavian artery via the left brachial artery, but we failed to pass through the left subclavian artery because of AAO, and therefore, we simply covered the orifice of the left subclavian artery using a stent graft without embolization.The presence of an asymptomatic AAO may alter the treatment plan but may be difficult to diagnose preoperatively. In those cases in which a brachial or radial artery access is planned, contrast medium should be injected from the contralateral upper extremity during preoperative enhanced CT since the absence of halation of the ipsilateral subclavian/axillary vein provides improved visualization of the AAO which may lead to a better preoperative strategy including the choice of the side of upper extremity access. Recently, endovascular aortic aneurysm repair has made remarkable progress, and it is becoming increasingly common for the access to originate in the upper extremity for complicated aortic aneurysmal cases.In such cases, a left brachial artery approach is commonly chosen. Since we often encounter asymptomatic left subclavian artery occlusion (LSAO), it is an important consideration when planning the operations.Here, we report two cases of a poor access route from the left brachial artery because of asymptomatic axillary artery occlusion (AAO), despite no preoperative upper arm blood pressure laterality, a normal ankle brachial pressure index, and no preoperative occlusion of the subclavian artery on CT scan.A 76-year-old woman  had previously undergone intestinal resection procedures because of superior mesenteric artery occlusion and carotid artery stenting for bilateral internal carotid artery stenosis. As a result, she had a past medical history of old cerebral infarction.We planned endovascular aneurysm repair (EVAR) for para-renal abdominal aortic aneurysm using the snorkel technique for the renal artery, but we failed to pass through the left subclavian artery when approaching from the left brachial artery because of AAO.Before the operation, her pulse was palpable and there was no difference between the left and right upper extremity. Her upper arm blood pressure at that time exhibited no laterality .Preoperative enhanced computed tomography (CT) imaging revealed a para-renal abdominal aortic aneurysm with a maximum diameter of 58 × 63 mm. The axillary artery was densely calcified, but the AAO was not obvious since the contrast medium was injected from the left upper extremity during preoperative enhanced CT, and this caused severe halation at the axillar/subclavian vein, which made visualization of the adjacent left subclavian artery difficult or impossible.We planned EVAR for her para-renal abdominal aortic aneurysm using the snorkel technique in the renal arteries. We attempted cannulation of the renal artery approaching from the left brachial artery, but failed to pass through the left subclavian artery because of AAO. Therefore, we decided to compromise the EVAR by landing the proximal stent in the short neck without the snorkel technique. Since the completion angiogram showed the absence of endoleak and complete exclusion of the aneurysm, we did not access the right upper extremity to perform the originally planned snorkel technique.A 73-year-old woman  had right renal arterial embolism, chronic kidney disease, and pleurisy in her past history.Preoperatively, her upper arm blood pressure exhibited no laterality .Preoperative enhanced computed tomography (CT) imaging revealed a thoracic aortic aneurysm with a maximum diameter of 52 × 50 mm, but the left AAO was not obvious because the left innominate vein’s enhancement concealed LSAO findings.We planned zone 2 thoracic endovascular aneurysm repair (TEVAR) for thoracic aortic aneurysm and embolization of the left subclavian artery via the left brachial artery, but we failed to pass through the left subclavian artery because of AAO, and therefore, we simply covered the orifice of the left subclavian artery using a stent graft without embolization. No endoleak was observed postoperatively.The number of surgical strategies has increased due to recent advancement in endovascular treatment. This, in turn, has increased the number of cases requiring access from the brachial artery in the treatment of aneurysms and peripheral artery diseases.In many of the treatments requiring upper extremity access, approaching from the left subclavian arteries to the aorta and the peripheral arteries is the preferred route because; unlike the right side, it is not necessary to pass across the aortic arch –4.It is well known that peripheral artery diseases or atherosclerosis mostly occurs in the lower extremity, and although less frequent, it does involve the upper arm also. AAO is more prevalent in the left side, and it sometimes makes endovascular treatment difficult when attempting to approach via the left brachial artery .Thoracic outlet syndrome is another cause of AAO and is a well-described disorder caused by thoracic outlet compression of the brachial plexus or the subclavian vessels. Prior reports indicate that subclavian artery compression caused by thoracic outlet syndrome can lead to LSAO, but there have been no reports concerning AAO.Therefore, the causes of AAO are unclear. Obstruction of the axillary artery in baseball pitchers results primarily from damage to the intima caused by repetitive compression of the pectoralis minor muscle by the tendon, the head of the humerus, or both during pitching . There aIn most cases, including asymptomatic patients, preoperative enhanced CT scan makes it possible to diagnose LSAO, and we can infer its presence by the laterality of upper arm blood pressure. However, it is difficult to detect AAO because preoperative CT scans usually focus on the trunk. Furthermore, injecting contrast material from the veins of the left upper arm makes it difficult to diagnosis AAO because the left innominate vein’s enhancement and halation conceal such findings. We believe that one solution is to inject the contrast from the upper extremity contralateral to the side of anticipated upper extremity access.In both of our cases, the patients’ radial pulses were palpable and there was no laterality in upper arm blood pressure, so we were unable to anticipate or identify AAO preoperatively.In our hospital, there have been 150 cases in the past 5 years involving endovascular therapy or angiogram involving access via the left brachial arteries. In two (1.3%) of these cases, AAO findings were observed. In both cases, it was difficult to diagnose AAO preoperatively, but there were similarities in that they were both relatively short, elderly women and experienced mesenteric ischemic events. We believe that the etiology of AAOs in these two cases were caused by atherosclerosis due to the fact that both lesions were densely calcified and also since both had previous medical history of mesenteric ischemia as well as risk factors for atherosclerosis including advanced age, CKD, and stroke.The presence of an asymptomatic AAO may alter the treatment plan but may be difficult to diagnose preoperatively. In those cases in which a brachial or radial artery access is planned, contrast medium should be injected from the contralateral upper extremity during preoperative enhanced CT since the absence of halation of the ipsilateral subclavian/axillary vein provides improved visualization of the AAO which may lead to a better preoperative strategy including the choice of the side of upper extremity access.