Synaptic architecture of leg and wing premotor control networks in Drosophila.

Animal movement is controlled by motor neurons (MNs), which project out of the central nervous system to activate muscles1. MN activity is coordinated by complex premotor networks that facilitate the contribution of individual muscles to many different behaviours2-6. Here we use connectomics7 to analyse the wiring logic of premotor circuits controlling the Drosophila leg and wing. We find that both premotor networks cluster into modules that link MNs innervating muscles with related functions. Within most leg motor modules, the synaptic weights of each premotor neuron are proportional to the size of their target MNs, establishing a circuit basis for hierarchical MN recruitment. By contrast, wing premotor networks lack proportional synaptic connectivity, which may enable more flexible recruitment of wing steering muscles. Through comparison of the architecture of distinct motor control systems within the same animal, we identify common principles of premotor network organization and specializations that reflect the unique biomechanical constraints and evolutionary origins of leg and wing motor control.

Connectomic reconstruction of a female Drosophila ventral nerve cord.

A deep understanding of how the brain controls behaviour requires mapping neural circuits down to the muscles that they control. Here, we apply automated tools to segment neurons and identify synapses in an electron microscopy dataset of an adult female Drosophila melanogaster ventral nerve cord (VNC)1, which functions like the vertebrate spinal cord to sense and control the body. We find that the fly VNC contains roughly 45 million synapses and 14,600 neuronal cell bodies. To interpret the output of the connectome, we mapped the muscle targets of leg and wing motor neurons using genetic driver lines2 and X-ray holographic nanotomography3. With this motor neuron atlas, we identified neural circuits that coordinate leg and wing movements during take-off. We provide the reconstruction of VNC circuits, the motor neuron atlas and tools for programmatic and interactive access as resources to support experimental and theoretical studies of how the nervous system controls behaviour.

Divergent neural circuits for proprioceptive and exteroceptive sensing of the Drosophila leg.

Somatosensory neurons provide the nervous system with information about mechanical forces originating inside and outside the body. Here, we use connectomics to reconstruct and analyze neural circuits downstream of the largest somatosensory organ in the Drosophila leg, the femoral chordotonal organ (FeCO). The FeCO has been proposed to support both proprioceptive sensing of the fly's femur-tibia joint and exteroceptive sensing of substrate vibrations, but it remains unknown which sensory neurons and central circuits contribute to each of these functions. We found that different subtypes of FeCO sensory neurons feed into distinct proprioceptive and exteroceptive pathways. Position- and movement-encoding FeCO neurons connect to local leg motor control circuits in the ventral nerve cord (VNC), indicating a proprioceptive function. In contrast, signals from the vibration-encoding FeCO neurons are integrated across legs and transmitted to auditory regions in the brain, indicating an exteroceptive function. Overall, our analyses reveal the structure of specialized circuits for processing proprioceptive and exteroceptive signals from the fly leg. They also demonstrate how analyzing patterns of synaptic connectivity can distill organizing principles from complex sensorimotor circuits.

Synaptic architecture of leg and wing motor control networks in Drosophila.

Animal movement is controlled by motor neurons (MNs), which project out of the central nervous system to activate muscles. Because individual muscles may be used in many different behaviors, MN activity must be flexibly coordinated by dedicated premotor circuitry, the organization of which remains largely unknown. Here, we use comprehensive reconstruction of neuron anatomy and synaptic connectivity from volumetric electron microscopy (i.e., connectomics) to analyze the wiring logic of motor circuits controlling the Drosophila leg and wing. We find that both leg and wing premotor networks are organized into modules that link MNs innervating muscles with related functions. However, the connectivity patterns within leg and wing motor modules are distinct. Leg premotor neurons exhibit proportional gradients of synaptic input onto MNs within each module, revealing a novel circuit basis for hierarchical MN recruitment. In comparison, wing premotor neurons lack proportional synaptic connectivity, which may allow muscles to be recruited in different combinations or with different relative timing. By comparing the architecture of distinct limb motor control systems within the same animal, we identify common principles of premotor network organization and specializations that reflect the unique biomechanical constraints and evolutionary origins of leg and wing motor control.

Letter to the Editor on: "The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-Analysis."

Dear Editor,We read with interest the recent article "The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-analysis" 1 and after careful appraisal and consideration we feel that some aspects of the data and analysis warrant further review. The study reported some promising results, namely that both chronic and acute exercise appear to improve intratumoral vascularisation in animal models. This is an important finding given increased vascularisation through tumor modulation may have the potential to improve chemotherapy delivery and efficacy 2. However, after conducting further investigations, we query several details in the data extraction and analysis decision-making that we believe impact the conclusions of this article.

Intra-Annual Variation of Eddy Diffusion (k zz ) in the MLT, From SABER and SCIAMACHY Atomic Oxygen Climatologies.

Atomic oxygen (O) in the mesosphere and lower thermosphere (MLT) results from a balance between production via photo-dissociation in the lower thermosphere and chemical loss by recombination in the upper mesosphere. The transport of O downward from the lower thermosphere into the mesosphere is preferentially driven by the eddy diffusion process that results from dissipating gravity waves and instabilities. The motivation here is to probe the intra-annual variability of the eddy diffusion coefficient (k zz ) and eddy velocity in the MLT based on the climatology of the region, initially accomplished by Garcia and Solomon (1985, https://doi.org/10.1029/JD090iD02p03850). In the current study, the intra-annual cycle was divided into 26 two-week periods for each of three zones: the northern hemisphere (NH), southern hemisphere (SH), and equatorial (EQ). Both 16 years of SABER (2002-2018) and 10 years of SCIAMACHY (2002-2012) O density measurements, along with NRLMSIS® 2.0 were used for calculation of atomic oxygen eddy diffusion velocities and fluxes. Our prominent findings include a dominant annual oscillation below 87 km in the NH and SH zones, with a factor of 3-4 variation between winter and summer at 83 km, and a dominant semiannual oscillation at all altitudes in the EQ zone. The measured global average k zz at 96 km lacks the intra-annual variability of upper atmosphere density data deduced by Qian et al. (2009, https://doi.org/10.1029/2008JA013643). The very large seasonal (and hemispherical) variations in k zz and O densities are important to separate and isolate in satellite analysis and to incorporate in MLT models.

Uterine plexiform tumourlets: multifocal and solitary cases with subsets expressing melanocytic markers.

AIMS: Uterine plexiform tumourlets are traditionally regarded as microscopic epithelioid leiomyomas. They are typically solitary incidental findings, but may be multifocal (plexiform leiomyomatosis). We aim to report novel immunohistochemical and morphological findings, specifically the presence of spindled and epithelioid cell nodules, in these lesions. METHODS AND RESULTS: Three cases of plexiform leiomyomatosis and 16 solitary plexiform tumourlets were included. Two cases of plexiform leiomyomatosis and four solitary plexiform tumourlets demonstrated spindled and epithelioid cell nodules which, in one of the former cases, formed expansile masses up to 15 mm. The nodules demonstrated mild cytological atypia and occasional mitotic activity, and they were associated with a myxoid stroma and a lymphohistiocytic infiltrate which imparted a granulomatous appearance to the microscopic lesions. The plexiform tumourlets (solitary and multifocal) consistently expressed desmin, smooth muscle actin, ER and PR, and they commonly co-expressed melanocytic and perivascular epithelioid cell (PEC) markers HMB45, MiTF and cathepsin K. The spindled and epithelioid cell nodules were generally negative for myoid markers and hormone receptors, but expressed p16, cyclin D1 and TFE3. All lesions tested were negative for cytokeratin, S100, melanA, inhibin, EMA, ALK and BCOR; fluorescence in-situ hybridisation was negative for ALK, TFE3 and BCOR rearrangements in one of the larger spindled and epithelioid cell nodules. CONCLUSIONS: Plexiform tumourlets commonly co-express myoid and melanocytic markers and may represent part of the spectrum of gynaecological PEC-related lesions. Some cases are associated with spindled and epithelioid cell nodules that could potentially mimic other uterine myxoid neoplasms.

Fall Creek Monitoring Station: Using Environmental Covariates To Predict Micropollutant Dynamics and Peak Events in Surface Water Systems.

This research aimed to further our understanding of how environmental processes control micropollutant dynamics in surface water systems as a means to predict peak concentration events and inform intermittent sampling strategies. We characterized micropollutant concentrations in daily composite samples from the Fall Creek Monitoring Station over 18 months. These data were compiled alongside environmental covariates, including daily measurements of weather, hydrology, and water quality parameters, to generate a novel data set with high temporal resolution. We evaluated the temporal trends of several representative micropollutants, along with cumulative metrics of overall micropollutant contamination, by means of multivariable analyses to determine which combination of covariates best predicts micropollutant dynamics and peak events. Peak events of agriculture-derived micropollutants were best predicted by positive associations with turbidity and UV254 absorbance and negative associations with baseflow index. Peak events of wastewater-derived micropollutants were best predicted by positive associations with alkalinity and negative associations with streamflow rate. We demonstrate that these predictors can be used to inform intermittent sampling strategies aimed at capturing peak events, and we generalize the approach so that it could be applied in other watersheds. Finally, we demonstrate how our approach can be used to contextualize micropollutant data derived from infrequent grab samples.

Local and Global Influences of Visual Spatial Selection and Locomotion in Mouse Primary Visual Cortex.

Sensory selection and movement locally and globally modulate neural responses in seemingly similar ways. For example, locomotion enhances visual responses in mouse primary visual cortex (V1), resembling the effects of spatial attention on primate visual cortical activity. However, interactions between these local and global mechanisms and the resulting effects on perceptual behavior remain largely unknown. Here, we describe a novel mouse visual spatial selection task in which animals either monitor one of two locations for a contrast change ("selective mice") or monitor both ("non-selective mice") and can run at will. Selective mice perform well only when their selected stimulus changes, giving rise to local electrophysiological changes in the corresponding hemisphere of V1 including decreased noise correlations and increased visual information. Non-selective mice perform well when either stimulus changes, giving rise to global changes across both hemispheres of V1. During locomotion, selective mice have worse behavioral performance, increased noise correlations in V1, and decreased visual information, while non-selective mice have decreased noise correlations in V1 but no change in performance or visual information. Our findings demonstrate that mice can locally or globally enhance visual information, but the interaction of the global effect of locomotion with local selection impairs behavioral performance. Moving forward, this mouse model will facilitate future studies of local and global sensory modulatory mechanisms and their effects on behavior.

Behavioral and epigenetic consequences of oxytocin treatment at birth.

Oxytocin is used in approximately half of all births in the United States during labor induction and/or augmentation. However, the effects of maternal oxytocin administration on offspring development have not been fully characterized. Here, we used the socially monogamous prairie vole to examine the hypothesis that oxytocin exposure at birth can have long-term developmental consequences. Maternally administered oxytocin increased methylation of the oxytocin receptor (Oxtr) in the fetal brain. As adults, oxytocin-exposed voles were more gregarious, with increased alloparental caregiving toward pups and increased close social contact with other adults. Cross-fostering indicated that these effects were the result of direct action on the offspring, rather than indirect effects via postnatal changes in maternal behavior. Male oxytocin-exposed offspring had increased oxytocin receptor density and expression in the brain as adults. These results show that long-term effects of perinatal oxytocin may be mediated by an epigenetic mechanism.

Laparohernioscopic right colectomy for bowel ischaemia within a strangulated inguinal hernia.

Visual inspection of the content of the hernia sac is a crucial step of the emergency repair of strangulated inguinal hernias, to rule out the presence of bowel ischaemia which would need resection. Occasionally the content of the hernia sac reduces spontaneously into the abdomen after the induction of general anaesthesia and cannot be assessed. We present a case where hernioscopy t(i.e. laparoscopy through the hernia sac) has been used to confirm the ischaemia of the strangulated bowel and perform a hybrid laparohernioscopic right colectomy with intracorporeal anastomosis without the need for a formal laparotomy. Hernioscopy is an easy and reliable method to assess the viability of the content of the hernia sac in strangulated hernias that have spontaneously reduced before it could be visually inspected. It can also be associated with a laparoscopic access in a hybrid laparohernioscopic technique to perform complex procedures.

Hernioscopy: a reliable method to explore the abdominal cavity in incarcerated or strangulated inguinal hernias spontaneously reduced after general anaesthesia.

PURPOSE: The diagnosis of bowel or omental ischaemia in strangulated inguinal hernias needs visual exploration of the content of the hernia sac. In some cases, the content of the sac retracts spontaneously into the abdomen at the induction of anaesthesia, so making sure of its viability can be quite difficult. Hernioscopy can allow direct inspection of the whole abdominal cavity and the performance of surgical procedures such as small bowel, large bowel or omental resection, without the need of a formal laparotomy. METHODS: Hernioscopy entails inserting a 10-12-mm trocars in the hernia sac, after its complete mobilization. A 30° camera is then passed into the abdomen through the sac and a thorough examination of the abdominal cavity is performed. If necessary, accessory trocars can be inserted into the hernia sac or through the abdominal wall to perform additional procedures such as bowel resection. After the exploration and the eventual resection, the operation is concluded with a tension-free mesh repair of the hernia. RESULTS: We performed hernioscopy on eight patients. In four of them, no ischaemia was found and the operation was concluded with mesh repair of the hernia. In four patients, a further operative procedure was necessary. No significant postoperative surgical complications were recorded. CONCLUSIONS: Hernioscopy is an easy and reliable method to explore the abdominal cavity and make sure of the viability of the bowel in patients with strangulated inguinal hernia and to proceed to minimally invasive resection if needed.

Urban blue: A global analysis of the factors shaping people's perceptions of the marine environment and ecological engineering in harbours.

Marine harbours are the focus of a diverse range of activities and subject to multiple anthropogenically induced pressures. Support for environmental management options aimed at improving degraded harbours depends on understanding the factors which influence people's perceptions of harbour environments. We used an online survey, across 12 harbours, to assess sources of variation people's perceptions of harbour health and ecological engineering. We tested the hypotheses: 1) people living near impacted harbours would consider their environment to be more unhealthy and degraded, be more concerned about the environment and supportive of and willing to pay for ecological engineering relative to those living by less impacted harbours, and 2) people with greater connectedness to the harbour would be more concerned about and have greater perceived knowledge of the environment, and be more supportive of, knowledgeable about and willing to pay for ecological engineering, than those with less connectedness. Across twelve locations, the levels of degradation and modification by artificial structures were lower and the concern and knowledge about the environment and ecological engineering were greater in the six Australasian and American than the six European and Asian harbours surveyed. We found that people's perception of harbours as healthy or degraded, but not their concern for the environment, reflected the degree to which harbours were impacted. There was a positive relationship between the percentage of shoreline modified and the extent of support for and people's willingness to pay indirect costs for ecological engineering. At the individual level, measures of connectedness to the harbour environment were good predictors of concern for and perceived knowledge about the environment but not support for and perceived knowledge about ecological engineering. To make informed decisions, it is important that people are empowered with sufficient knowledge of the environmental issues facing their harbour and ecological engineering options.

Fall Creek Monitoring Station: Highly Resolved Temporal Sampling to Prioritize the Identification of Nontarget Micropollutants in a Small Stream.

The goal of this research was to comprehensively characterize the occurrence and temporal dynamics of target and nontarget micropollutants in a small stream. We established the Fall Creek Monitoring Station in March 2017 and collected daily composite samples for one year. We measured water samples by means of high-resolution mass spectrometry and developed and optimized a postacquisition data processing workflow to screen for 162 target micropollutants and group all mass spectral (MS) features into temporal profiles. We used hierarchical clustering analysis to prioritize nontarget MS features based their similarity to target micropollutant profiles and developed a high-throughput pipeline to elucidate the structures of prioritized nontarget MS features. Our analyses resulted in the identification of 31 target micropollutants and 59 nontarget micropollutants with varying levels of confidence. Temporal profiles of the 90 identified micropollutants revealed unexpected concentration-discharge relationships that depended on the source of the micropollutant and hydrological features of the watershed. Several of the nontarget micropollutants have not been previously reported including pharmaceutical metabolites, rubber vulcanization accelerators, plasticizers, and flame retardants. Our data provide novel insights on the temporal dynamics of micropollutant occurrence in small streams. Further, our approach to nontarget analysis is general and not restricted to highly resolved temporal data acquisitions or samples collected from surface water systems.

Project HELP: a study protocol to pilot test a shared decision-making tool about treatment options for patients with hepatitis C and chronic kidney disease.

BACKGROUND: Recent advances in treatment have given patients with chronic kidney disease (CKD) access to safer and more effective medications to treat comorbid hepatitis C virus (HCV) infection. Given the variety and complexity of treatment options that depend on patients' clinical characteristics and personal preferences, education and decision support are needed to prepare patients better to discuss treatment options with their clinicians. METHODS: Drawing on International Patient Decision Aids Standards guidelines, literature reviews, and guidance from a diverse expert advisory group of nephrologists, hepatologists, and patients, we will develop and test a HCV and CKD decision support tool. Named Project HELP (Helping Empower Liver and kidney Patients), this tool will support patients with HCV and CKD during decisions about whether, when, and how to treat each illness. The tool will (1) explain information using plain language and graphics; (2) provide a step-by-step process for thinking about treating HCV and CKD; (3) tailor relevant information to each user by asking about the individual's stage of CKD, stage of fibrosis, prior treatment, and comorbidities; (4) assess user knowledge and values for treatment choices; and (5) help individuals use and consider information appropriate to their values and needs to discuss with a clinician. A pilot study including 70 individuals will evaluate the tool's efficacy, usability, and likelihood of using it in clinical practice. Eligibility criteria will include individuals who understand and read English, who are at least 18 years old, have a diagnosis of HCV (any genotype) and CKD (any stage), and are considering treatment options. DISCUSSION: This study can identify particular characteristics of individuals or groups that might experience challenges initiating treatment for HCV in the CKD population. This tool could provide a resource to facilitate patient-clinician discussions regarding HCV and CKD treatment options.

IL-11 is a crucial determinant of cardiovascular fibrosis.

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor ß1 (TGFß1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFß1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFß1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

Are the view of Helicobacter pylori colonized in the oral cavity an illusion?

Urea breath test (UBT), as a leading preferred non-invasive diagnostic technology, but may not be able to detect oral H. pylori. With negative results of UBT, the patient may have an oral infection. On the basis of the fact of success, eradication rate may increase by 21% in the 95% Cl range after the elimination of oral H. pylori, the author believes oral H. pylori does exist and the oral cavity is the second colonized site aside its primary site of the stomach. H. pylori migrated out of Africa along with its human host circa 60 000 years ago; they are not lives in stomach only. In this review article, evidence established in recent years studies with use more appropriate technology had been listed and discussed. The author considers the oral cavity is a black hole for H. pylori infection that significant effective on gastroenterology and another medical field. The role of the oral cavity as the source of H. pylori infection is so controvert in past years. It seems like a human being having a second-time face to discover H. pylori in the history.

Real-world weight change among patients treated with glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor and sulfonylureas for type 2 diabetes and the influence of medication adherence.

AIMS: The study aims to examine real-world weight change and the role of medication adherence among patients with type 2 diabetes who initiated one of three drug classes: glucagon-like peptide-1 receptor agonist (GLP-1RA), dipeptidyl peptidase-4 inhibitor (DPP4) and sulfonylureas (SUs). MATERIALS AND METHODS: A cohort of patients initiating one of the three drug classes was selected from a large US database of integrated electronic medical record and administrative claims. Adherence was defined as per cent of days covered ≥80% during the year following drug initiation. Weight change was calculated from drug initiation (-180, +30 d) to 1 year (±90 d) later. Multivariate regression controlled for baseline differences between adherent and poorly adherent patients and the addition of another drug class during follow-up. RESULTS: The study included 833 GLP-1RA, 2,272 DPP4 and 2,713 SU patients who contributed 2,279, 6,602 and 7,429 observations respectively. Patients initiating a GLP-1RA achieved the largest weight change (-2.46 kg of GLP-1RA, -1.26 kg of DPP4 and 0.18 kg of SU, P < 0.01). Adherent GLP-1 patients lost 1.73 kg more than poorly adherent patients, and adherent SU patients gained 1.11 kg more than poorly adherent patients (all P < 0.01). Adherent and poorly adherent DPP4 patients experienced approximately the same amount of weight loss. CONCLUSIONS: Medication adherence can mediate observed weight loss in patients treated with a GLP1-RA or weight gain in those treated with an SU. Medication adherence was low in a real-world population, particularly for GLP-1RA, which displayed the strongest weight loss benefit. Because recent American Diabetes Association guidelines recommend selecting drug therapies that have a weight loss or weight neutral effect for the management of type 2 diabetes patients, patients should be encouraged to enhance their adherence to benefit the most from therapies that have weight loss properties.

Utility of a precursor-to-product ratio in the evaluation of presumptive positives in newborn screening of congenital adrenal hyperplasia.

OBJECTIVE: Screening for congenital adrenal hyperplasia (CAH) caused by 21-α-hydroxylase deficiency is challenging because factors such as prematurity and stress increase intermediate steroid metabolite levels in newborn infants. The objective of this study was to explore the use of the 17-α-hydroxyprogesterone (17-OHP)/11-deoxycortisol ratio as an adjunct measure in the follow-up evaluation of infants with presumptive positive newborn screens for CAH to distinguish between infants with no disorder and those with CAH. STUDY DESIGN: This was a retrospective cohort study of infants with presumptive positive newborn screens for CAH. The precursor-to-product ratio of 17-OHP/11-deoxycortisol was compared between infants with no disorder (n=47) and infants with CAH (n=5). RESULTS: The CAH infants had higher 17-OHP/11-deoxycortisol ratios than infants with no disorder: 26 (18 to 58) and 1.05 (0.69 to 1.46), respectively (P<0.05). Among infants with no disorder, higher levels of serum 17-OHP did not reflect higher ratios, indicating sufficient enzyme activity. CONCLUSION: The results suggest that a low 17-OHP/11-deoxycortisol ratio represents 21-α-hydroxylase sufficiency among presumptive positives in newborn screening of CAH.

Risk factors for lymphoedema in women with breast cancer: A large prospective cohort.

A prospective study was conducted to identify women at increased risk for lymphoedema (LE) based on axillary surgery. Assessment occurred prior to surgery, within 4 weeks, and at 6, 12 and 18 months following surgery. Following post-surgery assessment, women were asked to complete weekly diaries regarding events that occurred in the previous week. Risk factors were grouped into demographic, lifestyle, breast cancer treatment-related, arm swelling-related, and post-surgical activities. Bioimpedance spectroscopy thresholds were used to determine presence of LE. At 18-months, 241 women with <5 nodes removed and 209 women with ≥5 nodes removed were assessed. For those with <5 nodes removed, LE was present in 3.3% compared with 18.2% for those with ≥5 nodes removed. There were insufficient events to identify risk factors for those with <5 nodes removed; for those with >5 nodes removed, independent risk factors included presence of arm swelling at 12-months (Odds Ratio (OR): 13.5, 95% CI 4.8, 38.1; P < 0.01), at 6-months (5.6 (2.0, 16.9); P < 0.01), and radiotherapy to the axilla (2.6 (0.7, 8.9); P = 0.14). Arm swelling at 6 and 12 months was associated with taxane-based chemotherapy, high body weight at diagnosis and arm swelling within 4 weeks post-surgery. Of the post-surgical events assessed in a sub-group of women with >5 nodes removed and who maintained weekly diaries, only blood drawn from the 'at-risk' arm was identified as a potential risk (OR 2.0; 0.8, 5.2). For women with ≥5 nodes removed, arm swelling in the first year poses a very strong risk for presence of LE at 18-months.