Computational fluid dynamic modeling of the lymphatic system: a review of existing models and future directions.

Historically, research into the lymphatic system has been overlooked due to both a lack of knowledge and limited recognition of its importance. In the last decade however, lymphatic research has gained substantial momentum and has included the development of a variety of computational models to aid understanding of this complex system. This article reviews existing computational fluid dynamic models of the lymphatics covering each structural component including the initial lymphatics, pre-collecting and collecting vessels, and lymph nodes. This is followed by a summary of limitations and gaps in existing computational models and reasons that development in this field has been hindered to date. Over the next decade, efforts to further characterize lymphatic anatomy and physiology are anticipated to provide key data to further inform and validate lymphatic fluid dynamic models. Development of more comprehensive multiscale- and multi-physics computational models has the potential to significantly enhance the understanding of lymphatic function in both health and disease.

Investigations into the Melitaea ornata species complex in the Levant: M. telona and the newly erected species Melitaea klili Benyamini, 2021 (Lepidoptera: Nymphalidae).

Melitaea klili Benyamini, 2021 was recently described from Israel as a species closely related to M. telona Fruhstorfer, 1908, but different in phenology, ecological preferences and with an allopatric distribution. Here, based on comparative examinations of mitochondrial DNA-barcodes, male genitalia and larval behaviour under laboratory conditions, we synonymize M. klili with M. telona. The COI barcodes of M. klili were found to be identical to those of M. telona. Analysis of 658 bp fragment of the mitochondrial gene COI demonstrated that the minimum uncorrected p-distance between M. ornata and M. telona was 1.98%. This value is remarkably less than the 3% threshold traditionally accepted as a species boundary in DNA barcoding studies. The morphological differences between these taxa are minimal. In fact, M. ornata and M. telona represent two phylogenetic lineages, the taxonomic status of which (separate species or subspecies of the same species) is intermediate and debatable.

Kidney Lymphatics.

Following significant advances in lymphatic biology, the important role of kidney lymphatics in kidney function and dysfunction is now being more fully appreciated. Kidney lymphatics begin in the cortex as blind-ended lymphatic capillaries and then coalesce into larger lymphatics that follow the main blood vessels out through the kidney hilum. Their function in draining interstitial fluid, macromolecules, and cells underpins their important role in kidney fluid and immune homeostasis. This article provides a comprehensive overview of recent and more established research findings on kidney lymphatics and the implications of these findings for kidney function and disease. The use of lymphatic molecular markers has greatly expanded our knowledge of the development, anatomy, and pathophysiology of kidney lymphatics. Significant recent discoveries include the diverse embryological source of kidney lymphatics, the hybrid nature of the ascending vasa recta, and the effects of lymphangiogenesis on kidney diseases such as acute kidney injury and renal fibrosis. On the basis of these recent advances, there is now an opportunity to link information from across multiple research disciplines to drive a new era of lymphatic-targeted therapies for kidney disease. © 2023 American Physiological Society. Compr Physiol 13:4945-4984, 2023.

Notes on the Melitaea ornata Christoph, 1893, complex in the Levant (Lepidoptera: Nymphalidae) including new synonymy and observations on lectotype designations for Melitaea phoebe dorae Graves, 1925.

Two independent designations for a lectotype of Melitaea phoebe dorae Graves, 1925, are discussed and resolved. Errors of labelling in presentation of some Melitaea taxa in recent literature are identified. Synonymy of the name klili Benyamini, 2021, with M. telona Fruhstorfer, 1908, is confirmed; the name tzinensis Benyamini, 2023 syn nov., is discussed and placed in synonymy with M. telona Fruhstorfer, 1908.

A Patient with Concurrent Legionella and COVID-19 Infection in a UK District General Hospital.

A 65 year-old gentleman had been brought to our Respiratory Emergency Department for patients with respiratory symptoms and a possible COVID-19 infection with a 3-day history of shortness of breath (SOB), fever, a productive cough of yellow sputum, and right-sided chest pain. The patient had received both vaccinations at the time and initially reported no travel history, although later it was revealed that he had recently stayed at a hotel. He tested positive for COVID-19 and had hyponatremia and a raised procalcitonin, indicating a bacterial infection as well. He had been initiated on our local treatment guidelines for COVID with antibiotics, guided by local hospital guidelines. An atypical pneumonia screen returned a positive result for Legionella urine antigen, and his antibiotic regime was changed accordingly. Our patient deteriorated significantly, and despite being escalated to our intensive care unit (ICU), he unfortunately passed away. Our case highlights the importance of early ICU involvement and escalation of antibiotics in cases of suspected concurrent Legionella and COVID-19 infections.

Reassessment of the status of some European and Asian Melitaea taxa described as subspecies of Melitaea phoebe ([Denis amp; Schiffermller], 1775), with designations of lectotypes where appropriate (Lepidoptera: Nymphalidae).

Morphological characters of value in distinguishing Melitaea phoebe from M. ornata are exemplified from photographs of specimens from sympatric and partially synchronic populations in the Russian Federation and Slovenia. Type material of a number of subspecies classified as M. phoebe have been examined and confirmed as being subspecies of M. phoebe or as subspecies of either M. ornata or M. telona. Larval and adult morphology of M. telona is very similar to those of M. ornata, making morphological separation difficult. Distribution of M. telona forms a major criterion for separation. Lectotypes are designated for amanica Rebel, 1917 and dorae Graves, 1925. The name enoch Higgins, 1941 is recognised as a distinct species and the names abbas Gross Ebert, 1975 and zagrosi Tth Varga, 2011 synonymised with Melitaea enoch.

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial.

BACKGROUND: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. METHODS: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. FINDINGS: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. INTERPRETATION: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. FUNDING: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.

A Review of Outcome Reporting Practices after Flexor Tendon Repair in Zones 1 and 2.

Background: Outcome reporting following flexor tendon repair has historically concentrated on range of movement. Recently, there has been an increase in the use of patient-reported outcome measures (PROMs). At present, there is no agreed set of outcomes to report following flexor tendon repair. The aim of this study is to review outcome reporting practices after flexor tendon repair in zones 1 and 2. Methods: A search of Ovid MEDLINE, Ovid EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between 1 January 1980 and 31 December 2019 was performed to identify the studies that reported outcomes following the repair of flexor tendons in zones 1 and 2. Study characteristics and data with regard to the reporting of eight outcome domains was extracted: functional outcome (quantitative), functional outcome (subjective), activities of daily living (ADL), satisfaction/quality of life, post-treatment recovery, resources, aesthetics and safety. Results: A total of 94 out of 4,118 articles identified were included in the review. All studies reported range of motion using 17 different methods of measurement. Eleven studies defined measurement methods incorrectly or unclearly. Only 16 studies reported PROMs, with only one reporting data on assessment of quality of life. Eighteen studies reported time away from employment. Minimal data on resource utilisation and aesthetics were included. Conclusion: This review highlights wide heterogeneity and paucity of data reporting clinical outcomes of flexor tendon surgery. The development of a core outcome set that would ensure essential outcomes are correctly defined, measured and reported is required. Level of Evidence: Level IV (Prognostic).

A comparative analysis of multidimensional computerized adaptive testing for the DASH and QuickDASH scores in Dupuytren's disease.

The QuickDASH is a short-form version of the DASH questionnaire, the most widely used patient-reported outcome measure in hand surgery. Multidimensional computerized adaptive testing (MCAT) can produce shorter and more precise testing than static short forms, like QuickDASH. We used DASH responses from 507 patients with Dupuytren's disease to develop a MCAT. The algorithm was evaluated in a Monte Carlo simulation, where the standard error of measurement (SEm) of scores obtained from the 11-item QuickDASH was compared with scores obtained from an MCAT that could administer up to 11 items from the full 30-item DASH. The MCAT asked a mean of 8.51 items (SD 2.93) and 265/1000 simulated respondents needed to complete ≤five items. Median SEms were better for DASH MCAT: 0.299 (hand function) and 0.256 (sensory symptoms) versus 0.320 and 0.290, respectively, for QuickDASH. Our study showed that the DASH MCAT can produce more precise DASH measurement than the QuickDASH, from fewer items.

Vmeasur: A software package for experimental and clinical measurement of mesenteric lymphatic contractile function over an extended vessel length.

OBJECTIVE: Conventionally, in vivo mesenteric lymphatic contractile function is measured using a high magnification transmission microscope (field of view 0.3-1.5 mm), which precludes visualization of extended lengths of vessels embedded in mesenteric fat. Existing software is not optimized for imaging at a low magnification using a contrast agent. We aimed to develop a simple and clinically transferable method for in situ visualization, image analysis, and quantitative assessment of mesenteric lymphatic contractile function over an extended area. METHODS: Subserosal injection of various blue dyes was taken up by mesenteric lymphatics and visualized under a stereomicroscope (25×), allowing for video recording of 1.4 × 1.1 cm of intact mesentery. A new R package ("vmeasur") that combines multiple high-performance image analyses into a single workflow was developed. The edges of each vessel were determined by applying an automated threshold to each frame (with real-time manual verification). The vessel width at every point in each frame was plotted to provide contractile parameters over time and along the lymphatic vessel length. RESULTS: Contractile parameters and their differences along the length of the vessel were accurately calculated in a rodent model. In a human mesenteric lymphatic, the algorithm was also able to measure changes in diameter over length. CONCLUSION: This software offers a low cost, rapid, and accessible method to measure lymphatic contractile function over a wide area, showing differences in contractility along the length of a vessel. Because the presence of mesenteric fat has less of an impact on imaging, due to the use of an exogenous contrast agent, there is potential for clinical application.

Lymphatic contractile function: a comprehensive review of drug effects and potential clinical application.

The lymphatic system and the cardiovascular (CV) system work together to maintain body fluid homeostasis. Despite that, the lymphatic system has been relatively neglected as a potential drug target and a source of adverse effects from CV drugs. Like the heart, the lymphatic vessels undergo phasic contractions to promote lymph flow against a pressure gradient. Dysfunction or failure of the lymphatic pump results in fluid imbalance and tissue oedema. While this can be due to drug effects, it is also a feature of breast cancer-associated lymphoedema, chronic venous insufficiency, congestive heart failure, and acute systemic inflammation. There are currently no specific drug treatments for lymphatic pump dysfunction in clinical use despite the wealth of data from pre-clinical studies. The aim of this study was to identify (i) drugs with direct effects on lymphatic tonic and phasic contractions with potential for clinical application, and (ii) drugs in current clinical use that have a positive or negative side effect on lymphatic function. We comprehensively reviewed all studies that tested the direct effect of a drug on the contractile function of lymphatic vessels. Of the 208 drugs identified from 193 studies, about a quarter had only stimulatory effects on lymphatic tone, contraction frequency, and/or contraction amplitude. Of Food and Drug Administration-approved drugs, there were 14 that increased lymphatic phasic contractile function. The most frequently used class of drugs with inhibitory effects on lymphatic pump function were the calcium channels blockers. This review highlights the opportunity for specific drug treatments of lymphatic dysfunction in various disease states and for avoiding adverse drug effects on lymphatic contractile function.

Osseointegrated implant survival, success and prosthodontic outcomes in composite free flaps: A 10-year retrospective cohort study.

OBJECTIVES: To evaluate implant survival, success and prosthodontic outcomes in a variety of composite free flaps. MATERIAL AND METHODS: A retrospective analysis of patient records was used for data collection of implants placed into flaps. Free flap donor sites included fibula, iliac crest, scapula, medial femoral condyle and radial forearm. Kaplan-Meier survival curves were used to estimate survival. Cox regression was used to assess variables affecting survival, and binary logistic regression was utilised to determine effect of variables on prosthodontic outcomes. RESULTS: There were 150 implants placed into 45 fibula, 98 implants into 29 iliac crest, 62 implants into 22 scapula, 6 implants into 3 medial femoral condyle and 2 implants in radial forearm composite free flaps. There was no difference in survival or success between or within the various flaps. Active smoking, increasing age, male gender and radiotherapy were associated with implant failure. Of patients completing prosthodontic rehabilitation, 93% were successful. There was no difference in likelihood of failure between different flap types. Fixed implant-supported dentures were associated with poor oral hygiene compared with removable designs (OR2.9, 95%CI 1.1-7.8, p = .03). CONCLUSIONS: There is adequate survival and success of implants in common flaps. Caution is required when planning implants in patients exposed to radiotherapy and smokers. Ability to maintain adequate oral hygiene is an important prosthetic design consideration.

Genome wide methylation profiling of selected matched soft tissue sarcomas identifies methylation changes in metastatic and recurrent disease.

In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genome-wide methylation changes occur during metastatic and recurrent (Met/Rec) disease. A range of sarcoma types were selected for this study: leiomyosarcoma (LMS), myxofibrosarcoma (MFS), rhabdomyosarcoma (RMS) and synovial sarcoma (SS). We identified differential methylation in all Met/Rec matched samples, demonstrating that epigenomic differences develop during the clonal evolution of sarcomas. Differentially methylated regions and genes were detected, not been previously implicated in sarcoma progression, including at PTPRN2 and DAXX in LMS, WT1-AS and TNXB in SS, VENTX and NTRK3 in pleomorphic RMS and MEST and the C14MC / miR-379/miR-656 in MFS. Our overall findings indicate the presence of objective epigenetic differences across primary and Met/Rec human tissue samples not previously reported.

The Lymphovenous Junction of the Thoracic Duct: A Systematic Review of its Structural and Functional Anatomy.

Background: The lymphovenous junction (LVJ) of the thoracic duct (TD) is the principle outlet of the lymphatic system. Interest in this junction is growing as its role in lymphatic outflow obstruction is being realized, and as minimally invasive procedures for accessing the terminal TD become more common. Despite the growing clinical significance of the LVJ, its precise form and function remain unclear. The aim of this article was to systematically review the literature surrounding the structure and function of the LVJ and its associated lymphovenous valve (LVV). Methods and Results: A systematic review of the structure and function of the LVJ and LVV was undertaken using the MEDLINE, Scopus, and Google Scholar databases. Human and animal studies up to November 2019, with no language or past date restriction, were included. Forty-six relevant articles were reviewed. The LVJ shows marked anatomical variation. A valve is frequently absent at the LVJ, but when present it displays numerous distinct morphologies. These include bicuspid semilunar, ostial, and flap-like structure. Other factors, such as functional platelet plugs, or the tangential/intramural course of the terminal TD across the vein wall, may work to prevent blood from entering the lymphatic system. Conclusions: The form and function of the LVJ remain unclear. Dedicated studies of this area in vivo are required to elucidate how this part of the body functions in both health and disease.

The effect of the COVID-19 lockdown on hand trauma surgery utilization.

AIMS: The aim of this study was to evaluate the need for hand trauma services during the COVID-19 pandemic lockdown, specifically related to surgical requirements. This will provide useful information for planning and resource allocation in the event of any further lockdown. METHODS: A prospective analsysis of all patients attending our hand trauma unit throughout the UK COVID-19 lockdown period (24 March to 10 May 2020) was carried out. Prospectively collected departmental data from the same period in 2019 was obtained and reviewed for comparison. The number of patients attending clinic, undergoing surgery, the type of surgical procedure, and rate of surgery was compared. RESULTS: In all, 463 patients attended hand trauma services during the lockdown period compared to 793 in 2019 (32% reduction); 190 surgical procedures were carried out during lockdown compared to 236 in 2019 (20% reduction). Intervention rate was higher during the lockdown period (41% compared to 30%). There was no difference in the type of cases. In the first half of lockdown, 47% fewer procedures were performed than in 2019, but in the second half of lockdown 13% more procedures were carried out than the same period in 2019. CONCLUSION: Requirements for hand trauma surgery remain high during a pandemic lockdown. Attendances and surgical requirements can be expected to steadily return to normal levels during a prolonged lockdown period. Throughout any future lockdown period adequate surgical provision must be maintained for patients with hand injuries.Cite this article: Bone Joint Open 2020;1-10:639-643.

Goal-directed haemodynamic therapy (GDHT) in surgical patients: systematic review and meta-analysis of the impact of GDHT on post-operative pulmonary complications.

BACKGROUND: Perioperative goal-directed haemodynamic therapy (GDHT), defined as the administration of fluids with or without inotropes or vasoactive agents against explicit measured goals to augment blood flow, has been evaluated in many randomised controlled trials (RCTs) over the past four decades. Reported post-operative pulmonary complications commonly include chest infection or pneumonia, atelectasis, acute respiratory distress syndrome or acute lung injury, aspiration pneumonitis, pulmonary embolism, and pulmonary oedema. Despite the substantial clinical literature in this area, it remains unclear whether their incidence is reduced by GDHT. This systematic review aims to determine the effect of GDHT on the respiratory outcomes listed above, in surgical patients. METHODS: We searched the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, EMBASE, and clinical trial registries up until January 2020. We included all RCTs reporting pulmonary outcomes. The primary outcome was post-operative pulmonary complications and secondary outcomes were specific pulmonary complications and intra-operative fluid input. Data synthesis was performed on Review Manager and heterogeneity was assessed using I 2 statistics. RESULTS: We identified 66 studies with 9548 participants reporting pulmonary complications. GDHT resulted in a significant reduction in total pulmonary complications (OR 0.74, 95% CI 0.59 to 0.92). The incidence of pulmonary infections, reported in 45 studies with 6969 participants, was significantly lower in the GDHT group (OR 0.72, CI 0.60 to 0.86). Pulmonary oedema was recorded in 23 studies with 3205 participants and was less common in the GDHT group (OR 0.47, CI 0.30 to 0.73). There were no differences in the incidences of pulmonary embolism or acute respiratory distress syndrome. Sub-group analyses demonstrated: (i) benefit from GDHT in general/abdominal/mixed and cardiothoracic surgery but not in orthopaedic or vascular surgery; and (ii) benefit from fluids with inotropes and/or vasopressors in combination but not from fluids alone. Overall, the GDHT group received more colloid (+280 ml) and less crystalloid (-375 ml) solutions than the control group. Due to clinical and statistical heterogeneity, we downgraded this evidence to moderate. CONCLUSIONS: This systematic review and meta-analysis suggests that the use of GDHT using fluids with inotropes and/or vasopressors, but not fluids alone, reduces the development of post-operative pulmonary infections and pulmonary oedema in general, abdominal and cardiothoracic surgical patients. This evidence was graded as moderate.PROSPERO registry reference: CRD42020170361.

Prevalence of PD-L1 expression in matched recurrent and/or metastatic sarcoma samples and in a range of selected sarcomas subtypes.

We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher's exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.