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.

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.

Anatomy of the lymphovenous valve of the thoracic duct in humans.

The majority of lymph generated in the body is returned to the blood circulation via the lymphovenous junction (LVJ) of the thoracic duct (TD). A lymphovenous valve (LVV) is thought to guard this junction by regulating the flow of lymph to the veins and preventing blood from entering the lymphatic system. Despite these important functions, the morphology and mechanism of this valve remains unclear. The aim of this study was to investigate the anatomy of the LVV of the TD. To do this, the TD and the great veins of the left side of the neck were harvested from 16 human cadavers. The LVJs from 12 cadavers were successfully identified and examined macroscopically, microscopically, and using microcomputed tomography. In many specimens, the TD branched before entering the veins. Thus, from 12 cadavers, 21 LVJs were examined. Valves were present at 71% of LVJs (15/21) and were absent in the remainder. The LVV, when present, was typically a bicuspid semilunar valve, although the relative size and position of its cusps were variable. Microscopically, the valve cusps comprised luminal extensions of endothelium with a thin core of collagenous extracellular matrix. This study clearly demonstrated the morphology of the human LVV. This valve may prevent blood from entering the lymphatic system, but its variability and frequent absence calls into question its utility. Further structural and functional studies are required to better define the role of the LVV in health and disease.

Establishing prostate cancer patient derived xenografts: lessons learned from older studies.

BACKGROUND: Understanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling. METHODS: We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G-banding. RESULTS: Tissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU-PR-1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU-PR-2, which combined epithelial and neuroendocrine features) have been described. UCRU-PR-4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43-46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), -5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), -22, +r4[cp8]. CONCLUSIONS: Xenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model.

Endocervical adenocarcinoma in situ presenting in fundal endometrial polyp: the mother of all skip lesions.

A 38-yr-old woman, with a previous history of low grade squamous intraepithelial lesion in the cervix, presented with heavy menstrual bleeding. At hysteroscopy, a fundal polyp was removed from the right cornu which displayed many glands lined by atypical, mitotically active epithelium with features characteristic of endocervical adenocarcinoma in situ (AIS) of intestinal subtype. Subsequent cervical liquid-based cytology and colposcopically directed biopsies revealed no causative lesion, but residual PreservCyt from the ThinPrep vial tested positive for high risk HPV type other than HPV 16 and 18. Further biopsies from the endocervical canal and base of the resected polyp showed intestinal type AIS, while all those from the intervening anterior and posterior endometrial lining exhibited normal endometrium only. Genomic DNA extracted from the endometrial polyp and second set of endocervical biopsies tested positive for HPV 31, an uncommon cause of endocervical glandular neoplasia. Endocervical AIS typically arises in the transformation zone but may be found exclusively in the endocervical canal and rarely as high as 30 mm from the ectocervix. Contiguous spread into the lower uterine segment is known to occur, as are proximate so-called skip lesions. However, finding a 'skip' lesion 80 mm from the transformation zone poses an interesting pathogenetic conundrum as well as a therapeutic dilemma in a young patient desirous of retaining fertility. Issues relating to pathogenesis include necessary metaplasia of the endometrial glandular epithelium to 'susceptible' endocervical type epithelium within the polyp or metastatic implantation of transformed endocervical glandular cells onto the polyp. The current management plan involves regular hysteroscopic surveillance of the uterine cavity.

Gynecologic Cancer InterGroup (GCIG) consensus review for mullerian adenosarcoma of the female genital tract.

Mullerian adenosarcomas of the female genital tract are rare malignancies, originally described in the uterus, the most common site of origin, but they may also arise in extrauterine locations. Uterine adenosarcomas make up 5% of uterine sarcomas and tend to occur in postmenopausal women. They are usually low-grade tumors and are characterized by a benign epithelial component with a malignant mesenchymal component, which is typically a low-grade endometrial stromal sarcoma but can also be a high-grade sarcoma. Tumors that exhibit a high-grade sarcomatous overgrowth have a worse outcome. Adenosarcomas have been described as being midway along the spectrum between benign adenofibromas and carcinosarcomas. They generally have a good prognosis with the exception of deeply invasive tumors or those with high-grade sarcomatous overgrowth. Extrauterine adenosarcomas also have a higher risk for recurrence. In view of their rarity, there have not been any clinical trials in mullerian adenosarcomas and relatively little research. This article reviews the current knowledge and provides recommendation for the management of mullerian adenosarcomas.

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.

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.

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.

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.

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.

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).

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.

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.

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.

Two cases of adenosquamous carcinoma of the cervix with extensive in situ and invasive endometrial extension.

Adenosquamous carcinoma of the cervix is rare. It is defined as having both glandular and squamous cell differentiation, each component malignant and clearly seen on haematoxylin and eosin-stained slides alone. We report two cases of adenosquamous carcinoma of the uterine cervix, both of which showed in situ and invasive components and both of which showed cephalad extension to involve the endometrium with invasive squamous and adenocarcinomatous components. The mechanisms for cephalad endomyometrial extension is discussed, as are the potential implications for management and staging.

Adenomyosis is a potential cause of recurrent implantation failure during IVF treatment.

Four women, who previously had undergone multiple unsuccessful in vitro fertilisation (IVF) cycles because of failure of implantation of good quality embryos, were identified as having coexisting uterine adenomyosis. Endometrial biopsies showed that adenomyosis was associated with a prominent aggregation of macrophages within the superficial endometrial glands, potentially interfering with embryo implantation. The inactivation of adenomyosis by an ultra-long pituitary downregulation regime promptly resulted in successful pregnancy for all women in this case series.

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.