Impaired instructive and protective barrier functions of the endothelial cell glycocalyx pericellular matrix is impacted in COVID-19 disease.

The aim of this study was to review the roles of endothelial cells in normal tissue function and to show how COVID-19 disease impacts on endothelial cell properties that lead to much of its associated symptomatology. This places the endothelial cell as a prominent cell type to target therapeutically in the treatment of this disorder. Advances in glycosaminoglycan analytical techniques and functional glycomics have improved glycosaminoglycan mimetics development, providing agents that can more appropriately target various aspects of the behaviour of the endothelial cell in-situ and have also provided polymers with potential to prevent viral infection. Thus, promising approaches are being developed to combat COVID-19 disease and the plethora of symptoms this disease produces. Glycosaminoglycan mimetics that improve endothelial glycocalyx boundary functions have promising properties in the prevention of viral infection, improve endothelial cell function and have disease-modifying potential. Endothelial cell integrity, forming tight junctions in cerebral cell populations in the blood-brain barrier, prevents the exposure of the central nervous system to circulating toxins and harmful chemicals, which may contribute to the troublesome brain fogging phenomena reported in cognitive processing in long COVID disease.

Real-world application of Wound, Ischemia, and foot Infection scores in peripheral arterial disease patients.

OBJECTIVE: The Society for Vascular Surgery (SVS) Wound, Ischemia, and foot Infection (WIfI) classification system aims to risk stratify patients with chronic limb-threatening ischemia (CLTI), predicting both amputation rates and the need for revascularization. However, real-world use of the system and whether it predicts outcomes accurately after open revascularization and peripheral interventions is unclear. Therefore, we sought to determine the adoption of the WIfI classification system within a contemporary statewide collaborative as well as the impact of patient factor, and WIfI risk assessment on short- and long-term outcomes. METHODS: Using data from a large statewide collaborative, we identified patients with CLTI undergoing open surgical revascularization or peripheral vascular intervention (PVI) between 2016 and 2022. The primary exposure was preoperative clinical WIfI stage. Patients were categorized according to the SVS Lower Extremity Threatened Limb Classification System into clinical WIfI stages 1, 2, 3, or 4. The primary outcomes were 30-day and 1-year amputation and mortality rates. Multivariable logistic regression was performed to estimate the association of WIfI stage on postrevascularization outcomes. RESULTS: In the cohort of 17,417 patients, 83.4% (n = 14,529) had WIfI stage documented. PVIs were performed on 57.6% of patients, and 42.4% underwent an open surgical revascularization. Of the patients, 49.5% were classified as stage 1, 19.3% stage 2, 12.8% stage 3, and 18.3% of patients met stage 4 criteria. Stage 3 and 4 patients had higher rates of diabetes, congestive heart failure, and renal failure, and were less likely to be current or former smokers. One-half of stage 3 patients underwent open surgical revascularization, whereas stage 1 patients were most likely to have received a PVI (64%). As WIfI stage increased from 1 to 4, 1-year mortality increased from 12% to 21% (P < .001), 30-day amputation rates increased from 5% to 38% (P < .001), and 1-year amputation rates increased from 15% to 55% (P < .001). Finally, patients who did not have WIfI scores classified had significantly higher 30-day and 1-year mortality rates, as well as higher 30-day and 1-year amputation rates. CONCLUSIONS: The SVS WIfI clinical stage is significantly associated with 1-year amputation rates in patients with CLTI after lower extremity revascularization. Because nearly 55% of stage 4 patients require a major amputation within 1 year of intervention, this finding study supports use of the WIfI classification system in clinical decision-making for patients with CLTI.

Comparative evaluation of transcutaneous oxygen tension and ankle-brachial index as predictors of reoperation following below-knee amputation.

OBJECTIVE: Decision-making regarding level of lower extremity amputation is sometimes challenging. Selecting an appropriate anatomic level for major amputation requires consideration of tradeoffs between postoperative function and risk of wound complications that may require additional operations, including debridement and/or conversion to above-knee amputation (AKA). We evaluated the utility of common, non-invasive diagnostic tests used in clinical practice to predict the need for reoperations among patients undergoing primary, elective, below knee-amputations (BKAs) by vascular surgeons. METHODS: Patients undergoing elective BKA over a 5-year period were identified using Current Procedural Terminology codes. Medical records were reviewed to characterize demographics, pre-amputation testing transcutaneous oxygen tension (TcPO2), and ankle-brachial index (ABI). The need for ipsilateral post-BKA reoperation (including BKA revision and/or conversion to AKA) regardless of indication was the primary outcome. Associations were evaluated using univariable and multivariable logistic regression models. Cutpoints for TcPO2 values associated with amputation reoperation were evaluated using receiver operating characteristic curves. RESULTS: We identified 175 BKAs, of which 46 (26.3%) required ipsilateral reoperation (18.9% BKA revisions and 14.3% conversions to AKA). The mean age was 63.3 ± 14.8 years. Most patients were male (65.1%) and White (72.0%). Mean pre-amputation calf TcPO2 was 40.0 ± 20.5 mmHg, and mean ABI was 0.64 ± 0.45. In univariable models, post-BKA reoperation was associated with calf TcPO2 (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = .013) but not ABI (OR, 0.53; 95% CI, 0.19-1.46; P = .217). Univariable associations with reoperation were also identified for age (OR, 0.97; 95% CI, 0.94-0.990; P = .003) and diabetes (OR, 0.43; 95% CI, 0.21-0.87; P = .019). No associations with amputation revision were identified for gender, race, end-stage renal disease, or preoperative antibiotics. Calf TcPO2 remained associated with post-BKA reoperation in a multivariable model (OR, 0.97; 95% CI, 0.94-0.99; P = .022) adjusted for age (OR, 0.98; 95% CI, 0.94-1.01; P = .222) and diabetes (OR, 0.98; 95% CI, 0.94-1.01; P = .559). Receiver operating characteristic analysis suggested a TcPO2 ≥38 mmHg as an appropriate cut-point for assessing risk for BKA revision (area under the curve = 0.682; negative predictive value, 0.91). CONCLUSIONS: Reoperation after BKA is common, and reoperation risk was associated with pre-amputation TcPO2. For patients undergoing elective BKA, higher risk of reoperation should be discussed with patients with an ipsilateral TcPO2 <38 mmHg.

A recombinant signalling-selective activated protein C that lacks anticoagulant activity is efficacious and safe in cutaneous wound preclinical models.

Various preclinical and clinical studies have demonstrated the robust wound healing capacity of the natural anticoagulant activated protein C (APC). A bioengineered APC variant designated 3K3A-APC retains APC's cytoprotective cell signalling actions with <10% anticoagulant activity. This study was aimed to provide preclinical evidence that 3K3A-APC is efficacious and safe as a wound healing agent. 3K3A-APC, like wild-type APC, demonstrated positive effects on proliferation of human skin cells (keratinocytes, endothelial cells and fibroblasts). Similarly it also increased matrix metollaproteinase-2 activation in keratinocytes and fibroblasts. Topical 3K3A-APC treatment at 10 or 30 µg both accelerated mouse wound healing when culled on Day 11. And at 10 µg, it was superior to APC and had half the dermal wound gape compared to control. Further testing was conducted in excisional porcine wounds due to their congruence to human skin. Here, 3K3A-APC advanced macroscopic healing in a dose-dependent manner (100, 250 and 500 µg) when culled on Day 21. This was histologically corroborated by greater collagen maturity, suggesting more advanced remodelling. A non-interference arm of this study found no evidence that topical 3K3A-APC caused either any significant systemic side-effects or any significant leakage into the circulation. However the female pigs exhibited transient and mild local reactions after treatments in week three, which did not impact healing. Overall these preclinical studies support the hypothesis that 3K3A-APC merits future human wound studies.

Cross Sectional Survey of Antenatal Educators' Views About Current Antenatal Education Provision.

OBJECTIVES: Antenatal education (ANE) is part of National Health Service (NHS) care and is recommended by The National Institute for Health and Care Excellence (NICE) to increase birth preparedness and help pregnant women/birthing people develop coping strategies for labour and birth. We aimed to understand antenatal educator views about how current ANE supports preparedness for childbirth, including coping strategy development with the aim of identifying targets for improvement. METHODS: A United Kingdom wide, cross-sectional online survey was conducted between October 2019 and May 2020. Antenatal educators including NHS midwives and private providers were purposively sampled. Counts and percentages were calculated for closed responses and thematic analysis used for open text responses. RESULTS: Ninety-nine participants responded, 62% of these did not believe that ANE prepared women for labour and birth. They identified practical barriers to accessing ANE, particularly for marginalised groups, including financial and language barriers. Educators believe class content is medically focused, and teaching is of variable quality with some midwives being ill-prepared to deliver antenatal education. 55% of antenatal educators believe the opportunity to develop coping strategies varies between location and educators and only those women who can pay for non-NHS classes are able to access all the coping strategies that can support them with labour and birth. CONCLUSIONS FOR PRACTICE: Antenatal educators believe current NHS ANE does not adequately prepare women for labour and birth, leading to disparities in birth preparedness for those who cannot access non-NHS classes. To reduce this healthcare inequality, NHS classes need to be standardised, with training for midwives in delivering ANE enhanced.

The TightRope study: a cadaveric, biomechanical comparison of generations of suspensory fixation with internal brace for Rockwood grade V acromioclavicular joint injuries.

BACKGROUND: Surgical treatment of Rockwood grade V acromioclavicular (AC) joint injuries remains varied. We hypothesized that the addition of a second suspensory device between the clavicle and coracoid would yield superior biomechanical results over a single device. We also hypothesized that the addition of an internal brace across the AC joint to a suspensory device would yield superior results over the suspensory device in isolation. METHODS: A total of 24 cadaveric shoulders were dissected and randomized to 4 groups with 4 different constructs implanted: group A, single AC TightRope (Arthrex Inc.); group B, double AC TightRope; group C, single Knotless AC TightRope (Arthrex Inc.); group D: single Knotless AC TightRope with AC InternalBrace ligament augmentation (Arthrex Inc.). These were then loaded in a robotic arm (SIMVITRO), where 250 cycles of 50 N of force in the superior plane was applied. Dynamic creep, displacement, translation, and stiffness were assessed. RESULTS: Testing was successfully completed for all specimens. There were no failures due to fracture or translation of the clavicle >5 mm from the starting position. Reduction was maintained with a mean superior displacement of 1.7 mm (±1.4 mm). The mean peak-to-peak displacement, superior and posterior translation, dynamic creep, and stiffness did not differ significantly between the construct groups. CONCLUSION: This study did not demonstrate any significant biomechanical differences between groups in terms of displacement, translation, creep, or stiffness.

Midterm follow-up of the Nexel total elbow arthroplasty.

BACKGROUND: Aseptic loosening is one of the most common complications of total elbow arthroplasty (TEA). Modern implants, such as the Nexel, have been designed in an attempt to decrease loosening. The present study aims to report implant survivorship, radiographic assessment of loosening and lucency, and patient-reported outcome measures (PROMs) in patients treated with the Nexel TEA at midterm follow-up. METHODS: Consecutive series of adult patients underwent TEA using the Nexel by a single surgeon via standardized technique. Patients with minimum 3-year follow-up with radiographic and PROM data were included. Survivorship was defined by the absence of revision. Loosening was assessed via the Wrightington method by 3 independent fellowship-trained shoulder and elbow surgeons. Lucency was analyzed across individual radiographic zones on orthogonal radiographs. PROMs included the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire (QuickDASH), Patient-Rated Elbow Evaluation (PREE), and EuroQoL-5 Dimensions (EQ-5D). RESULTS: Thirty-eight consecutive patients (22 female, 16 male) with a mean age of 67 years underwent TEA via a triceps-sparing isolated medial window approach. Mean follow-up was 5.5 years (range 3-9). Primary diagnoses were as follows: 19 osteoarthritis (OA), 9 rheumatoid arthritis (RA), 9 post-traumatic arthritis (PA), and 1 conversion of elbow arthrodesis. Overall survivorship was 97.4%, with 1 patient undergoing revision for infection. Loosening was found in 5.3% of elbows, averaged across 3 observers. Lucency was most pronounced at the level of the humeral condyles. PROMs demonstrated significant and clinically meaningful improvements in 76%, 92%, and 73% of patients for QuickDASH, PREE, and EQ-5D, respectively. No significant correlations were found between patient age, gender, loosening, lucency, and PROMs. CONCLUSION: At midterm follow-up, the Nexel TEA demonstrated excellent overall survivorship and low rate of implant loosening. The single failure requiring revision for infection was conversion of a prior elbow arthrodesis. PROMs overall exhibited marked and consistent improvement from preoperative to final postoperative follow-up. Although promising, these results should be interpreted with some caution as long-term data regarding this prosthesis are still lacking.

Accidental Gunshot Wound Fatalities Related to Dropped Firearms.

ABSTRACT: A death resulting from the accidental discharge of a firearm represents a rare but oftentimes preventable tragedy. Such deaths may occur in a variety of settings. One such setting involves the discharge of a loaded firearm, which occurs when it is accidentally dropped, thrown, or falls to the ground. We report on 3 cases in which a loaded firearm discharged when it was dropped, resulting in the deaths of 3 individuals. In 2 cases, the person carrying the dropped firearm was killed, whereas in the third case, a child standing near the person who dropped the weapon was killed. We discuss the risk factors involved in these tragic incidents and present preventive strategies.

Lumican, a Multifunctional Cell Instructive Biomarker Proteoglycan Has Novel Roles as a Marker of the Hypercoagulative State of Long Covid Disease.

This study has reviewed the many roles of lumican as a biomarker of tissue pathology in health and disease. Lumican is a structure regulatory proteoglycan of collagen-rich tissues, with cell instructive properties through interactions with a number of cell surface receptors in tissue repair, thereby regulating cell proliferation, differentiation, inflammation and the innate and humoral immune systems to combat infection. The exponential increase in publications in the last decade dealing with lumican testify to its role as a pleiotropic biomarker regulatory protein. Recent findings show lumican has novel roles as a biomarker of the hypercoagulative state that occurs in SARS CoV-2 infections; thus, it may also prove useful in the delineation of the complex tissue changes that characterize COVID-19 disease. Lumican may be useful as a prognostic and diagnostic biomarker of long COVID disease and its sequelae.

Why surveys are 'very hard': exploring challenges and insights for collection of authentic patient experience information with speakers of Australian First Nations languages.

INTRODUCTION: Health services collect patient experience data to monitor, evaluate and improve services and subsequently health outcomes. Obtaining authentic patient experience information to inform improvements relies on the quality of data collection processes and the responsiveness of these processes to the cultural and linguistic needs of diverse populations. This study explores the challenges and considerations in collecting authentic patient experience information through survey methods with Australians who primarily speak First Nations languages. METHODS: First Nations language experts, interpreters, health staff and researchers with expertise in intercultural communication engaged in an iterative process of critical review of two survey tools using qualitative methods. These included a collaborative process of repeated translation and back translation of survey items and collaborative analysis of video-recorded trial administration of surveys with languages experts (who were also receiving dialysis treatment) and survey administrators. All research activities were audio- or video-recorded, and data from all sources were translated, transcribed and inductively analysed to identify key elements influencing acceptability and relevance of both survey process and items as well as translatability. RESULTS: Serious challenges in achieving equivalence of meaning between English and translated versions of survey items were pervasive. Translatability of original survey items was extensively compromised by the use of metaphors specific to the cultural context within which surveys were developed, English words that are familiar but used with different meaning, English terms with no equivalent in First Nations languages and grammatical discordance between languages. Discordance between survey methods and First Nations cultural protocols and preferences for seeking and sharing information was also important: the lack of opportunity to share the 'full story', discomfort with direct questions and communication protocols that preclude negative or critical responses constrained the authenticity of the information obtained through survey methods. These limitations have serious implications for the quality of information collected and result in frustration and distress for those engaging with the survey. CONCLUSION: Profound implications for the acceptability of a survey tool as well as data quality arise from differences between First Nations cultural and communication contexts and the cultural context within which survey methods have evolved. When data collection processes are not linguistically and culturally congruent there is a risk that patient experience data are inaccurate, miss what is important to First Nations patients and have limited utility for informing relevant healthcare improvement. Engagement of First Nations cultural and language experts is essential in all stages of development, implementation and evaluation of culturally safe and effective approaches to support speakers of First Nations languages to share their experiences of health care and influence change.

Anti-CD30 (Ber-H2) epitope requires structural elements as shown by mass spectroscopy and dual-site associated kinetics.

The Ber-H2 mouse monoclonal antibody has been in use for 35 years for detecting the CD-30 biomarker in a variety of lymphomas. Despite the wide use of this clone, we have not been successful in applying synthetic peptides derived from the published epitope sequence and affinity data toward the development of a new Ber-H2-based in vitro diagnostic reagent assay. We found that synthetic peptides based on the published epitope sequence do not function to inhibit antibody-binding activity, thus indicating that the sequence is not the full epitope recognized by Ber-H2. In this report, we used mass spectroscopic analysis of proteolyzed CD30 fragments capable of binding Ber-H2 to identify additional regions within the epitope that participate in binding. Using surface plasmon resonance binding kinetic analyses and immuno-histochemical peptide-inhibition assays, we also demonstrate that the epitope sequence as originally reported is missing two key elements necessary for binding the Ber-H2 antibody.

Representation of patients with non-English language preferences in motor vehicle collision trauma and emergency medicine research.

BACKGROUND: Individuals with non-English language preferences (NELP) represent a growing proportion of the USA population. Prior studies demonstrate disparate health outcomes related to NELP status; however, this patient population is often excluded from medical research. There is a paucity of literature describing the impact of NELP status on trauma, specifically injury and outcomes related to vehicle occupants injured during motor vehicle collisions (MVCs). The goal of this study was to evaluate the representation of patients with NELP in both emergency medicine and trauma literature. METHODS: We conducted a systematic search of US-based publications from 2010 to 2021. Titles, abstracts and full texts of eligible articles were evaluated. Data were extracted using an a priori determined standardised reporting tool to evaluate language as study inclusion/exclusion criteria, manuscript reporting of language, assessment of language as a primary variable and consideration of language in study methodology. RESULTS: A total of 82 studies met inclusion criteria. Twenty-three studies (28%) excluded NELP populations and only one study explicitly included the NELP population. None of the studies evaluated language as a primary outcome of the study or included language as a variable in the analysis. Over half of the studies (53.6%) used a public data set or registry. CONCLUSION: NELP populations are routinely excluded from and are difficult to identify in MVC trauma research. Without appropriate inclusion and identification, it will be difficult to understand the prevalence and outcomes of traumatic injury in NELP patients and to develop culturally and linguistically appropriate interventions.

Consultations for clinical features of possible cancer and associated urgent referrals before and during the COVID-19 pandemic: an observational cohort study from English primary care.

BACKGROUND: It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients. METHODS: Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019. FINDINGS: Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04-24.34%) between 2019 and 2020, particularly in the 6-12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82-11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years. CONCLUSION: Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features.

Compressive hyperspectral imaging in the molecular fingerprint band.

Spectrally-resolved imaging provides a spectrum for each pixel of an image that, in the mid-infrared, can enable its chemical composition to be mapped by exploiting the correlation between spectroscopic features and specific molecular groups. The compatibility of Fourier-transform interferometry with full-field imaging makes it the spectroscopic method of choice, but Nyquist-limited fringe sampling restricts the increments of the interferometer arm length to no more than a few microns, making the acquisition time-consuming. Here, we demonstrate a compressive hyperspectral imaging strategy that combines non-uniform sampling and a smoothness-promoting prior to acquire data at 15% of the Nyquist rate, providing a significant acquisition-rate improvement over state-of-the-art techniques. By illuminating test objects with a sequence of suitably designed light spectra, we demonstrate compressive hyperspectral imaging across the 700-1400 cm-1 region in transmission mode. A post-processing analysis of the resulting hyperspectral images shows the potential of the method for efficient non-destructive classification of different materials on painted cultural heritage.

Model of severe malaria in young mice suggests unique response of CD4 T cells.

Severe malaria occurs most in young children but is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of the disease. Though functional and quantitative deficiencies in innate response and a biased T helper 1 (Th1) response are reported in newborn pups, there is little information available about this intermediate stage of the adaptive immune system in murine neonates. To fill this gap in knowledge, we have developed a mouse model of severe malaria in young mice using 15-day old mice (pups) infected with Plasmodium chabaudi. We observe similar parasite growth pattern in pups and adults, with a 60% mortality and a decrease in the growth rate of the surviving young mice. Using a battery of behavioral assays, we observed neurological symptoms in pups that do not occur in infected wildtype adults. CD4+ T cells were activated and differentiated to an effector T cell (Teff) phenotype in both adult and pups. However, there were relatively fewer and less terminally differentiated pup CD4+ Teff than adult Teff. Interestingly, despite less activation, the pup Teff expressed higher T-bet than adults' cells. These data suggest that Th1 cells are functional in pups during Plasmodium infection but develop slowly.

"I might not fit that doctor image": Ideal worker norms and women medical students.

Despite the increasing numbers of women students in medical schools, focused attention on their perceptions about medical school and the medical profession remain underexamined. These perceptions are important to understand, particularly since women students are likely burdened with a host of gender norms related to work, family, and their future roles as physicians. Early experiences in medical school offer important insights into the larger student experience and are tied to academic outcomes and feelings of belonging. To examine early experiences of women medical students, this qualitative study used sensemaking theory to describe the current context and "story" of ideal worker norms. Critical qualitative interviews of 38 women students were performed during their first 2 months of medical school and explored both how the students perceived and experienced ideal worker norms, and how they made sense of the "story" of ideal worker norms. The participants described ways they encountered gendering and ideal worker norms through displays of nurturing behaviour, expectations to balance a future family, and whether they looked or acted the part of a doctor. This article highlights the challenges women medical students are already aware they will face, the opportunities they look forward to, and the strengths they anticipate leaning on to navigate their profession. Results from this study have implications for women medical students' learning experiences and transitions into medical school and for faculty, staff, and scholars concerned with challenging gendering norms that shape medical education.

The effect of single-dose, preoperative intravenous tranexamic acid on early postoperative pain scores after rotator cuff repair: a double-blind, randomized controlled trial.

BACKGROUND: Tranexamic acid (TXA) is commonly used in upper and lower limb arthroplasty to limit blood loss and postoperative hematoma formation. The role of TXA in rotator cuff repair (RCR) surgery is less defined. This trial assessed the effect of preoperative TXA on early postoperative pain scores. METHODS: A randomized double-blind trail was conducted in 89 patients undergoing RCR. Patients were randomized to either 2 g of intravenous TXA or placebo at induction. The primary outcome was visual analog scale (VAS)-pain score at day 3 postoperation, with secondary outcomes including VAS-pain, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), and Constant scores at 2, 8, 24, and 52 weeks. RESULTS: There was no significant difference in VAS-pain scores between groups at day 3 postoperation. Pain scores were significantly better in the TXA group at 8 weeks. There was no difference between groups at any time point in the ASES or Constant score. The TXA group had improved motion at 6 months with a reduced rate of secondary adhesive capsulitis. CONCLUSION: TXA did not improve postoperative pain scores after RCR, however, patients who received the intervention demonstrated greater range of motion at 6 months with lower rates of secondary adhesive capsulitis.

Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. METHODS: This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. FINDINGS: 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. INTERPRETATION: Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. FUNDING: Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Genome sequence, transcriptome, and annotation of rodent malaria parasite Plasmodium yoelii nigeriensis N67.

BACKGROUND: Rodent malaria parasites are important models for studying host-malaria parasite interactions such as host immune response, mechanisms of parasite evasion of host killing, and vaccine development. One of the rodent malaria parasites is Plasmodium yoelii, and multiple P. yoelii strains or subspecies that cause different disease phenotypes have been widely employed in various studies. The genomes and transcriptomes of several P. yoelii strains have been analyzed and annotated, including the lethal strains of P. y. yoelii YM (or 17XL) and non-lethal strains of P. y. yoelii 17XNL/17X. Genomic DNA sequences and cDNA reads from another subspecies P. y. nigeriensis N67 have been reported for studies of genetic polymorphisms and parasite response to drugs, but its genome has not been assembled and annotated. RESULTS: We performed genome sequencing of the N67 parasite using the PacBio long-read sequencing technology, de novo assembled its genome and transcriptome, and predicted 5383 genes with high overall annotation quality. Comparison of the annotated genome of the N67 parasite with those of YM and 17X parasites revealed a set of genes with N67-specific orthology, expansion of gene families, particularly the homologs of the Plasmodium chabaudi erythrocyte membrane antigen, large numbers of SNPs and indels, and proteins predicted to interact with host immune responses based on their functional domains. CONCLUSIONS: The genomes of N67 and 17X parasites are highly diverse, having approximately one polymorphic site per 50 base pairs of DNA. The annotated N67 genome and transcriptome provide searchable databases for fast retrieval of genes and proteins, which will greatly facilitate our efforts in studying the parasite biology and gene function and in developing effective control measures against malaria.