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Abstract Background Information regarding response rate to tigilanol tiglate for mast cell tumors in dogs is limited. Objectives Report the response rate and durability of tigilanol tiglate intratumoral treatment in dogs with mast cell tumors presented to veterinary oncologists. Animals One hundred forty‐nine dogs; 151 individual tumors. Methods Multicenter, retrospective survey‐based study. Veterinary oncologists subscribed to the American College of Veterinary Internal Medicine (ACVIM) oncology listserv were solicited for information from dogs treated with tigilanol tiglate. An electronic survey was used to collect information at initial treatment, 1 month and 1 year after treatment. Results Most tumors were cutaneous, occurred on the limbs and were cytologically low grade. Seventy‐five percent of dogs achieved a complete response after 1 dose of tigilanol tiglate 1 month after treatment. This response was durable at 1 year in 64% of dogs for which data were available (n = 88). Wound formation, an expectation after treatment, occurred after a median of 7 days (range, 1‐91 days), with a median wound area of 4.71 cm2 (range, 0.09‐100 cm2). Wounds took a median of 30 days to heal completely (range, 14‐154 days). A moderate association between tumor volume and wound size was confirmed. Conclusions and Clinical Importance Tigilanol tiglate is an effective local treatment option for mast cell tumors in dogs with a predictable clinical course and response. Because of the unique mode of action and clinical course, client education and careful case selection is necessary before electing tigilanol tiglate for local treatment.

Abstract Background Limited information is available regarding the clinical features, treatment, and prognosis of neosporosis in adult dogs. Objective Describe the clinical signs, laboratory findings, magnetic resonance imaging (MRI) findings, treatment and outcome in adult dogs (>6 months) diagnosed with neosporosis based on consistent clinical signs and positive serology (titer ≥1 : 800) at a referral hospital in Sydney, Australia. Animals Twenty‐one client‐owned dogs. Methods Retrospective case series of affected dogs between 2010 and 2023. Survival times were determined from onset of clinical signs to date of death or censoring. Results Clinical signs varied, and were indicative of generalized myopathy (6 dogs), multifocal intracranial disease (7 dogs), myelopathy (4 dogs), polyneuropathy (2 dogs) and single cases of focal myopathy and cerebellar disease. Serum creatine kinase activity was markedly increased (median, 3369 U/L) in most dogs. The most common MRI abnormalities were multifocal intracranial abnormalities (7/13 dogs) and muscle changes (5/13 dogs) whereas T2‐weighted cerebellar abnormalities (2/13 dogs) and cerebellar atrophy (1/13) were less common. Treatment response was complete (resolution to normal) in 8 dogs, incomplete (persistent neurological deficits) in 6 dogs, but there was minimal response in 7 dogs. Thirteen dogs (62%) were alive after 6 months and 12 dogs (57%) alive after 1 year. Relapse was common, with 4 dogs experiencing at least 1 relapse event during the follow‐up period. Conclusion and Clinical Importance Adult‐onset neosporosis is uncommon and has variable clinical presentations. Treatment response also is variable, and relapse can occur, even among patients that respond completely to initial treatment.

Abstract Antiplatelet therapy with a P2Y12 receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss‐of‐function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on‐clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate‐stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E‐allele carriers vs. non‐carriers, respectively, p = 3.8 × 10−5). Similar significant effects on platelet aggregation were also noted between 143E‐allele carriers versus non‐carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10−3). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on‐clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response‐modifying alleles in CES1.

Abstract Introduction Perspectives on long‐acting injectable cabotegravir/rilpivirine (CAB/RPV‐LA) from HIV health disparity populations are under‐represented in current literature yet crucial to optimize delivery. Methods Between August 2022 and May 2023, we conducted in‐depth interviews with people with HIV (PWH) at four HIV clinics in Atlanta, Chicago and San Francisco. Eligibility criteria were current CAB/RPV‐LA use with receipt of ≥3 injections or CAB/RPV‐LA discontinuation. We purposefully sampled for PWH who initiated with viraemia (plasma HIV RNA >50 copies/ml) due to adherence challenges, discontinuers, and cis and trans women. Interviews were coded and analysed using thematic methods grounded in descriptive phenomenology. Clinical data were abstracted from the medical record. Results The sample (San Francisco n = 25, Atlanta n = 20, Chicago n = 14 for total n = 59, median number of injections = 6) consisted of 48 PWH using CAB/RPV‐LA and 11 who had discontinued. The median age was 50 (range 25–73) and 40 (68%) identified as racial/ethnic minorities, 19 (32%) cis or trans women, 16 (29%) were experiencing homelessness/unstable housing, 12 (20%) had recently used methamphetamine or opioids and 11 (19%) initiated with viraemia. All participants except one (who discontinued) had evidence of viral suppression at interview. Typical benefits of CAB/RPV‐LA included increased convenience, privacy and freedom from being reminded of HIV and reduced anxiety about forgetting pills. However, PWH who became virally suppressed through CAB/RPV‐LA use also experienced an amelioration of feelings of shame and negative self‐worth related to oral adherence challenges. Regardless of baseline viral suppression status, successful use of CAB/RPV‐LA amplified positive provider/clinic relationships, and CAB/RPV‐LA was often viewed as less “work” than oral antiretroviral therapy, which created space to attend to other aspects of health and wellness. For some participants, CAB/RPV‐LA remained “work,” particularly with regard to injection site pain and visit frequency. At times, these burdens outweighed the aforementioned benefits, resulting in discontinuation. Conclusions CAB/RPV‐LA offers a range of logistical, psychosocial and care engagement benefits, which are experienced maximally by PWH initiating with viraemia due to adherence challenges; however, benefits do not always outweigh treatment burdens and can result in discontinuation. Our findings on rationales for persistence versus discontinuation can inform both initial and follow‐up patient counselling.

Abstract Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML‐exclusive, non‐HSPC‐expressed cell‐surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface‐directed immunotherapy in this disease setting, time‐limited combined immune‐targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single‐chain variable fragment‐based bispecific T‐cell engaging and activating antibody directed against CD3 on T‐cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117‐positive healthy human HSPCs, AML cell lines and patient‐derived AML blasts in the presence of T‐cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117‐expressing leukemia cells and human T‐cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117‐positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117‐expressing leukemia cells and HSPCs prior to HSCT.

Abstract Pulmonary arteriovenous malformations (PAVMs) universally develop in patients with single ventricle congenital heart disease. Single ventricle PAVMs have been recognized for over 50 years but remain poorly understood. To improve our understanding, we developed a surgical rat model of Glenn circulation and characterized PAVM physiology over multiple time points. We performed a left thoracotomy and end‐to‐end anastomosis of the left superior vena cava to the left pulmonary artery (unilateral Glenn), or sham surgical control. To assess PAVM physiology, we quantified intrapulmonary shunting using two independent methods (bubble echocardiography and fluorescent microsphere injection). Additionally, we performed arterial blood gas measurements to assess oxygenation and plethysmography to assess ventilation. We identified pathologic intrapulmonary shunting by bubble echocardiography as early as 2 weeks post‐Glenn, and shunting continued at 2‐ and 6‐months post‐Glenn. Shunting also progressed over time, demonstrated by increased shunting of 10 μm microspheres at 6 months. Shunting was accompanied by mildly decreased oxygenation but no differences in ventilation. Our surgical animal model of unilateral Glenn circulation recreates the clinical condition of single ventricle PAVMs with early and progressive intrapulmonary shunting. This model is poised to characterize single ventricle PAVM pathophysiology and lead to mechanistic and therapeutic discovery.

Abstract Recent discoveries have identified intrapulmonary bronchopulmonary anastomoses (IBAs) as a relatively common phenomenon forming intrapulmonary right‐to‐left shunts. This study hypothesizes that IBAs play a significant role in the pathophysiology of heart failure. We aim to investigate the impact of these intrapulmonary right‐to‐left shunts on pulmonary arterial and venous pressures in heart failure patients, utilizing mixed venous oxygen saturation (SvO₂) as a key measurement. This study included 237 patients with heart failure who underwent cardiac catheterization. The relationships between SvO₂ and pulmonary artery systolic pressure (sPAP), pulmonary artery wedge pressure (PAWP), and left ventricular end‐diastolic pressure (LVEDP) were examined using various statistical methods (single regression analysis, partial correlation analysis, structural equation modeling, and Bayesian estimation). All statistical methods that we performed showed that SvO₂ was significantly and negatively correlated with both sPAP and PAWP (p

Abstract Currently, the available literature provides insufficient support to differentiate between primary ovarian neuroendocrine tumors (PON) and neuroendocrine ovarian metastases (NOM) in patients. For this reason, patients with a well‐differentiated ovarian neuroendocrine tumor (NET) were identified through electronic patient records and a nationwide search between 1991 and 2023. Clinical characteristics were collected from electronic patient files. This resulted in the inclusion of 71 patients with NOM and 17 patients with PON. Histologic material was stained for Ki67, SSTR2a, CDX2, PAX8, TTF1, SATB2, ISLET1, OTP, PDX1, and ARX. DNA methylation analysis was performed on a subset of cases. All PON were unilateral and nine were found within a teratoma (PON‐T+). A total of 78% of NOM were bilateral, and none were associated with a teratoma. PON without teratomous components (PON‐T−) displayed a similar insular growth pattern and immunohistochemistry as NOM (p > 0.05). When compared with PON‐T+, PON‐T− more frequently displayed ISLET1 positivity and were larger, and patients were older at diagnosis (p

ABSTRACT Background and Aim Multiparametric magnetic resonance imaging (mpMRI) is recognized as the most indicative method for diagnosing prostate cancer. The purpose of this narrative review is to provide a comprehensive evaluation aligned with the Prostate Imaging and Reporting Data System (PI‐RADS) guidelines, offering an in‐depth insight into the various MRI sequences used in a standard mpMRI protocol. Additionally, it outlines the critical technical requirements necessary to perform a standard mpMRI examination of the prostate, as defined by the PI‐RADS specifications. Methods European Society of Urogenital Radiology has released PI‐RADS guideline detailing its suggestions aimed at improving the standards of the procedure. The purpose of this guideline is to establish a standard strategy for MRI protocols and image interpretation, aiming to prevent variability in each of the imaging and interpretation stages. Results A standard mpMRI protocol comprises morphological sequences and functional sequences. Morphological sequences which encompass T1‐ and T2‐weighted images, and various functional sequences include diffusion‐weighted imaging, and dynamic contrast‐enhanced MRI. The PI‐RADS recommendations assert that having a standard and uniform protocol for all MRI centers is imperative. Furthermore, the existence of a standardized checklist for interpreting MRI images can foster greater consensus in the process of diagnosing and treating patients. Conclusion Standardized protocols and checklists for mpMRI interpretation are essential for achieving greater consensus among radiologists, ultimately leading to improved diagnostic outcomes in prostate cancer.

ABSTRACT Acute pancreatitis (AP) is a rare but life‐threatening complication in patients with systemic lupus erythematosus (SLE). The case highlights the diagnostic challenges and treatment complexities in managing SLE‐associated pancreatitis. A 20‐year‐old female with a history of SLE presented with acute onset epigastric pain, vomiting, and signs of systemic inflammation. Laboratory findings revealed elevated amylase and lipase levels, confirming AP. Imaging studies showed interstitial edematous pancreatitis and bilateral pleural effusion. The patient was managed with aggressive fluid resuscitation, pain management, and supportive care. A systemic inflammatory response complicated her clinical course, and she required intensive care unit monitoring. This case underscores the importance of early recognition of AP in SLE patients and highlights the need for a multidisciplinary approach to manage this severe complication.

Key message Plastic bronchitis is rare in adult pulmonology and has a wide range of aetiology. Cast analysis is key in narrowing down the differential diagnosis of plastic bronchitis. If suspected of having lymphocytic PB, complete imaging to evaluate thoracic lymphatics is important to find out the potential causes for PB.

Abstract Pulmonary veno‐occlusive disease (PVOD) is a rare form of pulmonary vascular disease that is difficult to distinguish clinically from pulmonary arterial hypertension (PAH). Multiple genes have been implicated in disease pathogenesis in PAH and PVOD and the diseases are thought to be genetically distinct. In this report we present a case of first‐degree relatives with pathological evidence of PVOD and PAH. The index patient was diagnosed with PAH at age 42, was treated with escalating pulmonary vasodilator therapy, but eventually succumbed to her disease. On autopsy, her pathology was consistent with PAH. Her son was diagnosed with PAH at age 16, did well on pulmonary vasodilator therapy for over 10 years, but ultimately developed refractory right ventricular failure and received a heart and lung transplantation. Pathology of his explanted lung was consistent with PVOD, and genetic testing was negative for recognized variants that cause PAH or PVOD.

Abstract Introduction The present study sought to examine the relationships between systemic inflammatory composite ratios/cumulative scores, magnitude of systemic inflammatory response (SIR) and survival in good performance status patients (ECOG‐PS 0/1) with advanced NSCLC receiving palliative radiotherapy. Methods Systemic inflammatory composite ratios/cumulative scores included the neutrophil‐lymphocyte ratio (NLR), platelet‐lymphocyte ratio (PLR), lymphocyte‐monocyte ratio (LMR), C‐reactive protein, (CRP)‐albumin ratio (CAR), neutrophil‐ lymphocyte score (NLS), platelet‐lymphocyte score (PLS), lymphocyte‐monocyte score (LMS), neutrophil‐platelet score (NPS), modified Glasgow prognostic score (mGPS). The magnitude of SIR was determined by serum CRP concentration, with a median CRP concentration of >10 m mg/L considered to be systemically inflamed. Relationships between systemic inflammatory composite ratios/ cumulative scores and clinicopathological characteristics were examined using chi‐square analysis. Relationships between overall survival (OS) and systemic inflammatory composite ratios/ cumulative scores were examined using cox regression analysis. Results 479 patients were included. 48% (n = 231) of patients were male and 70% (n = 338) were ≥65 years of age. 29% (n = 140) patients were ECOG‐PS 0 and 71% (n = 339) were ECOG‐PS 1. 98% (n = 469) of patients died during follow‐up. The median survival was 5 months (2–11). A similar prevalence of systemic inflammation was noted across the various ratios/scores (NLR >3 68%; LMR 150 70%; CAR >0.20 83%; NLS ≥1 66%; LMS ≥1 71%; NPS≥1 50%; PLS≥1 60% and mGPS≥1 75%). Despite not considered to be systemically inflamed, an NLR 10 mg/L. When adjusted for ECOG‐PS, CAR>0.40 (p

Background Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient

Abstract Introduction There are well‐documented racial and ethnic disparities in mortality after cancer in the general population, but less is known about whether disparities also exist in disaster‐exposed populations. Methods We conducted a longitudinal cohort study of 4341 enrollees in the World Trade Center Health Registry (WTCHR) with a first‐ever primary invasive cancer diagnosis after 9/11/2001 and followed through 2020. We examined associations of race and ethnicity with all‐cause mortality risk and cause‐specific mortality risk using multivariable Cox proportional hazards regression models and Fine and Gray's proportional sub‐distribution hazards models, respectively. Models were adjusted for baseline characteristics and tumor characteristics. We also examined models further adjusted for socioeconomic status (SES), and we used inverse odds weighting to formally test for mediation by SES. Results Compared to non‐Hispanic White enrollees with cancer, non‐Hispanic Blacks had higher risks for all‐cause mortality (adjusted hazard ratio (aHR) = 1.20, 95% CI = 1.02–1.41) and non‐cancer mortality (aHR = 1.48, 95% CI = 1.09–2.01) in the full model. In the model without SES, Hispanic enrollees with cancer had higher risks for all‐cause mortality (aHR = 1.32, 95% CI = 1.09–1.60) and cancer mortality (aHR = 1.31, 95% CI = 1.05–1.64) compared to non‐Hispanic Whites; these associations became not statistically significant in the full model. In the inverse odds weighting analysis, SES explained 24% and 29% of the disparity in all‐cause mortality risk observed in non‐Hispanic Blacks and Hispanics, respectively, compared to non‐Hispanic Whites. Conclusion This study found that there are racial and ethnic disparities in mortality after cancer in the WTCHR. Additional studies are needed to further explore the factors mediating these disparities.

Abstract Background Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2‐negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. Methods In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). Results We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple‐negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. Conclusion This retrospective, real‐world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.

Background Cognitive impairment after stroke is common and is present in up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of 2 stroke severity ratings and a caregiver‐report of poststroke functioning with longitudinal cognitive outcomes. Methods and Results One hundred fifty‐seven caregivers and stroke survivor dyads participated in the CARES (Caring for Adults Recovering From the Effects of Stroke) project, an ancillary study of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) national cohort study. The Glasgow Outcome Scale and modified Rankin Scale scores collected at hospitalization discharge were included as 2 primary predictors of cognitive impairment. The number of caregiver‐reported problems and impairments at 9 months following stroke were included as a third predictor. Cognition was measured using a biennial telephone battery and included the domains of learning, memory, and executive functioning. Multiple cognitive assessments were analyzed up to 5 years poststroke, controlling for prestroke cognition and demographic variables of the stroke survivor. Separate mixed models showed significant main effects of the Glasgow Outcome Scale (b=0.3380 [95% CI, 0.14–0.5]; P=0.0009), modified Rankin Scale (b=−0.2119 [95% CI, −0.32 to −0.10]; P=0.0002), and caregiver‐reported problems (b=−0.0671 [95% CI, −0.09 to −0.04]; P

Background Although related, the precise mechanisms linking obstructive sleep apnea (OSA) and cardiovascular disease (CVD) are unclear. Platelets are mediators of CVD risk and thrombosis and prior studies suggested associations of OSA and platelet activity. The aim of this study is to assess the link between OSA, platelet activity, and CVD‐related risk factors. Methods and Results We studied the association of OSA‐measures and platelet aggregation in participants dually enrolled in the SHHS (Sleep Heart and Health Study) and FHS (Framingham Heart Study). We applied linear regression models with adjustment for demographic and clinical covariates and explored interactions with OSA and CVD‐related factors, including age, sex, body mass index, hypertension, OSA diagnosis (apnea‐hypopnea index 4%≥5), and aspirin use. Our final sample was of 482 participants (60 years [14.00], 50.4% female). No associations were observed between apnea‐hypopnea index 4% and platelet aggregation in the main sample. Stratified analysis revealed an association in aspirin users (n=65) for our primary exposure (apnea‐hypopnea index 4%, β=0.523; P

Background Exposure to fine particulate matter (

Background Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory New York Heart Association (NYHA) IV versus III functional class at the time of device implantation. Methods and Results In this meta‐analysis, we pooled patient‐level data from the MIRACLE (Multicenter InSync Randomized Clinical Evaluation), MIRACLE‐ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation), and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. Outcomes evaluated were time to the composite end point of the first heart failure hospitalization or all‐cause mortality, and time to all‐cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian hierarchical Weibull survival regression model. We assessed if this association differed between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from RAFT (Resynchronization‐Defibrillation for Ambulatory Heart Failure). Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to heart failure hospitalization or all‐cause mortality (adjusted hazard ratio [aHR], 0.79 [95% credible interval [CI], 0.64–0.99]; posterior probability or P=0.044), with a similar association with time to all‐cause mortality (aHR, 0.78 [95% CI, 0.59–1.03]; P=0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR, 0.72 [95% CI, 0.30–1.27]; P=0.23 for heart failure hospitalization/mortality; ratio of aHR, 0.70 [95% CI, 0.35–1.34]; P=0.27 for all‐cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. Conclusions Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Background Venous thromboembolism is associated with endothelial cell activation that contributes to the inflammation‐dependent activation of the coagulation system. Cellular damage is associated with the release of different species of extracellular RNA (eRNA) involved in inflammation and coagulation. TLR3 (toll‐like receptor 3), which recognizes (viral) single‐stranded or double‐stranded RNAs and self‐RNA fragments, might be the receptor of these species of eRNA during venous thromboembolism. Here, we investigate how the TLR3/eRNA axis contributes to venous thromboembolism. Methods and Results Thrombus formation and size in wild‐type and TLR3 deficient (−/−) mice were monitored by ultrasonography after venous thrombosis induction using the ferric chloride and stasis models. Mice were treated with RNase I, with polyinosinic‐polycytidylic acid, a TLR3 agonist, or with RNA extracted from murine endothelial cells. Gene expression and signaling pathway activation were analyzed in HEK293T cells overexpressing TLR3 in response to eRNA or in human umbilical vein endothelial cells transfected with a small interference RNA against TLR3. Plasma clot formation on treated human umbilical vein endothelial cells was analyzed. Thrombosis exacerbated eRNA release in vivo and increased eRNA content within the thrombus. RNase I treatment reduced thrombus size compared with vehicle‐treated mice (P

Abstract Objectives Natural killer (NK) cells make important contributions to anti‐malarial immunity through antibody‐dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear. Methods We compared the functions and phenotypes of NK cells from malaria‐exposed and malaria‐naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation. Results Natural killer cells from malaria‐exposed adult Ugandan donors had enhanced ADCC, but an impaired pro‐inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria‐naive adult North American donors. Cellular phenotypes from malaria‐exposed donors reflected this specialisation for ADCC, with a compartment‐wide downregulation of the Fc receptor γ‐chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild‐type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont‐specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays. Conclusion This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.

We describe the case of a 27-year-old male, previously healthy though with a social history notable for recreational cocaine use, who developed bone marrow failure due to aplastic anemia (AA) with associated serous fat atrophy (SFA). After the SFA was corrected with nutritional supplementation, the patient underwent successful allogeneic, haploidentical stem cell transplantation with a regimen designed to treat AA. To our knowledge, this is the first case of hematopoietic stem cell transplantation (HSCT) performed following correction of SFA. Herein we propose our novel hypothesis that SFA, once resolved, is not a contraindication to stem cell transplantation, which we believe adds valuable insight toward an improved understanding of nutrition’s role in HSCT. Additionally, the AA is thought to be toxin-induced and specifically levamisole-mediated after exposure to levamisole-adulterated cocaine. We highlight potential connections between levamisole, AA, and SFA and call for further efforts to understand these relationships—especially as the use of levamisole as a cocaine adulterant continues to rise across the globe.

Abstract Background Clinical practice guidelines recommend to inform female cancer patients about their infertility risks due to cancer treatment. Unfortunately, it seems that guideline adherence is suboptimal. In order to improve quality of integrated female oncofertility care, a systematic assessment of current practice is necessary. Methods A multicenter cross‐sectional survey study in which a set of systematically developed quality indicators was processed, was conducted among female cancer patients (diagnosed in 2016/2017). These indicators represented all domains in oncofertility care; risk communication, referral, counseling, and decision‐making. Indicator scores were calculated, and determinants were assessed by multilevel multivariate analyses. Results One hundred twenty‐one out of 344 female cancer patients participated. Eight out of 11 indicators scored below 90% adherence. Of all patients, 72.7% was informed about their infertility, 51.2% was offered a referral, with 18.8% all aspects were discussed in counseling, and 35.5% received written and/or digital information. Patient's age, strength of wish to conceive, time before cancer treatment, and type of healthcare provider significantly influenced the scores of three indicators. Conclusions Current quality of female oncofertility care is far from optimal. Therefore, improvement is needed. To achieve this, improvement strategies that are tailored to the identified determinants and to guideline‐specific barriers should be developed.