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BACKGROUND Menthol cigarette use among women who smoke cigarettes during pregnancy is high, but little is known about the factors that contribute to preference for menthol cigarette use during pregnancy. OBJECTIVE This study investigated preferences, perceptions, and intentions to use menthol vs. non-menthol cigarettes in a sample of pregnant women. METHODS Pregnant women (N = 124, Mage = 26.2 years, 50% minorities) completed a study investigating the impact of maternal smoking on biobehavioral markers of fetal risk. During the third trimester, participants self-reported preferences (liking, attractiveness, smoothness, interest), perceptions of harm (general, pregnancy-specific), and intentions to use menthol and non-menthol cigarettes. We examined differences in responses based on whether participants endorsed (1) cigarette use during pregnancy (yes/no) and (2) lifetime cigarette use (yes/no). RESULTS Sixty-two participants endorsed cigarette smoking during pregnancy (85.5% smoked menthol cigarettes), and 94 participants reported lifetime use. Overall, menthol cigarettes were perceived as more likeable and smoother vs. non-menthol (ps

Stress management interventions (SMIs) can alleviate the psychosocial stress often experienced by women with heart failure. The purpose of this meta-analysis was to summarize women's participation rates, and predictors of participation, in SMIs for the management of psychosocial distress in women with chronic HF. Studies were retrieved from bibliographic databases, reference sections of relevant papers, and research registries. Included studies (a) evaluated a SMI approach for the management of chronic HF, (b) sampled chronic HF patients, and (c) used a randomized controlled trial (RCT) design. Independent coders extracted the relevant data. Thirty-five RCTs met inclusion criteria (N = 3,649; mean age = 63.5 ± 7.0 years). All studies sampled both men and women; the mean proportion of women who participated in the trials was 38.8% (95% confidence interval [CI] = 34.5-43.4; I 2 = 82.4, 95% CI = 81.0-83.6). Women's participation rates were higher in studies sampling more HF patients with hypertension (B = 1.01, SE = 0.45, P = .046) but fewer HF patients prescribed beta blockers (B = -1.10, SE = 0.33, P = .006), F (2,12) = 6.27, P = 0.014, adjusted R 2 = 61%. SMIs may offer women a complementary or integrative approach to standard treatment to help manage the psychological distress associated with HF. Future research should explore the potential benefits of offering stress management approaches to women as part of comprehensive HF care.

Background The Society of Thoracic Surgeons (STS) Quality Measurement Task Force has developed risk models and composite performance measures for isolated coronary artery bypass grafting (CABG), isolated aortic valve replacement (AVR), isolated mitral valve replacement or repair (MVRR), AVR+CABG, and MVRR+CABG. To further enhance its portfolio of risk-adjusted performance metrics, STS has developed new risk models for multiple valve operations ± CABG procedures. Methods Using July 2011 to June 2019 STS Adult Cardiac Surgery Database data, risk models for AVR+MVRR (n = 31,968) and AVR+MVRR+CABG (n = 12,650) were developed with the following endpoints: Operative Mortality, major morbidity (any 1 or more of the following: cardiac reoperation, deep sternal wound infection/mediastinitis, stroke, prolonged ventilation, and renal failure), and combined mortality and/or major morbidity. Data were divided into development (July 2011 to June 2017; n = 35,109) and validation (July 2017 to June 2019; n = 9509) samples. Predictors were selected by assessing model performance and clinical face validity of full and progressively more parsimonious models. Performance of the resulting models was evaluated by assessing discrimination and calibration. Results C-statistics for the overall population of multiple valve ± CABG procedures were 0.7086, 0.6734, and 0.6840 for mortality, morbidity, and combined mortality and/or morbidity in the development sample, and 0.6953, 0.6561, and 0.6634 for the same outcomes, respectively, in the validation sample. Conclusions New STS Adult Cardiac Surgery Database risk models have been developed for multiple valve ± CABG operations, and these models will be used in subsequent STS performance metrics.

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This study assessed factors associated with disability and life satisfaction in a large cohort of 2246 Australian adults with neurological disorders who completed an online survey of mental health and wellbeing. It was hypothesised that depressive symptoms and perceived cognitive difficulties would be significantly associated with both outcomes, even after controlling for significant demographic/medical covariates (e.g., age, marital-status, employment, multi-morbidity, medication). Differences in profiles of four neurological subgroups (i.e., multiple sclerosis; n = 738, epilepsy; n = 672, Parkinson's disease; n = 263, and Acquired Bran Injury; n = 278) were explored.Multiple hierarchical linear regressions were run using cross-sectional data.Depressive symptoms made a significant and large unique contribution to higher levels of disability (β = 0.333, p .001), and poorer life satisfaction (β = -0.434, p .001), in the overall sample and across all four neurological subgroups (β = 0.349 to 0.513, p .001) Greater perceived cognitive difficulties were associated with disability in the overall sample (β = 0.318, p .001) and across all neurological subgroups (β = 0.231 to 0.354, p .001), but only life satisfaction in epilepsy (β = -0.107, p = 006).The findings underscore the importance of managing psychological/neuropsychiatric comorbidities in neurological disorders.

Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and ‘smart’ actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.

Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum.

Introduction: We evaluated the association between carotid compliance, a measure of arterial stiffness, to parahippocampal volume (PHV) and hippocampal volume (HV) over 20 years later in the Atherosclerosis Risk in the Community study. Methods: We included participants with common carotid compliance measurements at visit 1 (1987–1989) and volumetric brain MRI at visit 5 (2011–2013). The primary outcomes are pooled bilateral PHV and HV. We performed linear regression models adjusting for age, sex, vascular risk factors, and total brain volume. Results: Of the 614 participants, higher compliance was correlated with higher PHV (R = 0.218[0.144–0.291], p < 0.001) and HV (R = 0.181 [0.105–0.255, p < 0.001]). The association was linear and significant after adjusting for confounders. At follow-up MRI, 30 patients with dementia had lower PHV and HV than patients without dementia (p < 0.001 and p < 0.001, respectively). Conclusion: Carotid compliance is associated with higher PHV and HV when measured 20 years later, further supporting the link between arterial stiffness and cognitive decline.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.

Triple negative breast cancer (TNBC) is a highly metastatic and aggressive subtype of breast cancer and cases presenting with lymph node involvement have worse outcomes. This study aimed to determine the regions of copy number variation (CNV) associated with lymph node metastasis in TNBC patients. CNV analyses were performed in a study cohort of 23 invasive ductal carcinomas (IDCs), 12 lymph node metastases (LNmets), and 7 normal adjacent tissues (NATs); as well as in an independent cohort containing 70 TNBC IDCs and the same 7 NATs. CNV-associated genes were analyzed using GO-enrichment and Pathway analysis. The prognostic role for genes showing CNV-based changes in messenger RNA expression was determined using the Kaplan-Meier plotter database. For the IDCs, there were a number of variations that were common in both the study and independent cohorts in the amplified regions of 1q, 8q, 19 (p and q), 2p, 5p and the deleted regions in 8p followed by 5q, and 19p. The most frequently amplified regions in the LNmets of the study cohort were 4q28.3, 2p, 3q24, 1q21.2, 10p, 12p11.1, 8q, 20p11.22-20p11.21, 21q22.13, 6p22.1 and the most frequently deleted regions were in 1p36.23, 4q21.1 and 5q. A total of 686 (441 amplified and 245 deleted) genes were associated with LNmets. The LNmet-associated genes were highly enriched for "regulation of complement activation," "regulation of protein activation cascade," "regulation of humoral immune response," "oxytocin signalling pathway," and "TRAIL binding" pathways. Moreover, 6/686 LNmet-associated genes showed CNV-based changes in their mRNA expression of which, high expression of ASPM and KIF14 was significantly associated with worse relapse-free survival. This study has identified several CNV regions in TNBC that could play a major role in metastasis to the lymph node.

Stroke is a leading cause of disability and mortality, and the incidence of ischemic stroke is projected to continue to rise in coming decades. These projections emphasize the need for improved imaging techniques for accurate diagnosis allowing effective treatments for ischemic stroke. Ischemic stroke is commonly evaluated with computed tomography (CT) or magnetic resonance imaging (MRI). Noncontrast CT is typically used within 4.5 hours of symptom onset to identify candidates for thrombolysis. Beyond this time window, thrombolytic therapy may lead to poor outcomes if patients are not optimally selected using appropriate imaging. MRI provides an accurate method for the earliest identification of core infarct, and MR perfusion can identify salvageable hypoperfused penumbra. The prognostic value for a better outcome in these patients lies in the ability to distinguish between core infarct and salvageable brain at risk-the ischemic penumbra-which is a function of the degree of ischemia and time. Many centers underutilize MRI for acute evaluation of ischemic stroke. This review will illustrate how perfusion-diffusion mismatch calculated from diffusion-weighted MRI and MR perfusion is a reliable approach for patient selection for stroke therapy and can be performed in timeframes that are comparable to CT-based algorithms while providing potentially superior diagnostic information.

Inherited polyposis syndromes are predominantly caused by pathogenic variants in APC and are linked to Familial Adenomatous Polyposis (FAP). However, after clinical screening, 20% to 30% of individuals diagnosed with FAP do not carry a pathogenic variant in APC (often categorised as FAP-like). Other known inherited adenomatous polyposis syndromes such as MUTYH, POLD1/E, or NTHL1-associated polyposis only account for a fraction of the remaining cases. A cohort of 48 individuals clinically diagnosed with a FAP-like phenotype was selected based on a strong family history of colorectal cancer (CRC) and no previous pathogenic variant found in APC and/or MUTYH, by genetic screening. Using whole exome sequencing, FAP-like patients were found to carry pathogenic variants in MUTYH, APC, POLE and TP53, as well as DNA-repair genes and inflammation related genes. Additionally, a comprehensive assessment of copy number variation (CNV) revealed two loci of interest that appeared to be associated with polyposis risk. In total, 6 out of 48 polyposis were explained through re-sequencing. This study highlights the potential role of DNA-repair as well as inflammation-related variants towards polyp development.

Xiaomeng Xu,1 Dominique Milea,1 Aldo Amador Navarro Rojas,1 Anthony Braganza,1 Tim Holbrook,2 Brett Marett,3 Robert Young,4 Raewyn J Scott,4 Barry Gribben5 1Value Evidence and Outcomes, GlaxoSmithKline plc., 139234, Singapore; 2Real World Evidence, Adelphi Real World, Bollington, Macclesfield, Cheshire, UK; 3Medical Affairs, GlaxoSmithKline NZ Limited, Auckland, 1010, New Zealand; 4Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 5CBG Health Research Limited, Faculty of Medical and Health Sciences, Auckland, New ZealandCorrespondence: Xiaomeng XuValue Evidence and Outcomes, GlaxoSmithKline Plc., 23 Rochester Park, 139234, SingaporeTel +65 81616659Email Xiaomeng.x.xu@gsk.comPurpose: Real-world data on maintenance treatment and prescription patterns provide insights into healthcare management among patients with chronic obstructive pulmonary disease (COPD), which benefits our understanding of current COPD treatment patterns in New Zealand.Methods: We retrospectively analyzed real-world data from the HealthStat general practice database to evaluate treatment patterns among patients with COPD in New Zealand who initiated multiple-inhaler triple therapy (MITT): inhaled corticosteroid (ICS) + long-acting muscarinic antagonist + long-acting β2-agonist (LABA). Our main objective described treatment patterns (class, duration, modification, persistence, and adherence) and characteristics of patients with COPD initiating MITT between 1 May 2016 and 30 April 2017, with 12-months’ follow-up. We also assessed the number of patients receiving MITT between 2015 and 2017, among a larger patient population receiving long-acting bronchodilator and ICS-containing therapies.Results: Of 6249 eligible patients, 421 (mean age 67.3 years; mean numberexacerbations at baseline 1.8) initiated MITT: 59.1% received combination ICS/LABA therapy prior to MITT initiation, and median treatment duration prior to MITT initiation was 350 days. Overall, 33.5% of patients remained on index treatment for 12 months. Of the remaining patients who modified treatment (on average at 144.4 days), those who had a direct switch (24.9%) or retreatment (13.5%) remained on MITT, 19.7% of patients stepped down to mono/dual therapy, and 8.3% discontinued treatment. Mean (standard deviation) persistence to any MITT over 12 months was 47.3 (50.0), and 53.4% of patients were considered adherent to MITT. Total proportions of patients receiving long-acting bronchodilator therapy and MITT increased between 2015 and 2017.Conclusion: Most patients with COPD in New Zealand who initiated MITT had characteristics appropriate for triple therapy prescription, suggesting prescription behavior among general practitioners was largely consistent with treatment guidelines. Our findings may help optimize treatment decisions, with a focus on improving long-term triple therapy persistence and adherence.Keywords: chronic obstructive pulmonary disease, inhaled corticosteroid, long-acting β-agonist, long-acting muscarinic antagonist, New Zealand, multiple-inhaler triple therapy

Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

BackgroundCurrent incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).MethodsAn international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared.Findings12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved.InterpretationMore than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.

Background Streptococcus pneumoniae is a causative agent of community-acquired pneumonia (CAP). The 13-valent pneumococcal conjugate vaccine (PCV13) has significantly decreased the burden of PCV13-serotype pneumococcal disease; however, disease from nonvaccine serotypes remains substantial. A recent study documented the persistence of PCV13 serotypes among US adults hospitalized with radiographically confirmed CAP. The current analysis used a recently developed urinary antigen detection (UAD) assay (UAD2) to extend these results to additional serotypes included in an investigational PCV20 vaccine. Methods This prospective study enrolled adults aged ≥18 years hospitalized with radiographically confirmed CAP between October 2013 and September 2016. Presence of S pneumoniae was determined by blood and respiratory sample culture, BinaxNOW urine testing, and UAD. In addition to Quellung on cultured isolates when available, serotypes were identified from urine specimens using UAD1 for PCV13 serotypes and UAD2 for 7 PCV20-unique serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) and 4 additional serotypes (2, 9N, 17F, and 20). Results Among 12 055 subjects with radiographically confirmed CAP, 1482 were positive for S pneumoniae. PCV13- and PCV20-unique serotypes were associated with 37.7% (n = 559) and 27.0% (n = 400) of cases, respectively; 288 subjects were exclusively diagnosed as positive for S pneumoniae by UAD2. Demographic and clinical disease characteristics were similar between subjects with CAP caused by PCV13 and PCV20-unique serotypes. Conclusions The current analysis using UAD2 identified a sizeable proportion of hospitalized adult CAP associated with PCV20-unique serotypes. PCV20 may therefore address the burden of CAP caused by the additional serotypes present in the vaccine., A novel urinary antigen detection assay substantially increased detection of non-pneumococcal conjugate vaccine 13 (PCV13) serotypes included in an investigational PCV20 among US adults with community-acquired pneumonia (CAP). PCV20 may address the burden of CAP due to the additional serotypes.

The blacklegged tick ( Ixodes scapularis), which transmits Borrelia burgdorferi, the causative agent of Lyme disease, has undergone rapid range expansion in Ontario. In horses, Lyme disease remains an enigmatic disease, with limited understanding of the pathogenesis and many issues pertaining to selection and interpretation of laboratory tests. We evaluated B. burgdorferi seropositivity in naturally exposed horses over a 12-mo period and compared paired samples with 2 common serologic tests. Serum samples were collected in 2017, ~1 y after initial testing, from a cohort of 22 horses that were seropositive in a 2016 seroprevalence study. Samples were tested using a C6 ELISA and a multiplex ELISA targeting outer surface proteins A, C, and F. 1 y after initial testing, 14 of 22 (64%) horses remained seropositive; 7 (32%) were positive on the multiplex ELISA, 2 (9%) on C6 ELISA, and 5 (23%) on both tests. Repeatability was 100% for the C6 ELISA, and 95% for the multiplex ELISA, with no significant difference between paired sample multiplex titer values. Our results indicate strong intra-test reliability, although further investigation is required to determine the clinical significance of serologic testing.

Purpose Genetic testing and results return pose many challenges, even in the era of electronic medical records. Whether results are positive or negative, genetic testing and return of results necessitate patient follow-up, referrals, and coordination between providers. Genetic evaluations typically utilize a variety of testing modalities with differing timetables and/or avenues to return. Therefore, genetic information requires a secondary, unified mechanism for storing and tracking results and communication to facilitate patient care. Methods We developed an electronic medical record (EMR) episodes-based module called Pediatric Genetic Tracking to provide a centralized summary of patient tracking information in a single-institution pediatric genetics setting. Results We created episodes for 6,133 patients evaluated in our division over a 3-year period. They highlighted clinical information for 1,901 different diagnoses and 547 genetic tests, and the involvement of 9 providers, 7 genetic counselors, 61 trainees, and 15 students using two modes of follow-up. Conclusion This Pediatric Genetic Tracking episodes system serves as a "one-stop shop" living document for updated patient genetic information and can be easily expanded to include variant content for broader population level sharing or analysis. These episodes-based modules facilitate communication to support timely and accurate return of genetic test results and follow-up.

Lay abstractInfections are a common cause of severe disease and death in older patients. Antibiotic treatment may also be complicated by age-related changes within the body. The present study analyzed results from three large clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in the older population. In patients aged over 65 years with skin infections or with pneumonia acquired either in the community or in a hospital setting, ceftobiprole offered similar benefits to established antibiotics. There was also some preliminary evidence that older patients may respond more quickly to ceftobiprole compared with the other antibiotics used in these studies. Overall, ceftobiprole was well tolerated and will be a useful treatment option for infections in older patients.Aim: To evaluate the efficacy and safety of ceftobiprole in patients aged >= 65 years. Materials & methods: We conducted a post hoc analysis of three randomized, double-blind, Phase III studies in patients with acute bacterial skin and skin structure infections, community-acquired pneumonia and hospital-acquired pneumonia. Results: Findings for patients aged >= 65 years (n = 633) were consistent with those for the overall study populations, although a trend toward improved outcomes was reported in some subgroups, for example, patients aged >= 75 years with community-acquired pneumonia were more likely to achieve an early clinical response with ceftobiprole than comparator (treatment difference 16.3% [95% CI:1.8-30.8]). The safety profile was similar between treatment groups in all studies. Conclusion: This analysis further supports the efficacy and safety of ceftobiprole in older patients with acute bacterial skin and skin structure infections or pneumonia.Clinicaltrials.gov trial identifiers: , ,

Despite the dramatic increase in antimicrobial resistance, there is a dearth of antibiotics in development and few pharmaceutical companies working in the field. Further, any new antibiotics are likely to have a short shelf life. Ab-based interventions offer alternatives that are not likely to be circumvented by the widely prevalent antibiotic resistance genes. Bovine colostrum (BC)—the first milk after parturition, rich in nutrients and immune components—promotes gut integrity and modulates the gut microbiome. We developed a hyperimmune BC (HBC) enriched in Abs to a highly conserved LOS core region of Gram-negative bacteria by immunizing pregnant cows with a vaccine comprised of detoxified LOS from Escherichia coli O111 Rc (J5) mutant non-covalently complexed to group B meningococcal outer membrane protein (J5dLOS/OMP). This vaccine generated robust levels of anti-J5 LOS Ab in the colostrum. When given orally to neutropenic rats challenged orally with Pseudomonas aeruginosa, administration of HBC improved survival compared to non-immune rats, while both BC preparations improved survival compared to PBS controls. Elevated circulating endotoxin levels correlated with mortality. HBC and to a lesser extent non-immune BC reduced bacterial burden from the liver, lung, and spleen. We conclude that HBC and to a lesser extent BC may be effective supplements that improve outcome from lethal gut-derived disseminated infection and may reduce transmission of Gram-negative bacilli from the gastrointestinal tract.

Purpose Recent studies have shown that many children who stutter may have elevated characteristics of attention-deficit/hyperactivity disorder (ADHD). Although childhood ADHD commonly persists into adulthood, it is unclear how many adults who stutter experience aspects of ADHD (e.g., inattention or hyperactivity/impulsivity). This study sought to increase understanding of how ADHD characteristics might affect individuals who stutter by evaluating (a) whether elevated ADHD characteristics are common in adults who stutter, (b) whether elevated ADHD characteristics in adults who stutter were significantly associated with greater adverse impact related to stuttering, and (c) whether individual differences in Repetitive Negative Thinking (RNT) and Effortful Control influenced this relationship. Method Two hundred fifty-four adults who stutter completed the Adult ADHD Self-Report Scale, the Perseverative Thinking Questionnaire, the Adult Temperament Questionnaire short form, and the Overall Assessment of the Speaker's Experience of Stuttering. Data were analyzed via multiple linear regression to determine whether the number of inattention or hyperactivity/impulsivity characteristics was significantly associated with RNT, Effortful Control, or Adverse Impact related to stuttering. Results Almost one quarter of participants (23.2%; 60/254) self-reported experiencing six or more inattention characteristics, while fewer participants (8.3%; 21/254) self-reported experiencing six or more hyperactivity/impulsivity characteristics. Participants with lower Effortful Control and higher levels of both RNT and Adverse Impact were significantly more likely to self-report experiencing more inattention characteristics. Discussion Many adults who stutter may exhibit previously unaccounted for characteristics of ADHD, especially inattention. Results highlight the value of continued research on the intersectionality of stuttering, ADHD, and attention, and the importance of individualizing therapy to the needs of each unique person who stutters.

Background Leptospirosis is a zoonotic disease of concern and an investigation of recent spatio-temporal trends of leptospirosis in dogs in the United States is needed. Leptospira PCR testing has become increasingly used in veterinary clinical medicine and these data might provide information on recent trends of disease occurrence. Objectives To identify and describe clusters of PCR-positive Leptospira test results in dogs in the United States. Animals Leptospira real-time PCR test results from dogs (n = 40 118) in the United States from IDEXX Laboratories, Inc., between 2009 and 2016 were included in the analysis. Methods In this retrospective study, spatio-temporal clusters for a real-time PCR-positive test were identified using the space-time permutation scan statistic and the centroid of the zip code reported for each test. A maximum spatial window of 20% of the population at risk, and a maximum temporal window of 6 months were used. Results Seven statistically significant space-time clusters of Leptospira real-time PCR-positive test results were identified across the United States: 1 each located within the states of Arizona (2016), California (2014-2015), Florida (2010), South Carolina (2015), and 1 each located within the south-central region (2015), midwest region (2014), and northeast region (2011). Clusters ranged from 3 to 108 dogs and were identified during all years under study, except 2009, 2012, and 2013. Conclusions and clinical importance The spatial and temporal components of leptospirosis in dogs in this study are similar to those in previous work. However, clusters were identified in new areas, demonstrating the complex epidemiology of this disease.

There is growing interest in the potential of internet-delivered pain management programs (PMPs) to increase access to care for people with chronic pain. However, very few economic evaluations of these interventions have been reported. Using existing data, the current study examined the cost-effectiveness of an internet-delivered PMP for a mixed group chronic pain patients (n = 490) provided with different levels of clinician support. The findings indicated that each additional clinical outcome (defined as a ≥ 30% reduction in disability, depression, anxiety, and pain) was associated with cost-savings when the intervention was provided in a self-guided format (ICER range: −$404–−$808 AUD) or an optional-guided format (ICER range: −$314–−$541 AUD), and a relatively small fixed cost when provided in the clinician-guided format (ICER range: $88–$225 AUD). The results were driven by a reduction in service use costs among the treatment groups, which offset the costs of providing the internet-delivered PMP in the self-guided and optional-guided formats. The same general pattern of results was found when more stringent clinical outcomes (defined as a ≥ 50% reduction) were employed. These findings suggest that carefully developed and administered internet-delivered PMPs, provided with different levels of clinician support, can be highly cost effective for patients with a broad range of pain conditions. Perspective This study examines the cost-effectiveness of an internet-delivered PMP provided to adults with a broad range of chronic pain conditions. Evidence of cost-effectiveness was found across a broad range of clinical outcomes and with different levels of clinician support.

See Huuskonen et al. (doi:10.1093/brain/awab168) for a scientific commentary on this article. Systemic infection exacerbates Alzheimer’s disease. In this postmortem study, Asby et al. provide evidence that it does so by raising the levels of multiple cytokines in the brain and by exacerbating cerebral hypoperfusion and vascular leakage in Alzheimer’s disease, independently of the level of insoluble amyloid-β42., We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer’s disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer’s disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V–VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III–IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in Alzheimer’s disease with systemic infection. Cerebral hypoperfusion—indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)—and blood–brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer’s disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-β42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of Alzheimer’s disease, and with infection (even in Braak stage 0–II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer’s disease; these were related to amyloid-β level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood–brain barrier leakiness associated with Alzheimer’s disease and vascular dementia, independently of the level of insoluble amyloid-β, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

Objective This study identifies trajectories of parent depressive symptoms after having a child born with genital atypia due to a disorder/difference of sex development (DSD) or congenital adrenal hyperplasia (CAH) and across the first year postgenitoplasty (for parents who opted for surgery) or postbaseline (for parents who elected against surgery for their child). Hypotheses for four trajectory classes were guided by parent distress patterns previously identified among other medical conditions. Methods Participants included 70 mothers and 50 fathers of 71 children diagnosed with a DSD or CAH with reported moderate to high genital atypia. Parents were recruited from 11 US DSD specialty clinics within 2 years of the child’s birth and prior to genitoplasty. A growth mixture model (GMM) was conducted to identify classes of parent depressive symptoms over time. Results The best fitting model was a five-class linear GMM with freely estimated intercept variance. The classes identified were termed “Resilient,” “Recovery,” “Chronic,” “Escalating,” and “Elevated Partial Recovery.” Four classes have previously been identified for other pediatric illnesses; however, a fifth class was also identified. The majority of parents were classified in the “Resilient” class (67.6%). Conclusions This study provides new knowledge about the trajectories of depressive symptoms for parents of children with DSD. Future studies are needed to identify developmental, medical, or familial predictors of these trajectories.

OBJECTIVEEndovascular thrombectomy (EVT) and tissue plasminogen activator (tPA) are effective ischemic stroke treatments in the initial treatment window. In the extended treatment window, these treatments may offer benefit, but CT and MR perfusion may be necessary to determine patient eligibility. Many hospitals do not have access to advanced imaging tools or EVT capability, and further patient care would require transfer to a facility with these capabilities. To assist transfer decisions, the authors developed risk indices that could identify patients eligible for extended-window EVT or tPA.METHODSThe authors retrospectively identified stroke patients who had concurrent CTA and perfusion and evaluated three potential outcomes that would suggest a benefit from patient transfer. The first outcome was large-vessel occlusion (LVO) and target mismatch (TM) in patients 5–23 hours from last known normal (LKN). The second outcome was TM in patients 5–15 hours from LKN with known LVO. The third outcome was TM in patients 4.5–12 hours from LKN. The authors created multivariable models using backward stepping with an α-error criterion of 0.05 and assessed them using C statistics.RESULTSThe final predictors included the National Institutes of Health Stroke Scale (NIHSS), the Alberta Stroke Program Early CT Score (ASPECTS), and age. The prediction of the first outcome had a C statistic of 0.71 (n = 145), the second outcome had a C statistic of 0.85 (n = 56), and the third outcome had a C statistic of 0.86 (n = 54). With 1 point given for each predictor at different cutoffs, a score of 3 points had probabilities of true positive of 80%, 90%, and 94% for the first, second, and third outcomes, respectively.CONCLUSIONSDespite the limited sample size, compared with perfusion-based examinations, the clinical variables identified in this study accurately predicted which stroke patients would have salvageable penumbra (C statistic 71%–86%) in a range of clinical scenarios and treatment cutoffs. This prediction improved (C statistic 85%–86%) when utilized in patients with confirmed LVO or a less stringent tissue mismatch (TM < 1.2) cutoff. Larger patient registries should be used to validate and improve the predictive ability of these models.

Introduction: Current ischemic stroke risk prediction is primarily based on clinical factors, rather than imaging or laboratory markers. We examined the relationship between baseline ultrasound and inflammation measurements and subsequent primary ischemic stroke risk. Methods: In this secondary analysis of the Multi-Ethnic Study of Atherosclerosis (MESA), the primary outcome is the incident ischemic stroke during follow-up. The predictor variables are 9 carotid ultrasound-derived measurements and 6 serum inflammation measurements from the baseline study visit. We fit Cox regression models to the outcome of ischemic stroke. The baseline model included patient age, hypertension, diabetes, total cholesterol, smoking, and systolic blood pressure. Goodness-of-fit statistics were assessed to compare the baseline model to a model with ultrasound and inflammation predictor variables that remained significant when added to the baseline model. Results: We included 5,918 participants. The primary outcome of ischemic stroke was seen in 105 patients with a mean follow-up time of 7.7 years. In the Cox models, we found that carotid distensibility (CD), carotid stenosis (CS), and serum interleukin-6 (IL-6) were associated with incident stroke. Adding tertiles of CD, IL-6, and categories of CS to a baseline model that included traditional clinical vascular risk factors resulted in a better model fit than traditional risk factors alone as indicated by goodness-of-fit statistics. Conclusions: In a multiethnic cohort of patients without cerebrovascular disease at baseline, we found that CD, CS, and IL-6 helped predict the occurrence of primary ischemic stroke. Future research could evaluate if these basic ultrasound and serum measurements have implications for primary prevention efforts or clinical trial inclusion criteria.

Objective Moyamoya disease (MMD) is a vasculopathy of the internal carotid arteries with ischemic and hemorrhagic sequelae. Surgical revascularization confers upfront peri-procedural risk and costs in exchange for long-term protective benefit against hemorrhagic disease. The authors present a cost-effectiveness analysis (CEA) of surgical versus non-surgical management of MMD. Methods A Markov Model was used to simulate a 41-year-old suffering a transient ischemic attack (TIA) secondary to MMD and now faced with operative versus nonoperative treatment options. Health utilities, costs, and outcome probabilities were obtained from the CEA registry and the published literature. The primary outcome was incremental cost-effectiveness ratio which compared the quality adjusted life years (QALYs) and costs of surgical and nonsurgical treatments. Base-case, one-way sensitivity, two-way sensitivity, and probabilistic sensitivity analyses were performed with a willingness to pay threshold of $50,000. Results The base case model yielded 3.81 QALYs with a cost of $99,500 for surgery, and 3.76 QALYs with a cost of $106,500 for nonsurgical management. One-way sensitivity analysis demonstrated the greatest sensitivity in assumptions to cost of surgery and cost of admission for hemorrhagic stroke, and probabilities of stroke with no surgery, stroke after surgery, poor surgical outcome, and death after surgery. Probabilistic sensitivity analyses demonstrated that surgical revascularization was the cost-effective strategy in over 87.4% of simulations. Conclusions Considering both direct and indirect costs and the postoperative QALY, surgery is considerably more cost-effective than non-surgical management for adults with MMD.

Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the synthesis of oxalate, which is the toxic metabolite that is directly associated with the clinical manifestations of PH1. On 19 November 2020, lumasiran received its first global approval in the EU for the treatment of PH1 in all age groups. On 23 November 2020, lumasiran was approved in the USA for the treatment of adult and paediatric patients with PH1. This article summarizes the milestones in the development of lumasiran leading to this first approval.

Compared to adult AVMs, there is a paucity of data on the microsurgical treatment of pediatric AVMs. We report our institutional experience with pediatric AVMs treated by microsurgical resection with or without endovascular embolization and radiation therapy. We retrospectively reviewed all patients ≤ 18 years of age with cerebral AVMs that underwent microsurgical resection at Rady Children’s Hospital 2002–2019. Eighty-nine patients met inclusion criteria. The mean age was 10.3 ± 5.0 years, and 56% of patients were male. In total, 72 (81%) patients presented with rupture. Patients with unruptured AVMs presented with headache (n = 5, 29.4%), seizure (n = 9, 52.9%), or incidental finding (n = 3, 17.7%). The mean presenting mRS was 2.8 ± 1.8. AVM location was lobar in 78%, cerebellar/brainstem in 15%, and deep supratentorial in 8%. Spetzler-Martin grade was I in 28%, II in 45%, III in 20%, IV in 6%, and V in 1%. Preoperative embolization was utilized in 38% of patients and more frequently in unruptured than ruptured AVMs (62% vs. 32%, p = 0.022). Radiographic obliteration was achieved in 76/89 (85.4%) patients. Complications occurred in 7 (8%) patients. Annualized rates of delayed rebleeding and recurrence were 1.2% and 0.9%, respectively. The mean follow-up was 2.8 ± 3.1 years. A good neurological outcome (mRS score ≤ 2) was obtained in 80.9% of patients at last follow-up and was improved relative to presentation for 75% of patients. Our case series demonstrates high rates of radiographic obliteration and relatively low incidence of neurologic complications of treatment or AVM recurrence.

Reparative operations for insufficient cardiac valves constitute the surgical procedures of choice when pathoanatomies permit. At present, mitral and tricuspid repair techniques are well-established, but recent data also suggest that reconstruction of insufficient aortic valves may be associated with lower operative mortality, fewer valve-related complications, and improved survival. In an effort to increase adoption of aortic valve repair and to mitigate recurrent insufficiency, annuloplasty rings based on normal aortic root geometry have been developed to position in the inflow portion of the aortic annulus similar to mitral and tricuspid rings. This review will describe techniques for tri-leaflet and bicuspid geometric ring annuloplasty, and also will address leaflet reconstruction methods for the common leaflet pathologies. The application of a pathoanatomic approach to aortic insufficiency now permits the majority of aortic valves to be repaired with acceptable clinical outcomes.

Introduction The U.S. Navy Medicine has a long history of conducting global health missions that foster international diplomacy through medical knowledge exchange with a goal of increasing partner nation’s health care capacity. Pacific Partnership is an annual U.S. Navy-sponsored joint operation that enhances medical collaboration with participating nations throughout the Indo-Asia-Pacific region. Since 2015, a U.S. Navy Cardiology team has conducted a structural heart disease interventional workshop focused on congenital heart disease with the cardiologists at the Da Nang General Hospital, Da Nang, Vietnam. Herein, we describe the multinational collaborative project including the patient registry we developed to monitor the short- and long-term outcomes of structural heart disease interventions preformed during Pacific Partnership 2015 and 2016. Materials and Methods Our team developed a sustainable procedural registry with the goal of following the long-term outcomes of cardiac interventions for congenital heart disease in Vietnamese patients. Specifically, the registry was designed to record the changes in symptoms referable to the cardiovascular system and for device placement–associated complications for devices placed in 2015 and 2016 and has been updated annually thereafter. Results Twelve patients (age range, 7 months to 31 years) underwent successful atrial septal defect closure in 2015 without procedural complications. The follow-up rate was 75% at 1 year and 67% at 2 years, and all devices were in appropriate position with no complications identified. Fifteen patients (age range, 20-66 years) underwent successful atrial septal defect closure in 2016. The follow-up rate was 62.5% at 1 year, and all devices were in appropriate position with no complications identified. Three patients (age range, 5-25 months) underwent successful device closure of the patent ductus arteriosus in 2015 without complications. The follow-up rate was 67% in 2016 and again in 2017. Six patients (age range, 9-74 years) underwent successful patent ductus arteriosus closure in 2016 without complications. The follow-up rate was 67% in 2017, and all devices were in appropriate position with no device-related complications identified. Conclusions The development of a patient registry during these missions allowed for the longitudinal monitoring of outcomes for cardiac interventions. Notably, treated patients experienced symptomatic improvement without significant long-term procedural complications. Following patients longitudinally across medical missions is of recognized importance but remains a difficult objective to achieve for a multitude of factors including administrative and financial burdens on both the medical systems and the patients of host nations. Despite these limitations, longitudinal follow-up of patient care facilitated by a patient registry has a vital role in monitoring the quality of care provided and should be an integral part of all future global medical missions.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are attractive cancer targets as they can present peptides from tumour-selective proteins on the cell surface, which can be recognised by T cells via T cell receptors (TCRs). In this study, docetaxel-loaded polymeric NPs were conjugated to recombinant affinity-enhanced TCRs to target breast cancer cells presenting a tumour-selective peptide-HLA complex. The TCR-conjugated nanoparticles enabled enhanced delivery of docetaxel and induced cell death through tumour-specific peptide-HLA targeting. These in vitro data demonstrate the potential of targeting tumour-restricted peptide-HLA epitopes using high affinity TCR-conjugated nanoparticles, representing a novel treatment strategy to deliver therapeutic drugs specifically to cancer cells., High-affinity TCRs offer the potential to target chemotherapeutic drug-loaded nanoparticles specifically to tumour cells expressing tumour-specific peptides minimising off-target effects.

Purpose: In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion–mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α4β1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments. Experimental Design: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments. Results: V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity. Conclusions: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.

Prior to 2012, Echinococcus multilocularis was not known to occur in any host in Ontario, Canada. However, since that year, five cases of alveolar echinococcosis have been diagnosed in dogs that resided at the western end of Lake Ontario. In addition, E. multilocularis has been shown to be a common infection in wild canids (i.e. coyotes and foxes) across southern Ontario with a high-risk infection cluster in the area surrounding the western shores of Lake Ontario and northern shores of Lake Erie. In regions endemic for E. multilocularis, dog ownership is considered a risk factor for human alveolar echinococcosis. A study was therefore carried out to determine the prevalence of E. multilocularis intestinal infections in dogs within the high-risk infection cluster. From May to November 2018, faecal samples were collected from 477 dogs aged ≥6 months that visited 12 off-leash dog parks in the Halton, Hamilton and Niagara public health units. Faecal samples were analysed via a magnetic capture probe DNA extraction and real-time PCR method for E. multilocularis DNA. Overall, 0% (97.5% CI: 0%-0.80%) of samples tested positive. This result informs preventive recommendations for E. multilocularis infections in dogs in this region.

Background Lysosomal cysteine protease cathepsin V has previously been shown to exhibit elevated expression in breast cancer tissue and be associated with distant metastasis. Research has also identified that cathepsin V expression is elevated in tumour tissues from numerous other malignancies, but despite this, there has been limited examination of the function of this protease in cancer. Here we investigate the role of cathepsin V in breast cancer in order to delineate the molecular mechanisms by which this protease contributes to tumourigenesis. Methods Lentiviral transductions were used to generate shRNA cell line models, with cell line validation undertaken using RQ-PCR and Western blotting. Phenotypic changes of tumour cell biology were examined using clonogenic and invasion assays. The relationship between GATA3 expression and cathepsin V was primarily analysed using Western blotting. Site-directed mutagenesis was used to generate catalytic mutant and shRNA-resistant constructs to confirm the role of cathepsin V in regulating GATA3 expression. Results We have identified that elevated cathepsin V expression is associated with reduced survival in ER-positive breast cancers. Cathepsin V regulates the expression of GATA3 in ER-positive breast cancers, through promoting its degradation via the proteasome. We have determined that depletion of cathepsin V results in elevated pAkt-1 and reduced GSK-3β expression, which rescues GATA3 from proteasomal degradation. Conclusions In this study, we have identified that cysteine protease cathepsin V can suppress GATA3 expression in ER-positive breast cancers by facilitating its turnover via the proteasome. Therefore, targeting cathepsin V may represent a potential therapeutic strategy in ER-positive breast cancers, by restoring GATA3 protein expression, which is associated with a more favourable clinical outcome.

Background The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL). Methods We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex. Results Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis. Conclusions Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.

Oral darolutamide (Nubeqa™) is a novel second-generation, nonsteroidal, selective androgen receptor (AR) inhibitor indicated for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the pivotal multinational, phase 3 ARAMIS trial in men with nmCRPC, relative to placebo plus ongoing androgen deprivation therapy (ADT), darolutamide (+ ADT) significantly prolonged metastasis-free survival (MFS) at the time of the primary analysis and overall survival (OS) at the time of the final OS analysis and was generally well tolerated in extended follow-up. Albeit long-term data from the real-world setting are required to fully define the safety profile of darolutamide, current evidence from the final ARAMIS analysis indicates that darolutamide has a low propensity for CNS-related adverse events (AEs) associated with other currently approved second-generation AR inhibitors. Given the efficacy and safety evidence from the final ARAMIS analysis and the key role of second-generation AR inhibitors in the management of nmCRPC, darolutamide + ADT represents an important emerging option for the treatment of men with nmCRPC who are at high risk of developing metastatic prostate cancer.

PURPOSE: Extracranial ICA imaging has largely focused on the degree of luminal stenosis, but recent advances suggest specific plaque features are crucial in stroke risk assessment. We evaluated the current state of reporting carotid plaque features on neck CTAs at an academic institution. METHODS: In this retrospective observational study, we included neck CTAs performed on patients over age 50 with any reported carotid plaque. We evaluated reports for mention of the following: degree of luminal stenosis, soft plaque, calcified plaque, plaque thickness, quantification of soft and calcified plaque, plaque ulceration, and increased risk associated with specific features. We used Fisher’s exact test to compare how often each feature was mentioned. RESULTS: We included a total of 651 reports from unique patients (mean age, 68.1 ± 13.3 years). A total of 639 reports (98.1%) explicitly mentioned degree of stenosis per NASCET criteria. Specific plaque features were less frequently characterized: soft plaque in 116 (17.8%); calcified plaque in 166 (25.5%); quantification of the amount of soft plaque and calcified plaque in 24 (3.7%) and 16 (2.5%) reports, respectively; plaque thickness in 12 (1.8%); plaque ulceration in 476 (73.1%); and increased risk associated with plaque in 2 (0.3%). Degree of stenosis was statistically more likely to be mentioned than any other plaque feature (p < 0.001). CONCLUSION: Currently, nearly all reports mention the degree of luminal stenosis on neck CTAs while a significant minority mention specific plaque features. Despite mounting evidence of the importance of carotid plaque features in stroke risk assessment, radiology reports do not routinely report these findings.

Abdominal and peritoneal pain after surgery is common and burdensome, yet the lack of standardized diagnostic criteria for this type of acute pain impedes basic, translational, and clinical investigations. The collaborative effort among the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, American Pain Society, and American Academy of Pain Medicine Pain Taxonomy (AAAPT) provides a systematic framework to classify acute painful conditions. Using this framework, a multidisciplinary working group reviewed the literature and developed core diagnostic criteria for acute abdominal and peritoneal pain after surgery. In this report, we apply the proposed AAAPT framework to 4 prototypical surgical procedures resulting in abdominal and peritoneal pain as examples: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection. These diagnostic criteria address the 3 most common surgical procedures performed in the United States, capture diverse surgical approaches, and may also be applied to other surgical procedures resulting in abdominal and peritoneal pain. Additional investigation regarding the validity and reliability of this framework will facilitate its adoption in research that advances our comprehension of mechanisms, deliver better treatments, and help prevent the transition of acute to chronic pain after surgery in the abdominal and peritoneal region. Perspective Using AAAPT, we present key diagnostic criteria for acute abdominal and peritoneal pain after surgery. We provide a systematic classification using 5 dimensions for abdominal and peritoneal pain that occurs after surgery, in addition to 4 specific surgical procedures: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection.

Background Cluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking. Methods This was a Phase 3, randomized, double-blind, placebo-controlled study in patients (men or women aged 18-65 years) diagnosed with episodic CH as defined by the International Classification of Headache Disorders-3 beta criteria. In this post hoc analysis, we evaluated the median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attack frequency, and impact on acute medication use. An anchor-based assessment of clinically relevant attack frequency reduction using the Patient Global Impression of Improvement (PGI-I) scores at Week 4 was also assessed. Results The median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attacks was consistently shorter (9-10 days sooner) with galcanezumab vs placebo (median [95% confidence interval, 95% CI]: ≥50%, 5 days [4.0 to 7.0] vs 14 days [6.0 to 19.0]; ≥75%, 11 days [7.0 to 16.0] vs 21 days [13.0 to 26.0]; 100%, 22 days [16.0 to 37.0] vs 32 days [23.0 to 34.0]). Mean reduction from baseline in the overall frequency of weekly pooled acute medication use across Weeks 1-3 was significantly greater with galcanezumab vs placebo (11.0 vs 5.5; odds ratio, OR [95% CI]: 5.52 [1.02, 10.01]; P value = .017). Patients reporting "much better" on the PGI-I experienced a median weekly CH attack reduction of approximately 43% from baseline across Weeks 1-3. The overall odds of achieving an attack reduction threshold of 43% across Weeks 1-3 was significantly higher with galcanezumab vs placebo (Weeks 1-3: OR [95% CI], 2.60 [1.3 to 5.3]). Conclusions Faster median time-to-first occurrence of response rates, lower frequency of pooled acute medications use, and a greater proportion of patients achieving a response anchored by patient-reported improvement were observed for galcanezumab vs placebo.

Background and aims Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown. Approach and results We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury. Conclusions Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.

Informal caregivers for persons with dementia frequently report needing assistance, yet formal support service use has been low. To better understand factors associated with service use, correlates of self-reported service use (e.g. support groups, family mediation, family leave, classes/trainings, and respite care) among dementia caregivers were assessed. The National Poll on Healthy Aging conducted a nationally representative web-based survey of adults aged 50–80 (N=2,131) using Ispos’ KnowledgePanel®; 148 reported caregiving for an adult with memory loss [61.5% female; 25% non-White, 54.1% aged 50–64]. Multivariable logistic regression analyses assessed caregiver and care recipient characteristics associated with service use within the prior year. Nearly 25% of caregivers used at least one service. Caregiver characteristics associated with greater likelihood of service use included not working [7.5 OR; 2.73, 20.62 CI]; income

Background Antibody-drug conjugate (ADC) construction poses numerous challenges that limit clinical progress. In particular, common bioconjugation methods afford minimal control over the site of drug coupling to antibodies. Here, such difficulties are overcome through re-bridging of the inter-chain disulfides of cetuximab (CTX) with auristatin-bearing pyridazinediones, to yield a highly refined anti-epidermal growth factor receptor (EGFR) ADC. Methods In vitro and in vivo assessment of ADC activity was performed in KRAS mutant pancreatic cancer (PaCa) models with known resistance to CTX therapy. Computational modelling was employed for quantitative prediction of tumour response to various ADC dosing regimens. Results Site-selective coupling of an auristatin to CTX yielded an ADC with an average drug:antibody ratio (DAR) of 3.9, which elicited concentration- and EGFR-dependent cytotoxicity at sub-nanomolar potency in vitro. In human xenografts, the ADC inhibited tumour growth and prolonged survival, with no overt signs of toxicity. Key insights into factors governing ADC efficacy were obtained through a robust mathematical framework, including target-mediated dispositional effects relating to antigen density on tumour cells. Conclusions Together, our findings offer renewed hope for CTX in PaCa therapy, demonstrating that it may be reformatted as a next-generation ADC and combined with a predictive modelling tool to guide successful translation.

Background The objective of this study was to determine spectrum and prevalence of germline mutations in TP53 gene among Polish women with early-onset breast cancer (BC), which has not been determined until now. Methods A cohort of 100 females with BC diagnosed ≤ 30 years of age and with a positive family history of cancer was used as a discovery cohort. 1880 women with BC ≤ 45 years old and a control group of 2000 healthy women were genotyped as a replication phase of this study. Results Four heterozygous pathogenic missense mutations were detected in a group of 100 patients with early-onset breast cancer. On the basis of software prediction and available literature data, all these variants were defined as pathogenic. None of these TP53 variants were detected among 1880 breast cancer patients and 2000 healthy controls. No large mutations were found among early-onset cases using MLPA reaction. Conclusion Germline pathogenic TP53 variants were found in 4% early-onset Polish BC patients. No founder mutations were identified in Polish population. To improve the treatment and surveillance screening, the search for germline TP53 pathogenic variants is recommended for all female BC cases diagnosed ≤ 30 years old.

Background The obesity epidemic has spread rapidly across the United States. Although overweight and obese patients have a paradoxically lower risk for postoperative morbidity and mortality, the risks associated with extreme classes of obesity (morbid obesity, super obesity, and super-super obesity) have not been described. Methods We queried the National Surgical Quality Improvement Program database from 2012 to 2016. Of 1,815,251 surgical cases, there were 3,946 vascular cases, 237,777 emergency procedures, and 75,177 cases with missing data that were removed. The remaining 1,378,711 cases were included in this analysis. Multivariable linear and logistic regression was performed to assess the impact of body mass index on postoperative outcomes. Results Patients within the super obesity and super-super obesity groups had the highest procedure-adjusted mortality risk among all body mass index classes (odds ratio = 2.31 and 2.63, respectively). Morbid obesity and underweight groups had moderate risk (odds ratio = 1.37 and 1.88, respectively), while those in the overweight and obesity class I and II cohorts had improved or equivocal mortality risk compared to normal body mass index class patients. Risk-adjusted and unadjusted multivariable models demonstrated that extreme obesity classes (morbid obesity, super obesity, and super-super obesity) have a graduated escalation of perioperative morbidity, infectious, and critical care complications. Conclusion Further detailing extreme obesity-related risk beyond the obesity class III umbrella is necessary for accurate risk prediction, especially with the rising prevalence of elective nonbariatric surgery in this population. Preoperative risk assessment tools should consider subgroup risk adjustment to delineate true postoperative complication risk, facilitate patient education, and address modifiable risk factors before surgery.

Meta-analysis has been used to examine the effectiveness of childhood obesity prevention efforts, yet traditional conventional meta-analytic methods restrict the kinds of studies included, and either narrowly define mechanisms and agents of change, or examine the effectiveness of whole interventions as opposed to the specific actions that comprise interventions. Taxonomic meta-analytic methods widen the aperture of what can be included in a meta-analysis data set, allowing for inclusion of many types of interventions and study designs. The National Collaborative on Childhood Obesity Research Childhood Obesity Evidence Base (COEB) project focuses on interventions intended to prevent childhood obesity in children 2–5 years old who have an outcome measure of BMI. The COEB created taxonomies, anchored in the Social Ecological Model, which catalog specific outcomes, intervention components, intended recipients, and contexts of policies, initiatives, and interventions conducted at the individual, interpersonal, organizational, community, and societal level. Taxonomies were created by discovery from the literature itself using grounded theory. This article describes the process used for a novel taxonomic meta-analysis of childhood obesity prevention studies between the years 2010 and 2019. This method can be applied to other areas of research, including obesity prevention in additional populations.