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ObjectiveAntenatal anaemia is associated with increased peripartum transfusion requirement in South Africa. We studied whether HIV was associated with the response to treatment of iron-deficiency anaemia.DesignProspective cohort study.SettingHospital-based antenatal anaemia clinic in South Africa.SampleEqual-sized cohorts of pregnant women testing positive for HIV (HIV+) and testing negative for HIV (HIV-) with iron-deficiency anaemia.MethodsHaemoglobin trajectories of women with confirmed iron-deficiency anaemia (ferritin

Depot-medroxyprogesterone acetate is a commonly used injectable contraceptive that has been associated with an increased risk of HIV acquisition. This study compares effects of depot-medroxyprogesterone acetate on immune parameters from several upper reproductive tract compartments relevant to HIV-1 susceptibility in repetitive samples from 15 depot-medroxyprogesterone acetate users and 27 women not on hormonal contraceptives. Compared with samples from unexposed women in the mid-luteal phase, depot-medroxyprogesterone acetate use was associated with: increased endocervical concentrations of MCP1 and IFNalpha2; decreased endocervical concentrations of IL1beta and IL6; increased proportions of endometrial CD4+ and CD8+ cells expressing the activation marker HLADR; increased density of endometrial macrophages; and decreased density of endometrial regulatory T cells. Unlike previous reports with samples from the vagina, we did not observe increased expression of the HIV co-receptor CCR5 on CD4+ T cells in the endocervix or endometrium. Our results indicate important differences in anatomic compartments regarding mechanisms by which depot-medroxyprogesterone acetate could be associated with increased risk of HIV acquisition, including increased recruitment of macrophages to the endometrium, decreased levels of pro-inflammatory cytokines in the endocervix possibly leading to enhanced susceptibility to viral infection, and activation of endometrial T cells.

PurposeTo determine if asymmetry between hips in pain or radiographic osteoarthritis (RHOA) is associated with worse pain and joint space narrowing (JSN) at baseline and longitudinally in knees contralateral to more affected hips.MethodsWe studied 279 participants in the Osteoarthritis Initiative with baseline asymmetry between hips in pain and 483 with asymmetry in RHOA none of whom had a hip replacement for ≥4 years after baseline. RHOA assessed from pelvis radiographs was categorized as none, possible or definite and hip pain on most days of a month in the past year as present/absent. Knee pain (WOMAC scale) and JSN (fixed flexion radiographs) were categorized as none, mild and moderate-severe. We compared knees contralateral and ipsilateral to more affected hips on baseline knee pain and JSN using clustered multinomial regression and on change in knee pain and JSN over 4-5 years using generalized linear and logistic estimating equations.ResultsKnees contralateral to painful hips had less baseline pain ("moderate-severe" vs "none", relative risk ratio [RRR]: 0.39, 95% CI = 0.27-0.57), but greater baseline JSN ("moderate-severe" vs "none", RRR: 1.62, 95% CI = 1.09-2.38) and greater worsening of pain during follow-up (P = 0.001). Knees contralateral to hips with worse RHOA had nonsignificant trends for greater baseline JSN (P = 0.10) and JSN progression (P = 0.17).ConclusionThese findings provide limited support for the hypothesis that early asymmetry in hip pain and RHOA is associated with worse pain and structural outcomes in knees contralateral to the more affected hip.

Background(131)I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan.MethodsPatients 1-30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days -1 to +6, irinotecan (50 mg m(-2) per dose IV) on days 0-4, vincristine (2 mg m(-2)) on day 0, MIBG (555 or 666 MBq kg(-1)) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients.ResultsThirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg(-1). Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37%; P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients.ConclusionsMIBG (666 MBq kg(-1)) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.

ObjectiveTo describe cartilage matrix and morphology changes, assessed using quantitative magnetic resonance imaging (MRI), after acute anterior cruciate ligament (ACL) injury relative to controls and longitudinally during 2 years following reconstruction.MethodFifteen patients with acute ACL injuries and 16 healthy volunteers with a similar demographic profile but no history of osteoarthritis or knee injury were studied. The injured knee of each participant was imaged with a 3.0 T MR scanner at baseline (prior to ACL reconstruction); patients' knees were re-imaged 1 and 2 years after ACL reconstruction. Cartilage T1ρ and T2 values in full thickness, superficial layers, and deep layers, and cartilage thickness of the full layer were quantified within subcompartments of the knee joint.ResultsIn the posterolateral tibial cartilage, T1ρ values were significantly higher in ACL-injured knees than control knees at baseline and were not fully recovered 2 after ACL reconstruction. T1ρ values of medial tibiofemoral cartilage in ACL-injured knees increased over the 2-year study and were significantly elevated compared to that of the control knees. T2 values in cartilage of the central aspect of the medial femoral condyle at the 2-year follow-up were significantly elevated compared with control knees. Cartilage in the posterior regions of the lateral tibia was significantly thinner, while cartilage in the central aspect of the medial femur was significantly thicker than that of controls. Patients with lesions in the posterior horn of the medial meniscus exhibited significantly higher T1ρ values in weight-bearing regions of the tibiofemoral cartilage than that of control subjects over the 2-year period, whereas patients without medial meniscal tears did not.ConclusionQuantitative MRI provides powerful in vivo tools to quantitatively evaluate early changes of cartilage matrix and morphology after acute ACL injury and reconstruction, which may possibly relate to the development of post-traumatic osteoarthritis in such joints.

Background: The authors previously developed and validated the Cancer of the Prostate Risk Assessment (CAPRA) score to predict prostate cancer recurrence based on pretreatment clinical data. They aimed to develop a similar postsurgical score with improved accuracy via incorporation of pathologic data.Methods: A total of 3837 prostatectomy patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE™) national disease registry were analyzed. Cox regression was used to determine the predictive power of preoperative prostate-specific antigen (PSA), pathologic Gleason score (pGS), surgical margins (SM), extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph node invasion (LNI). Points were assigned based on the relative weights of these variables in predicting recurrence. The new postsurgical score (CAPRA-S) was tested and compared with a commonly cited nomogram with proportional hazards analysis, concordance (c) index, calibration plots, and decision-curve analysis.Results: Recurrence appeared in 16.8% of the men; actuarial progression-free probability at 5 years was 78.0%. The CAPRA-S was determined by adding up to 3 points for PSA, up to 3 points for pGS, 1 point each for ECE and LNI, and 2 points each for SM and SVI. The hazard ratio for each point increase in CAPRA-S score was 1.54 (95% confidence interval, 1.49-1.59), indicating a 2.4-fold increase in risk for each 2-point increase in score. The CAPRA-S c-index was 0.77, substantially higher than 0.66 for the pretreatment CAPRA score and comparable to 0.76 for the nomogram. The CAPRA-S score performed better in both calibration and decision curve analyses.Conclusions: The CAPRA-S offers good discriminatory accuracy, calibration, and ease of calculation for clinical and research settings. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between abnormal Pap test results and human papillomavirus (HPV) in Vietnamese-American women, who have the highest cervical cancer incidence in the United States.Materials and Methods: In 2001, we obtained specimens from 117 Vietnamese women, 24 with abnormal Pap test results including atypical squamous cells of undetermined significance (cases) and 93 with normal Pap test results (controls), as classified by the 1991 Bethesda System. We used L1 consensus primers MY09/MY11 to perform HPV polymerase chain reaction analysis and type-specific probes to perform genotyping.Results: Thirteen cases (54%) and 6 controls (6%) were HPV positive (p < .001). Ten of 24 cases (42%) and 0 controls (0%) had high-risk HPV types (16, 18, 45, 53, 56, or 66; p < .001). High-risk HPV types were significantly associated with increasing severity of Pap test results.Conclusions: Compared with those with normal Pap test results, Vietnamese-American women with abnormal Pap test results were more likely to have high-risk HPV types. Higher cervical cancer incidence among these women is likely the result of less frequent Pap screening rates and not different biology. [ABSTRACT FROM AUTHOR]

Background: Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoid-protease inhibitor interactions (because both share cytochrome P-450 metabolic pathways).Objective: To determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients.Design: Randomized, placebo-controlled, 21-day intervention trial.Setting: The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California.Participants: 67 patients with HIV-1 infection.Intervention: Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals.Measurements: HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors.Results: 62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 x 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was -0.07 (95% CI, -0.30 to 0.13) for marijuana and -0.04 (CI, -0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids.Conclusions: Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: To examine the prevalence of unhealthy behaviors among a cohort of Vietnamese adolescents in California; to examine the relationship between these behaviors and school-related variables (school performance, educational risk behaviors, higher-education aspirations, and participation in extracurricular activities); and to assess the differences that may exist between males and females with regard to these factors. METHODS: We conducted telephone interviews with 783 Vietnamese adolescents, aged 12-17 years, recruited through telephone listings from four California counties where large Vietnamese populations reside: San Francisco, Santa Clara, Los Angeles, and Orange. Of the 783 completed interviews, 60.8% were conducted in English and 39.2% in Vietnamese. The main outcome measure is a health risk behavior scale that includes adolescents' reports of ever smoking a cigarette, sedentary vs. active lifestyle, consumption of fruits and vegetables, consumption of foods high in fat, ever drinking alcohol, and ever engaging in sexual behavior. Multiple regression analyses were employed to estimate the association among the demographic variables, acculturation, school performance, aspirations, extracurricular activities, and the overall health risk. RESULTS: Females were significantly more sedentary than males. Over one-quarter (29%) of the females reported not having participated in vigorous physical activity on 3 or more days per week, compared with just 18% of the males. Most adolescents reported they had never tried cigarettes (84%), never used alcohol (77%), and never had sex (97%). Males were more likely than females to report a higher frequency of experimentation with smoking and drinking. Overall, school performance and participation in extracurricular activities were significantly related to the health risk behavior scale. Adolescents who demonstrated at least one educational risk (ever skipped school or ever sent out of the classroom) were more likely to engage in other risky behaviors. Also, older and more acculturated adolescents were at increased risk of engaging in health-compromising behaviors. Analysis by gender revealed that the variables age, educational risk, and chance of attending college were all related to health risk behavior for both males and females. Among the boys, those who reported achieving an average grade of B or better had a decreased risk of engaging in health-compromising behaviors; however, neither extracurricular activities nor acculturation was related to health-compromising behaviors in boys. Among the girls, the reverse was true: lack of participation in extracurricular activities was related to health-compromising behaviors, whereas grades were not a significant risk factor. CONCLUSIONS: Among sampled Vietnamese adolescents in California, health risk behaviors are common and inversely related to some school performance indicators. Using these indicators to identify high-risk groups could allow targeted educational programs or interventions for the mitigation of health-compromising behaviors. [ABSTRACT FROM AUTHOR]

Background: Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSILs). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years old, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH)., Setting: We enrolled MSM who were aged 50+ during 2018-2022 in San Francisco, CA., Methods: One hundred twenty-nine MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with a biopsy of visible lesions., Results: Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (odds ratio: 45.1, 95% confidence interval: 15.8-129); other oncogenic HPV types (odds ratio: 5.95, 95% confidence interval: 2.74-12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status., Conclusion: The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remains very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2., (© 2024. The Author(s).)

Adverse Childhood Experiences (ACEs) are very common and presently implicated in 9 out of 10 leading causes of death in the United States. Despite this fact, our mechanistic understanding of how ACEs impact health is limited. Moreover, interventions for reducing stress presently use a one-size-fits-all approach that involves no treatment tailoring or precision. To address these issues, we developed a combined cross-sectional study and randomized controlled trial, called the California Stress, Trauma, and Resilience Study (CalSTARS), to (a) characterize how ACEs influence multisystem biological functioning in adults with all levels of ACE burden and current perceived stress, using multiomics and other complementary approaches, and (b) test the efficacy of our new California Prec ision I ntervention for S tress and R e silience (PRECISE) in adults with elevated perceived stress levels who have experienced the full range of ACEs. The primary trial outcome is perceived stress, and the secondary outcomes span a variety of psychological, emotional, biological, and behavioral variables, as assessed using self-report measures, wearable technologies, and extensive biospecimens (i.e. DNA, saliva, blood, urine, & stool) that will be subjected to genomic, transcriptomic, proteomic, metabolomic, lipidomic, immunomic, and metagenomic/microbiome analysis. In this protocol paper, we describe the scientific gaps motivating this study as well as the sample, study design, procedures, measures, and planned analyses. Ultimately, our goal is to leverage the power of cutting-edge tools from psychology, multiomics, precision medicine, and translational bioinformatics to identify social, molecular, and immunological processes that can be targeted to reduce stress-related disease risk and enhance biopsychosocial resilience in individuals and communities worldwide.

Pulmonary arterial hypertension associated with schistosomiasis (SchPAH) and pulmonary arterial hypertension associated with portal hypertension (PoPAH) are lung diseases that develop in the presence of liver diseases. However, mechanistic pathways by which the underlying liver conditions and other drivers contribute to the development and progression of pulmonary arterial hypertension (PAH) are unclear for both etiologies. In turn, these unknowns limit certainty of strategies to prevent, diagnose, and reverse the resultant PAH. Here we consider specific mechanisms that contribute to SchPAH and PoPAH, identifying those that may be shared and those that appear to be unique to each etiology, in the hope that this exploration will both highlight known causal drivers and identify knowledge gaps appropriate for future research. Overall, the key pathophysiologic differences that we identify between SchPAH and PoPAH suggest that they are not variants of a single condition.

Introduction: Peer support has been recommended to promote smoking cessation, but results from prior meta-analyses have not established its efficacy. We conducted a systematic review and meta-analysis to assess current evidence and identify potential modifiers of efficacy., Methods: Randomized controlled trials of peer-support interventions with a smoking cessation outcome were identified in January 2022 from PubMed and references listed in identified studies. The meta-analysis outcome measure was mean risk ratio (RR, 95% confidence interval [CI]) for abstinence at the longest follow-up timepoint between 3 and 9 months from baseline. Potential modifiers tested were peer smoking status (former, current, or unknown), follow-up timepoint, abstinence measure, and cumulative engagement time between peers and smokers ("dose"). Studies were assessed for risk of bias and certainty of evidence., Results: We identified 16 trials, which varied in abstinence effect size (RR 0.61-3.07), sample size (23-2121), dose (41-207 minutes), and follow-up timepoint (<1-15 months). Across 15 trials with follow-up between 3 and 9 months (N = 8573 participants; 4565 intervention, 4008 control), the pooled Mantel-Haenszel RR was 1.34 (95% CI: 1.11-1.62). Effect sizes were greatest among interventions with formerly smoking peers (RR 1.43, 95% CI 1.17-1.74; five trials). We found positive effects for follow-up timepoints ≥3 months but no effect of intervention dose. The overall quality of evidence was deemed "very low.", Conclusions: Peer-support interventions increased smoking abstinence. There remains a lack of consensus about how to define a peer. Intervention features such as peer smoking status appear to have explanatory power. Additional high-quality and more comparable trials are needed., Implications: This study reviewed the latest evidence from randomized controlled trials and found that peer-support interventions enhance smoking cessation. Efficacy varies with key intervention features such as peer smoking status and follow-up timepoint, which may be used to facilitate development of more effective peer-support interventions. Future trials and reviews would benefit from careful consideration and clear reporting of peer smoking status, length of follow-up, abstinence measures, and intervention dose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The approval of CDK4/6 inhibitors has dramatically improved care for the treatment of HR+/HER2- advanced breast cancer, but navigating the rapidly-expanding treatment evidence base is challenging. In this narrative review, we provide best-practice recommendations for the first-line treatment of HR+/HER2- advanced breast cancer in Canada based on relevant literature, clinical guidelines, and our own clinical experience. Due to statistically significant improvements in overall survival and progression-free survival, ribociclib + aromatase inhibitor is our preferred first-line treatment for de novo advanced disease or relapse ≥12 months after completion of adjuvant endocrine therapy and ribociclib or abemaciclib + fulvestrant is our preferred first-line treatment for patients experiencing early relapse. Abemaciclib or palbociclib may be used when alternatives to ribociclib are needed, and endocrine therapy can be used alone in the case of contraindication to CDK4/6 inhibitors or limited life expectancy. Considerations for special populations-including frail and fit elderly patients, as well as those with visceral disease, brain metastases, and oligometastatic disease-are also explored. For monitoring, we recommend an approach across CDK4/6 inhibitors. For mutational testing, we recommend routinely performing ER/PR/HER2 testing to confirm the subtype of advanced disease at the time of progression and to consider ESR1 and PIK3CA testing for select patients. Where possible, engage a multidisciplinary care team to apply evidence in a patient-centric manner.

Objective: The aim of this study is to examine complementary and alternative medicine (CAM) use among women with symptomatic uterine fibroids in the United States. Materials and Methods: In this cross-sectional analysis of baseline data from a multicenter, prospective cohort study of premenopausal women undergoing surgery for symptomatic fibroids and who enrolled in the Uterine Leiomyoma Treatment with Radiofrequency Ablation study from 2017 to 2019, we contrast women indicating use of at least one CAM modality specifically for fibroid symptoms against women using CAM for other reasons and CAM nonusers. Multivariable logistic regression models were performed to identify participant characteristics independently associated with CAM use for fibroids. Results: Among 204 women, 55% were Black/African American and the mean age was 42 (standard deviation 6.6) years. CAM use was common (67%), with 42% (95% confidence interval [CI]: 35%-49%) reporting use of CAM specifically to treat fibroid symptoms. Most commonly, CAM treatments used for fibroids were diet (62%) and herbs (52%), while CAM treatments for other reasons were exercise (80%) and massage (43%). On average, each participant who reported CAM use utilized three different types of CAM modalities. In a multivariable model, participants were more likely to use CAM for fibroids if they had pelvic pressure (odds ratio [OR] 2.50, 95% CI: 1.07-5.87, p  = 0.04), a body-mass index lower than average (OR 0.76, 95% CI: 0.60-0.97, p  = 0.03), and a lower health-related quality of life score (OR 0.61, 95% CI: 0.46-0.81, p  = 0.001). Conclusions: In this diverse sample of women with symptomatic fibroids, CAM use was highly prevalent. Our findings highlight the need for providers to query patients about CAM use and understand the role of CAM in fibroid management. ClinicalTrials.gov Identifier: NCT02100904.

The incidence of anal cancer is increasing, especially in high-risk groups, such as PLWH. HPV 16, a high-risk (HR) HPV genotype, is the most common genotype in anal high-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinoma (SCC) in the general population. However, few studies have described the distribution of HR HPV genotypes other than HPV 16 in the anus of PLWH. HPV genotyping was performed by DNA amplification followed by dot-blot hybridization to identify the HR and low-risk (LR) genotypes in benign anal lesions (n = 34), HSIL (n = 30), and SCC (n = 51) of PLWH and HIV-negative individuals. HPV 16 was the most prominent HR HPV identified, but it was less common in HSIL and SCC from PLWH compared with HIV-negative individuals, and other non-HPV 16 HR HPV (non-16 HR HPV) types were more prevalent in samples from PLWH. A higher proportion of clinically normal tissues from PLWH were positive for one or more HPV genotypes. Multiple HPV infection was a hallmark feature for all tissues (benign, HSIL, SCC) of PLWH. These results indicate that the development of anal screening approaches based on HPV DNA testing need to include non-16 HR HPVs along with HPV 16, especially for PLWH. Along with anal cytology, these updated screening approaches may help to identify and prevent anal disease progression in PLWH.

Background: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C , which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation., Methods: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C , in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months., Results: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor β chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report., Conclusions: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: More than half of people living with HIV in the US are 50+ years old. Despite the benefits of antiretroviral therapy, older individuals with HIV are at higher risk for illnesses than their HIV-negative counterparts. Anal cancer, anal high-grade squamous intraepithelial lesions (HSIL), and anal HPV-16 infection occur most frequently among men who have sex with men living with HIV (MSMLWH). Men aged 60+ are 3-fold more likely to be diagnosed with anal cancer compared with younger men. Despite the increasing risk of anal cancer with age and HIV, little is known about the relationships among aging, HPV infection, HSIL and HIV., Methods and Analysis: The Anal HPV, HIV, and Aging (AHHA) Study is a two-stage project to evaluate the relationships among anal HPV infection, HSIL, HIV infection, and biomarkers of biological aging in MSM or trans women over the age of 50 years. Stage 1 will estimate the cross-sectional prevalence of both anal HPV infection and HSIL, based on outcomes of anal HPV DNA testing, and high-resolution anoscopy with biopsy. We will also study associations with study outcomes and serological biomarkers of inflammation (interleukin-6, C-reactive protein, D-dimer) and with the Veterans Aging Cohort Study Index and the Fried Frailty Phenotype using multivariable models. Participants living with HIV ( n = 150) and HIV-negative participants ( n = 150) will be enrolled. The 3-year Stage 2 longitudinal sample restricted to HSIL-negative and anal HPV-16 DNA-negative participants will estimate the 3-year incidence of both anal HSIL and anal HPV, stratified by HIV status through Cox proportional hazards regression. The effect of biomarkers of inflammation and markers of aging on study outcomes will be evaluated through multivariable repeated measures models stratified by HIV status., Ethics and Dissemination: This protocol was approved by the University of California, San Francisco Institutional Review Board (IRB: 16-18966). Results will be disseminated through presentations at national/international scientific conferences and publication in peer-reviewed journals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hernandez, Weatherly, Gonzalez, Farhat, Da Costa, Calderon, Kauffman, Akha, Hilton and Palefsky.)

Pancreas transplantation in patients with type 2 diabetes (T2D) remains relatively uncommon compared with pancreas transplantation in patients with type 1 diabetes (T1D); however, several studies have suggested similar outcomes between T2D and T1D, and the practice has become increasingly common. Despite this growing interest in pancreas transplantation in T2D, no study has systematically summarized the data to date. We systematically reviewed the literature on pancreas transplantation in T2D patients including patient and graft survival, glycemic control outcomes, and comparisons with outcomes in T2D kidney transplant alone and T1D pancreas transplant recipients. We searched biomedical databases from January 1, 2000, to January 14, 2021, and screened 3314 records, of which 22 full texts and 17 published abstracts met inclusion criteria. Full-text studies were predominantly single center (73%), whereas the remaining most often studied the Organ Procurement and Transplantation Network database. Methodological quality was mixed with frequent concern for selection bias and concern for inconsistent definitions of both T2D and pancreas graft survival across studies. Overall, studies generally reported favorable patient survival, graft survival, and glycemic control outcomes for pancreas transplantation in T2D and expressed a need to better characterize the T2D patients who would benefit most from pancreas transplantation. We suggest guidance for future studies, with the aim of supporting the safe and evidence-based treatment of end-stage T2D and judicious use of scarce resources., Competing Interests: The authors declare no conflict of interests., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH) worldwide, but the prevalence and risk factors for schistosomiasis-associated PAH (SchPAH) development are not well understood. Schistosomiasis-associated hepatosplenic disease (SchHSD) is thought to be a major risk factor for PAH development. Herein, we describe our plans for prospectively screening SchHSD subjects for clinical evidence of PAH at two major academic medical centers and national referral hospitals in Addis Ababa, Ethiopia and Lusaka, Zambia. The screening study will primarily be conducted by echocardiography, in addition to clinical assessments. Plasma samples will be drawn and banked for subsequent analysis based on preclinical animal model rationale. If successful, this study will demonstrate feasibility of conducting prospective cohort studies of SchPAH screening in schistosomiasis-endemic regions of Africa, and provide initial data on clinic-based disease prevalence and potential mechanistic biomarkers underlying disease pathogenesis., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Purpose: The optimal frequency for cardiac monitoring of left ventricular ejection fraction (LVEF) in patients receiving trastuzumab-based therapy for early breast cancer (EBC) is unknown. We conducted a randomized controlled trial comparing 3- versus 4-monthly cardiac monitoring., Patients and Method: Patients scheduled to receive trastuzumab-containing cancer therapy for EBC with normal (>53%) baseline LVEF were randomized to undergo LVEF assessments every 3 or 4 months. The primary outcome was the change in LVEF from baseline. Secondary outcomes included the rate of cardiac dysfunction (defined as a decrease in the LVEF of ≥10 percentage points, to a value <53%), delays in or discontinuation of trastuzumab therapy, and cardiology referral., Results: Of the 200 eligible and enrolled patients, 100 (50%) were randomized to 3-monthly and 100 (50%) to 4-monthly cardiac monitoring. Of these patients, 98 and 97 respectively underwent at least one cardiac scan. The estimated mean difference in LVEF from baseline was -0.94% (one-sided 95% lower bound: -2.14), which exceeded the pre-defined non-inferiority margin of -4%. There were also no significant differences between the two study arms for any of the secondary endpoints. The rate of detection of cardiac dysfunction was 16.3% (16/98) and 12.4% (12/97) in the 3- and 4-monthly arms, respectively (95% CI: 4.0 [-5.9, 13.8])., Conclusions: Cardiac monitoring every 4 months was deemed non-inferior to that every 3 months in patients with HER2-positive EBC being treated with trastuzumab-based therapy. Given its costs and inconvenience, cardiac monitoring every 4 months should be considered standard practice. Registration: NCT02696707, 18 February 2016.

Background: Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted., Methods: EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective., Results: 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = -6.7%, 95%CI = -13.5%-0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained., Conclusion: The primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective., Competing Interests: Declaration of competing interest MC reports personal fees (honoraria) from Pfizer. AAJ reports personal fees (honoraria or travel funds) from Mylan, Teva, Purdue, BMS, BI, Genomic Health, PUMA, Pfizer, Roche, Astra Zeneca, Novartis and Eli Lilly, outside the submitted work. JPH reports institutional research funds from Roche and BMS, outside the submitted work. JM reports personal fees (honorarium) from Pfizer and share ownership in Pacylex Pharmaceutical Inc, SMHeart Card Inc, and illumiSonics, outside the submitted work. TN reports personal fees (honoraria) from ARIAD, Takeda and Boehringer-Ingelheim, outside the submitted work. AA reports personal fees (honorarium for advisory board participation) from Novartis, outside the submitted work. LP reports personal fees (honorarium from advisory board participation) from Serono Oncology, outside the submitted work. NN reports personal fees (honorarium) from Roche, and institutional research funds from Pfizer, outside the submitted work. BH reports consulting fees from Cornerstone Research, outside the submitted work. JFH reports consulting fees from BMS, Pfizer, Eli-Lilly, Novartis and Merck, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To examine the association between the severity of obstructive sleep apnea (OSA) and nocturnal hypoxemia with incident cancer., Methods: This was a multicenter retrospective clinical cohort study using linked clinical and provincial health administrative data on consecutive adults who underwent a diagnostic sleep study between 1994 and 2017 in four academic hospitals (Canada) who were free of cancer at baseline. Cancer status was derived from the Ontario Cancer Registry. Cox cause-specific regressions were utilized to address the objective and to calculate the 10-year absolute risk difference (ARD) in the marginal probability of incident cancer and the number needed to harm (NNH)., Results: Of 33,997 individuals considered, 33,711 with no missing OSA severity were included: median age, 50 years; 58% male; and 23% with severe OSA (apnea-hypopnea index >30). Of the 18,458 individuals with information on sleep time spent with oxygen saturation (SaO 2 ) <90%, 5% spent >30% of sleep with SaO 2 <90% (severe nocturnal hypoxemia). Over a median of 7 years, 2,498 of 33,711 (7%) individuals developed cancer, with an incidence rate of 10.3 (10.0-10.8) per 1,000 person-years. Controlling for confounders, severe OSA was associated with a 15% increased hazard of developing cancer compared with no OSA (HR = 1.15, 1.02-1.30; ARD = 1.28%, 0.20-2.37; and NNH = 78). Severe hypoxemia was associated with about 30% increased hazard (HR = 1.32, 1.08-1.61; ARD = 2.38%, 0.47-4.31; and NNH = 42)., Conclusions: In a large cohort of individuals with suspected OSA free of cancer at baseline, the severity of OSA and nocturnal hypoxemia was independently associated with incident cancer., Impact: These findings suggest the need for more targeted cancer risk awareness in individuals with OSA., (©2020 American Association for Cancer Research.)

Introduction: Ex vivo fusion assays offer an efficient method for studying HIV-1 entry associated with contraceptive use and pregnancy outside of cohort studies of HIV-1 incidence., Methods: We measured ex vivo HIV-1 fusion to cervical or endometrial immune cells from three groups of women: pregnant, non-pregnant not using hormonal or intrauterine contraception, and using depot medroxyprogesterone acetate (DMPA)., Results and Conclusions: There was no excess susceptibility to HIV-1 fusion of cells from pregnant women or DMPA users compared to controls. Although the number of target cells in endometrium was higher in DMPA users compared to controls, HIV-1 fusion was lower., Implications: In ex vivo assays, HIV-1 showed no enhanced fusion to cervical immune cells from pregnant women or DMPA users compared to controls, and lower fusion to endometrial immune cells from DMPA users. This assay is useful for studying hormonal and contraceptive effects on HIV-1 entry into reproductive tract immune cells., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni . The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma -associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma -associated PAH development, course and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Sibomana, Campeche, Carvalho-Filho, Correa, Duani, Pacheco Guimaraes, Hilton, Kassa, Kumar, Lee, Loureiro, Mazimba, Mickael, Oliveira, Ota-Arakaki, Rezende, Silva, Sinkala, Ahmed and Graham.)

Purpose: Outpatients with hematologic disease often receive red cell transfusion to treat anemia and fatigue. The effect of transfusion on fatigue-related quality of life and how well this effect is sustained has not been quantified. The study aim was to describe the early and sustained impact over 4 weeks of red cells on patient-reported fatigue in outpatients age ≥ 50 receiving transfusion as routine clinical care., Methods: FACIT-Fatigue scale scores were measured pre-transfusion and at visits targeting 3, 7, and 28 days post-transfusion. Group-based trajectory modeling of patient fatigue scores by study day was used to identify the number of distinct trajectories (Groups), then longitudinal mixed effects modeling of fatigue scores was used to estimate group-specific mean improvements early after transfusion and between days 3 and 28 post-transfusion., Results: Four distinct fatigue score trajectory groups were identified and were found to be correlated with baseline fatigue scores (means 12, 26, 34, and 47 points). In the three groups with the lowest fatigue trajectories (indicating greater fatigue), improvements in fatigue early after transfusion achieved the established minimum clinically important difference (≥ 3 points, Group p = 0.0039). In all trajectory groups, mean fatigue levels did not change significantly between 3 and 28 days (± 1 point, Group p = 0.60)., Conclusion: Patient-reported fatigue varies widely among older adult outpatients with hematologic disorders. Nonetheless, trajectory modeling suggests that most anemic patients can expect a noticeable improvement in fatigue in the first few days after transfusion that generally is sustained up to 4 weeks.

Progression-free survival (PFS) curves follow first order kinetics on exponential decay nonlinear regression analysis (EDNLRA). Some exhibit 1-phase-decay, some have 2-phase-decay, some are convex. We digitized, performed EDNLRA and generated log-linear plots for 887 published PFS curves for incurable solid tumors treated with various systemic therapies. Proportion of curves fitting 2-phase-decay varied by therapy (p < 0.0001). For 13 therapies, >64 % of PFS curves had 2-phase-decay. This included epidermal growth factor receptor inhibitors in unselected lung cancer patients (some with, some without mutations), immune checkpoint inhibitors, interferon, breast cancer hormonal therapies, and selected others, suggesting 2 distinct, potentially identifiable subpopulations with differing progression rates. For 22 other therapies, <25 % of PFS curves had 2-phase-decay. Only 1 therapy was in the mid-range. Small cell lung and colon carcinomas were particularly likely to yield highly convex curves (p < 0.006), probably from discontinuation of effective therapies. PFS curve shape may yield biological and clinical insights., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Teenagers aged 16 to 18 are at increased risk for iron deficiency, exacerbated by losses with whole blood (WB) or double red blood cell (2RBC) donations. Required 56-day (WB) or 112-day (2RBC) interdonation intervals (IDIs) are too short for many to replace lost iron without supplements., Methods: Teenagers donating WB or 2RBCs at Vitalant, a national blood provider, had serum ferritin measured at their first and immediately subsequent successful donation from December 2016 to 2018. We modeled postindex log-ferritin as a function of IDI to estimate the shortest intervals that corresponded with 50% to 95% prevalence of adequate donor iron stores (ferritin ≥20 ng/mL female donors, ≥30 ng/mL male donors) at the subsequent donation., Results: Among 30 806 teenagers, 11.4% of female and 9.7% of male donors had inadequate iron stores at index donation. Overall, 92.6% had follow-up ferritin values within 13 months. Approximately 12 months after WB index donations, >60% of female and >80% of male donors had adequate iron stores (>50% and >70% after 2RBC donations). Follow-up-donation iron stores were highly dependent on index ferritin. Less than half of WB donors with low ferritin at index achieved adequate stores within 12 months. Achieving a ≥90% prevalence of adequate ferritin at 12 months required index values >50 ng/mL., Conclusions: These findings suggest that postdonation low-dose iron supplements should be strongly encouraged in teenagers with borderline or low iron stores to permit donation without increased risk for symptoms of mild iron depletion. Increasing the minimum recommended IDI to allow time for replacing donation-related iron losses may be desirable for teenagers., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Vassallo reported scientific advisory board membership for Fresenius Kabi and HemaStrat; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer., Methods: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up., Findings: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C., Interpretation: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer., Funding: Eli Lilly and Company., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Progression-free survival (PFS) hazard ratios and gain in median PFS are suggested predictors of overall survival (OS) gain (with gain defined as experimental arm minus control arm values). We assessed use of half-lives (time to progression/death of half remaining patients). We reviewed randomized trials from Journal of Clinical Oncology and New England Journal of Medicine, 01/2012-06/12/2017 (discovery series) and 01/01/2007-12/31/2011 (first validation series). If PFS or OS gains were significant, we used PFS/OS curve nonlinear regression analysis to estimate half-lives and defined "half-life gain" as experimental minus control arm half-life. With low crossover and significant PFS differences, PFS half-life gains ≥1.5 months had positive-predictive-values for OS gains ≥2 months of 79 % and 86 % and PFS half-life gains <1.5 months had negative-predictive-values for OS gains <2 months of 95 % and 75 %, in discovery and validation series, respectively. PFS half-life gains more reliably predicted OS gains than PFS hazard ratios or gains in median PFS. Findings were confirmed in a second validation series., Competing Interests: Declaration of Competing Interest D.J. Stewart: honoraria for consulting/advisory boards/speaking: Roche Canada, Boehringer-Ingelheim (BI) Canada, Merck Canada, AstraZeneca (AZ) Canada, Bristol-Myers Squib (BMS) Canada, Exactis; Clinical trials support: Celgene; D Bosse: honoraria/advisory board: BMS, AZ, Pfizer, AbbVie, Ipsen, Amgen, Janssen; J.F. Hilton: Advisory/Consulting with BMS, AZ, Novartis, Pfizer, Lilly, Roche, PUMA; G. Goss: Advisory Boards/honoraria with AZ, BI, Pfizer, BMS; D. Jonker: none; M Fung-Kee-Fung: Advisory Boards/honoraria: AZ, Roche, Merck., (Copyright © 2020 Elsevier B.V. All rights reserved.)