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This paper sets out for fellow consultants: (i) internal controls to avoid a client’s hiring of a chief executive officer (CEO) who may have had a past or current instance(s) or pattern of misconduct; (ii) the forms of possible misconduct of a CEO; (iii) the component steps and process to follow in investigating such misconduct; and (iv) respecting a CEO’s procedural rights during the investigation. This paper provides consultants with content upon which to advise during their practices, including their advice to organizational clients, senior management, and boards of directors.

Multiple myeloma usually affects older adults. However, younger patients constitute a significant subset as approximately 10% of cases occur in subjects younger than 50 years old. Young patients, who are underrepresented in the literature, are diagnosed during their most productive years of life, urging the need for tailored treatment approaches. This literature review aims to report recent studies specifically addressing young patients with a focus on characteristics at diagnosis, cytogenetics, treatments, and outcomes. We searched PubMed for studies involving young patients with multiple myeloma ≤50 years old. The time span of our literature review search was from 1 January 2010 to 31 December 2022. Overall, 16 retrospective studies were analyzed for this review. Young patients with multiple myeloma tend to have less advanced disease, more frequent light chain subtypes, and survive longer compared to their older counterparts. However, available studies included a limited number of patients; the newest revised international staging system was not used to stratify patients, cytogenetics varied from one cohort to another, and most patients did not receive contemporary triplet/quadruplet treatments. This review emphasizes the need to perform contemporary, large-scale retrospective studies to improve knowledge regarding the presentation and outcomes of young myeloma patients in the era of modern treatments.

Palliative care (PC) benefits patients undergoing hematopoietic stem cell transplantation (HSCT), but it remains underutilized. Although transplant physicians report concerns regarding how patients perceive PC, HSCT recipients’ perceptions about PC remain unaddressed. We conducted a multisite, cross-sectional survey of autologous and allogeneic HSCT recipients 3 to 12 months after transplant to assess their familiarity, knowledge, and perception of PC, as well as their unmet PC needs. We computed a composite score of patients’ perceptions of PC and used a generalized linear regression model to examine factors associated with these perceptions. We enrolled 69.6% (250/359) of potential participants (median age = 58.1; 63.1% autologous HSCT). Overall, 44.3.8% (109/249) reported limited knowledge about PC and 52% (127/245) endorsed familiarity with PC. Most patients felt hopeful (54%) and reassured (50%) when they heard the term PC; 83% saw referral as a sign their doctor cared about what was happening to them. In multivariate analyses, patients who were more knowledgeable about PC were more likely to have positive perceptions of PC (B = 7.54, standard error = 1.61, P < .001). Patients’ demographics, HSCT features, quality of life, and symptom burden were not significantly associated with perceptions of PC. HSCT recipients have positive perceptions of PC, though many have limited knowledge about its role. Patients who were more knowledgeable about PC were more likely to have positive perceptions of PC. These data do not support transplant physicians’ negative concerns about how patients perceive PC and underscore the need to further educate patients and transplant physicians about PC.

Cet article porte un regard sur la réalité des personnes qui vivent avec des animaux de compagnie dans la rue. Plus spécifiquement, il documente la manière dont l’animal de compagnie peut favoriser l’intégration sociale des personnes en situation d’itinérance et d’un autre côté, la maintenir dans un processus de désaffiliation sociale. La démarche utilisée est de type qualitatif où des entrevues semi-dirigées ont été réalisées auprès de huit personnes ayant déjà vécu dans la rue avec des animaux de compagnie. Les résultats de cette recherche s’appuient sur un ancrage conceptuel issu de la pratique du « care » et du processus de désaffiliation sociale. Ils ont permis de mettre en lumière différents types de relations qui peuvent être vécues avec un animal lorsqu’une personne vit en situation d’itinérance et ainsi soulever les bénéfices et les contraintes qu’elle peut vivre en sa présence. Cette étude montre ainsi l’importance de la mise en place de services adaptés pour soutenir les personnes en situation d’itinérance dans leur relation avec leur animal de compagnie et ainsi mener davantage de recherches pour comprendre la retombée de ces services sur leur bien-être et celui de leur animal.

PURPOSE In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.

Objectives. To examine whether, and if so how, US national and state survey response rates changed after the onset of the COVID-19 pandemic. Methods. We compared the change in response rates between 2020 and 2019 of 6 (3 social and economic, 3 health focused) major US national surveys (2 with state response rates). Results. All the ongoing surveys except 1 reported relative decreases (∼29%) in response rates. For example, the household response rate to the US Census American Community Survey decreased from 86.0% in 2019 to 71.2% in 2020, and the response rate of the US National Health Interview Survey decreased from 60.0% to 42.7% from the first to the second quarter of 2020. For all surveys, the greatest decreases in response rates occurred among persons with lower income and lower education. Conclusions. Socially patterned decreases in response rates pose serious challenges and must be addressed explicitly in all studies relying on data obtained since the onset of the pandemic. Public Health Implications. Artifactual reduction of estimates of the magnitude of health inequities attributable to differential response rates could adversely affect efforts to reduce these inequities. (Am J Public Health. Published online ahead of print April 6, 2023:e1–e4. https://doi.org/10.2105/AJPH.2023.307267 )

Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants in TARDBP, the gene encoding TDP-43, can cause ALS and cluster in the C-terminal prion-like domain (PrLD), where they modulate the liquid condensation and aggregation properties of the protein. TDP-43-positive inclusions are also found in rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 variants have not been reported. Using genome-wide linkage analysis and whole exome sequencing in an extended five-generation family with an autosomal dominant rimmed vacuole myopathy, we identified a conclusively linked frameshift mutation in TDP-43 producing a C-terminally altered PrLD (TDP-43p.Trp385IlefsTer10) (maximum multipoint LOD-score 3.61). Patient-derived muscle biopsies showed TDP-43-positive sarcoplasmic inclusions, accumulation of autophagosomes and transcriptomes with abnormally spliced sarcomeric genes (including TTN and NEB) and increased expression of muscle regeneration genes. In vitro phase separation assays demonstrated that TDP-43Trp385IlefsTer10 does not form liquid-like condensates and readily forms solid-like fibrils indicating increased aggregation propensity compared to wild-type TDP-43. In Drosophila TDP-43p.Trp385IlefsTer10 behaved as a partial loss-of-function allele as it was able to rescue the TBPH (fly ortholog of TARDBP) neurodevelopmental lethal null phenotype while showing strongly reduced toxic gain-of-function properties upon overexpression. Accordingly, TDP-43p.Trp385IlefsTer10 showed reduced toxicity in a primary rat neuron disease model. Together, these genetic, pathological, in vitro and in vivo results demonstrate that TDP-43p.Trp385IlefsTer10 is an aggregation-prone partial loss-of-function variant that causes autosomal dominant vacuolar myopathy but not ALS/FTD. Our study genetically links TDP-43 proteinopathy to myodegeneration, and reveals a tissue-specific role of the PrLD in directing pathology.

International audience; The rapid identification of early hits by fragment-based approaches and subsequent hit-to-lead optimization represents a challenge for drug discovery. To address this challenge, we created a strategy called 'DOTS' that combines molecular dynamic simulations, computer-based library design (chemoDOTS) with encoded medicinal chemistry reactions, constrained docking, and automated compound evaluation. To validate its utility, we applied our DOTS strategy to the challenging target syntenin, a PDZ domain containing protein and oncology target. Herein, we describe the creation of a 'best-in-class' sub-micromolar small molecule inhibitor for the second PDZ domain of syntenin validated in cancer cell assays. Key to the success of our DOTS approach was the integration of protein conformational sampling during hit identification stage and the synthetic feasibility ranking of the designed compounds throughout the optimization process. This approach can be broadly applied to other protein targets with known 3D structures to rapidly identify and optimize compounds as chemical probes and therapeutic candidates.

Background: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. Methods: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1–5; prednisone 60 mg/m2 orally on days 1–15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006–000995-33) and is completed. Findings: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1–69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3–89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8–92·5), for which the 95% CI included the 90% target rate. The most common grade 3–4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. Interpretation: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. Funding: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

BACKGROUND: The impact of treatment delays on cancer outcomes has been well documented, but few published studies explicitly attempt to identify subgroups which would benefit the most from potential interventions improving timeliness of care. Using the state of North Carolina and breast cancer as an example, we sought to quantify race-specific associations between frontline treatment delay and breast cancer mortality, and estimate the potential impact of improvements in timeliness by racial sub-group. METHODS: We conducted a retrospective cohort study, utilizing multipayer insurance claims linked to cancer registry data from the Cancer Information and Population Health Resource, of females diagnosed with stage I-III breast cancer from 2004 to 2014. Our exposure of interest was treatment delay, defined as initial cancer directed therapy received ≥ 60 days after diagnosis. Our outcome was death certificate identified breast cancer mortality within 5-years of follow-up. To quantify the association between treatment delay and mortality we estimated hazard ratios (HR) and 95% confidence limits (CL) where non-breast cancer deaths were treated as competing events. We then simulated the effect of treating all patients within 60 days using inverse probability of treatment weighting (IPTW), and estimated the potential impact by comparing the simulated data with observed data. Models were adjusted for age and stage at diagnosis, tumor grade, hormone receptor status, and modality of first treatment. Models were stratified by race, dichotomized as Black or non-Black, and geographic subregion for evaluation. RESULTS: Our analytic cohort comprised 21,200 patients, of whom 19% were Black. Treatment delays >60 days were twice as frequent among Black compared with non-Black patients (13.5% vs. 6.5%). We found a positive association between treatment delay and breast cancer mortality in the overall cohort (HR=1.3; CL: 1.1, 1.6). The association differed between Black (HR=1.4; CL: 1.1, 1.8) and Non-Black (HR=1.2; CL: 0.9, 1.6) patient subgroups. For both racial groups, the strength of the relationship between treatment delay and mortality varied across geographic subregions. The estimated potential improvement in 5-year cumulative breast cancer mortality from delivering timely care to all patients differed in magnitude across sub-populations. The magnitude of potential improvement in breast cancer mortality at 5 years in the overall analytic cohort was 0.3% (5-year risk of breast cancer mortality in observed cohort: 7.2% vs 6.9% with simulated universal timely treatment). In the Black subcohort, the potential decrease in mortality for timely treatment was 1.0% (observed: 12.3% vs simulated: 11.4%), while in the non-Black population the potential decrease was 0.1% (observed: 6.1% vs simulated: 5.9%). CONCLUSIONS: The magnitude of association between delayed treatment of stage I-III breast cancer and breast cancer mortality differed between Black and non-Black patients, highlighting that interventions to avert treatment delays may have a meaningful impact for this group. Further research is needed to identify factors underlying this difference, which may include a direct effect of differences in timeliness, or downstream differences in the intensity and quality of cancer care beyond the 60-day landmark for delayed patients. Our findings suggest that comprehensive intervention at the state level to improve the timeliness of breast cancer treatment could potentially reduce breast cancer mortality, and that targeting such intervention to patient groups with larger projected benefit, such as Black patients, may be a more efficient use of resources. We have illustrated how a counterfactual approach may be useful in identifying subgroups where focused intervention efforts may yield greater improvements in outcomes. Citation Format: Bradford Jackson, Stephanie Wheeler, Juan Yanguela, Matthew LeBlanc, Tzy-Mey Kuo, Christopher Baggett, Katherine Reeder-Hayes. IMPACTS OF TREATMENT DELAY ON BREAST CANCER MORTALITY AND BENEFIT OF TIMELY CARE IN BLACK AND NON-BLACK WOMEN [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-06-04.

In response to the coronavirus (COVID-19) pandemic, there has been an increased need for personal and environmental decontamination to aid in curbing transmission of the SARS-CoV-2 virus. Products used for this purpose include sanitizers for hands and disinfectants for surfaces. The active chemical ingredients used in these products, termed antimicrobials, can enter waste streams after application and may be emerging as more prominent environmental contaminants. Even prior to COVID-19, there was recognized need to examine their implications for aquatic biota, which is now made more pressing due to their exaggerated use in response to the pandemic. Our objectives were to identify current antimicrobial active ingredients, quantify their increased use, and determine which may be candidates for further consideration as possible aquatic contaminants. By consulting multiple sources of publicly available information in Canada, we identified current-use antimicrobials from the lists of sanitizers and surface disinfectants approved for use against SARS-CoV-2 by Health Canada and the drug registration database. To estimate the use of sanitizers and disinfectants, we evaluated import quantities and grocery store retail sales of related compounds and products (Statistics Canada) and both lines of evidence supported increased use trends. The list of identified antimicrobials was refined to include only candidates with potential to reach aquatic ecosystems, and information on their environmental concentrations and toxicity to aquatic biota was reviewed. Candidate antimicrobials ( n = 32) fell into four main categories: quaternary ammonium compounds (QACs), phenols, acids, and salts. Benzalkonium chloride, a QAC, was the most prominent active ingredient used in both nonalcohol-based hand sanitizers and surface disinfectants. Four QACs followed in prevalence and the next most used antimicrobial was triclosan (hand sanitizers only), an established and regulated environmental contaminant. Little information was found on environmental concentrations of other candidates, suggesting that the majority would fall into the category of emerging contaminants if they enter aquatic systems. Several were classified as acutely or chronically toxic to aquatic biota (Globally Harmonized System), and thus we recommend empirical research begin focusing on environmental monitoring of all candidate antimicrobials as a critical next step, with detection method development first where needed.

Atlantic Brant (Branta bernicla hrota) is an Arctic-breeding migratory waterfowl that relies heavily on Common Eelgrass (Zostera marina) for food during migration and overwintering. Although the abundance of Atlantic Brant along the coasts of the Maritime provinces has declined drastically over the past decades, some flocks continue to migrate through the area in spring. Here, we present field observations of Atlantic Brant spring staging in the Tabusintac Bay, New Brunswick, Canada. We surveyed the Tabusintac Bay seven times between 26 May and 6 June 2018. We observed a maximum daily count of 1259 individuals, which is comparable to high counts from the 1970s. These spring surveys indicate the continuing importance of Tabusintac Bay to Atlantic Brant for spring staging. There is a pressing need to increase monitoring and research in the region and to preserve or enhance the quality of the area for spring staging brant.