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Abstract We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Purpose To describe the first reported instance of an acute chorioretinal inflammatory response to cabozantinib. Methods Case report. Results A 54-year-old Asian male presented with blurred vision 2 weeks following the commencement of cabozantinib for metastatic renal cell carcinoma. Ophthalmic examination revealed bilateral exudative retinal detachments and choroiditis in a pattern similar to Vogt–Koyanagi–Harada disease. Further investigations revealed latent tuberculosis (TB), and management of this ocular adverse event was with cabozantinib cessation, high-dose oral prednisone, single-agent anti-TB therapy, and methotrexate. Return of visual function and ocular anatomy occurred within 1 month. Conclusions Modern pharmacotherapy for metastatic cancer may increase survival, but a range of ocular and systemic adverse events are frequently seen. Screening and early intervention can mitigate adverse events and treatment burden, while maximizing benefits for this disadvantaged patient group.

Abstract Background Adaptation of evidence-based interventions (EBIs) often occurs when implemented in new local contexts and settings. It is unclear, however, during which phase of implementation adaptations are most frequently made and how these changes may impact the fidelity, effectiveness, and sustainability of the EBI. Pediatric Early Warning Systems (PEWS) are EBIs for early identification of deterioration in hospitalized children with cancer. This study evaluates adaptations of PEWS made among resource-variable pediatric oncology hospitals in Latin America implementing and sustaining PEWS. Methods We conducted a cross-sectional survey among pediatric oncology centers participating in Proyecto Escala de Valoración de Alerta Temprana (EVAT), a collaborative to implement PEWS. Adaptations to PEWS were assessed via 3 multiple choice and 1 free text question administered as part of a larger study of PEWS sustainability. Descriptive statistics quantitatively described what, when, and why adaptations were made. Qualitative analysis of free text responses applied the Framework for Reporting Adaptations and Modifications Expanded (FRAME) to describe respondent perspectives on PEWS adaptations. Results We analyzed 2,094 responses from 58 pediatric oncology centers across 19 countries in Latin America. Participants were predominantly female (82.5%), consisting of nurses (57.4%) and physicians (38.2%) who were PEWS implementation leaders (22.1%) or clinical staff (69.1%). Respondents described multiple PEWS adaptations across all implementation phases, with most occurring during the planning and piloting of EBIs. Adaptations included changes to PEWS content (algorithm, scoring tool, terminology, and use frequency) and context (personnel delivering or population). Respondents felt adaptations streamlined monitoring, enhanced effectiveness, improved workflow, increased comprehension, and addressed local resource limitations. Qualitative analysis indicated that most adaptations were categorized as fidelity consistent and planned; fidelity inconsistent adaptations were unplanned responses to unanticipated challenges. Conclusion Adaptations made to PEWS across implementation phases demonstrate how EBIs are adapted to fit dynamic, real-world clinical settings. This research advances implementation science by highlighting EBI adaptation as a potential strategy to promote widespread implementation and sustainability in hospitals of all resource levels.

Abstract Background There are no criteria specifically for evaluating the quality of implementation research and recommending implementation strategies likely to have impact to practitioners. We describe the development and application of the Best Practices Tool, a set of criteria to evaluate the evidence supporting HIV-specific implementation strategies. Methods We developed the Best Practices Tool from 2022–2023 in three phases. (1) We developed a draft tool and criteria based on a literature review and key informant interviews. We purposively selected and recruited by email interview participants representing a mix of expertise in HIV service delivery, quality improvement, and implementation science. (2) The tool was then informed and revised through two e-Delphi rounds using a survey delivered online through Qualtrics. The first and second round Delphi surveys consisted of 71 and 52 open and close-ended questions, respectively, asking participants to evaluate, confirm, and make suggestions on different aspects of the rubric. After each survey round, data were analyzed and synthesized as appropriate; and the tool and criteria were revised. (3) We then applied the tool to a set of research studies assessing implementation strategies designed to promote the adoption and uptake of evidence-based HIV interventions to assess reliable application of the tool and criteria. Results Our initial literature review yielded existing tools for evaluating intervention-level evidence. For a strategy-level tool, additions emerged from interviews, for example, a need to consider the context and specification of strategies. Revisions were made after both Delphi rounds resulting in the confirmation of five evaluation domains – research design, implementation outcomes, limitations and rigor, strategy specification, and equity – and four evidence levels – best, promising, more evidence needed, and harmful. For most domains, criteria were specified at each evidence level. After an initial pilot round to develop an application process and provide training, we achieved 98% reliability when applying the criteria to 18 implementation strategies. Conclusions We developed a tool to evaluate the evidence supporting implementation strategies for HIV services. Although specific to HIV in the US, this tool is adaptable for evaluating strategies in other health areas.

International Ocean Discovery Program (IODP) Expedition 374 sailed to the Ross Sea in 2018 to reconstruct paleoenvironments, track the history of key water masses, and assess model simulations that show warm-water incursions from the Southern Ocean led to the loss of marine-based Antarctic ice sheets during past interglacials. IODP Site U1523 (water depth 828 m) is located at the continental shelf break, northeast of Pennell Bank on the southeastern flank of Iselin Bank, where it lies beneath the Antarctic Slope Current (ASC). This site is sensitive to warm-water incursions from the Ross Sea Gyre and modified Circumpolar Deep Water (mCDW) today and during times of past warming climate. Multiple incursions of subpolar or temperate planktic foraminifera taxa occurred at Site U1523 after 3.8 Ma and prior to ∼ 1.82 Ma. Many of these warm-water taxa incursions likely represent interglacials of the latest Early Pliocene and Early Pleistocene, including Marine Isotope Stage (MIS) Gi7 to Gi3 (∼ 3.72–3.65 Ma), and Early Pleistocene MIS 91 or 90 (∼ 2.34–2.32 Ma) and MIS 77–67 (∼ 2.03–1.83 Ma) and suggest warmer-than-present conditions and less ice cover in the Ross Sea. However, a moderately resolved age model based on four key events prohibits us from precisely correlating with Marine Isotope Stages established by the LR04 Stack; therefore, these correlations are best estimates. Diatom-rich intervals during the latest Pliocene at Site U1523 include evidence of anomalously warm conditions based on the presence of subtropical and temperate planktic foraminiferal species in what likely correlates with interglacial MIS G17 (∼ 2.95 Ma), and a second interval that likely correlates with MIS KM3 (∼ 3.16 Ma) of the mid-Piacenzian Warm Period. Collectively, these multiple incursions of warmer-water planktic foraminifera provide evidence for polar amplification during super-interglacials of the Pliocene and Early Pleistocene. Higher abundances of planktic and benthic foraminifera during the Mid- to Late Pleistocene associated with interglacials of the MIS 37–31 interval (∼ 1.23–1.07 Ma), MIS 25 (∼ 0.95 Ma), MIS 15 (∼ 0.60 Ma), and MIS 6–5e transition (∼ 0.133–0.126 Ma) also indicate a reduced ice shelf and relatively warm conditions, including multiple warmer interglacials during the Mid-Pleistocene Transition (MPT). A decrease in sedimentation rate after ∼ 1.78 Ma is followed by a major change in benthic foraminiferal biofacies marked by a decrease in Globocassidulina subglobosa and a decrease in mud (< 63 µm) after ∼ 1.5 Ma. Subsequent dominance of Trifarina earlandi biofacies beginning during MIS 15 (∼ 600 ka) indicate progressive strengthening of the Antarctic Slope Current along the shelf edge of the Ross Sea during the mid to Late Pleistocene. A sharp increase in foraminiferal fragmentation after the MPT (∼ 900 ka) and variable abundances of T. earlandi indicate higher productivity, a stronger but variable ASC during interglacials, and/or corrosive waters, suggesting changes in water masses entering (mCDW) and exiting (High Salinity Shelf Water or Dense Shelf Water) the Ross Sea since the MPT.

PURPOSEThe Brazilian Public Health System (BPHS) serves approximately 71,730 patients with prostate cancer (PC) every year for which androgen deprivation therapy (ADT) is the primary treatment for patients with advanced hormone-sensitive prostate cancer (aHSPC). Androgen receptor pathway inhibitors (ARPIs) are not accessible through the BPHS. Using the BPHS as a model, this study assesses the long-term economic effect of surgical versus medical castration in aHSPC treatment to strategize cost reduction and the incorporation of ARPI in developing countries.PATIENTS AND METHODSData of patients with aHSPC (ie, TxN1M0 ineligible for local treatment or TxNxM1) from the BPHS database were analyzed from January 1, 2011, to December 31, 2021, using the TECHTRIALS artificial intelligence platform. The main outcomes were quantitative and descriptive analyses as well as a cost analysis of surgical versus chemical castration.RESULTSOf the 274,519 patients with aHSPC who received active treatment during the 11-year study period, 90% (n = 246,683) underwent chemical castration and 10% (n = 27,836) underwent bilateral subcapsular orchiectomy (BSO). The median duration of chemical castration was 28 months. The BPHS spent an estimated total of $665,552,091.40 US dollars (USD) on chemical castration and $5,939,348.47 USD on BSO, respectively. The cost per patient was $2,698 USD and $213.37 USD for chemical castration and BSO, respectively. Hypothetically, if all patients with aHSPC had undergone BSO, the total direct cost for the BPHS would have been $42,774,832.20 USD, saving $622,777,259.20 USD over 11 years, making it possible to offer low-dose abiraterone to 65% of aHSPC patients.CONCLUSIONOn the basis of this extensive financial analysis from the world's largest public health system database, BSO appears to be a valuable alternative to chemical castration for treating aHSPC. In resource-limited environments, the cost savings from using BSO may allow access to drugs that will improve survival such as ARPIs.

Abstract Antigenic characterization of circulating influenza A virus (IAV) isolates is routinely assessed by using the hemagglutination inhibition (HI) assays for surveillance purposes. It is also used to determine the need for annual influenza vaccine updates as well as for pandemic preparedness. Performing antigenic characterization of IAV on a global scale is confronted with high costs, animal availability, and other practical challenges. Here we present a machine learning model that accurately predicts (normalized) outputs of HI assays involving circulating human IAV H3N2 viruses, using their hemagglutinin subunit 1 (HA1) sequences and associated metadata. Each season, the model learns an updated nonlinear mapping of genetic to antigenic changes using data from past seasons only. The model accurately distinguishes antigenic variants from non-variants and adaptively characterizes seasonal dynamics of HA1 sites having the strongest influence on antigenic change. Antigenic predictions produced by the model can aid influenza surveillance, public health management, and vaccine strain selection activities.

Background: At-risk alcohol use is associated with increased adverse health consequences, yet is undertreated in healthcare settings. People residing in rural areas need improved access to services; however, few interventions are designed to meet the needs of rural populations. Mobile interventions can provide feasible, low-cost, and scalable means for reaching this population and improving health, and behavioral economic approaches are promising. Methods: We conducted a pilot randomized controlled trial focused on acceptability and feasibility of a mobile behavioral economic intervention for 75 rural-residing adults with at-risk alcohol use. We recruited participants from a large healthcare system and randomized them to one of four virtually-delivered conditions reflecting behavioral economic approaches: episodic future thinking (EFT), volitional choice (VC), both EFT and VC, or enhanced usual care control (EUC). The intervention included a telephone-delivered induction session followed by two weeks of condition-consistent ecological momentary interventions (EMIs; 2x/day) and ecological momentary assessments (EMAs; 1x/day). Participants completed assessments at baseline, post-intervention, and two-month follow-up, and provided intervention feedback. Results: All participants completed the telephone-delivered session and elected to receive EMI messages. Average completion rate of EMAs across conditions was 92.9%. Among participants in active intervention conditions, 89.3% reported the induction session was helpful and 80.0% reported it influenced their future drinking. We also report initial alcohol use outcomes. Discussion: The behavioral economic intervention components and trial procedures evaluated here appear to be feasible and acceptable. Next steps include determination of their efficacy to reduce alcohol use and public health harms.

Abstract Background Non‐canonical WNT family (WNT5A pathway) signaling via WNT5A through ROR1 and its partner, ROR2, or Frizzled2 (FZD2) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non‐canonical WNT signaling through WNT5A, ROR1, ROR2, or FZD2 expression. Methods NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4125 UC tumors submitted to Caris Life Sciences. High and low expression of WNT5A, ROR1, ROR2, and FZD2 was defined as ≥ top and

Abstract Direct-acting antiviral agents (DAAs) provide efficacious therapeutic treatments for chronic Hepatitis C virus (HCV) infection. However, emergence of drug resistance mutations (DRMs) can greatly affect treatment outcomes and impede virological cure. While multiple DRMs have been observed for all currently used DAAs, the evolutionary determinants of such mutations are not currently well understood. Here, by considering DAAs targeting the nonstructural 3 (NS3) protein of HCV, we present results suggesting that epistasis plays an important role in the evolution of DRMs. Employing a sequence-based fitness landscape model whose predictions correlate highly with experimental data, we identify specific DRMs that are associated with strong epistatic interactions, and these are found to be enriched in multiple NS3-specific DAAs. Evolutionary modelling further supports that the identified DRMs involve compensatory mutational interactions that facilitate relatively easy escape from drug-induced selection pressures. Our results indicate that accounting for epistasis is important for designing future HCV NS3-targeting DAAs.

Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

The COVID pandemic placed a spotlight on alcohol use and the hardships of working within the food and beverage industry, with millions left jobless. Following previous studies that have found elevated rates of alcohol problems among bartenders and servers, here we studied the alcohol use of bartenders and servers who were employed during COVID. From February 12-June 16, 2021, in the midst of the U.S. COVID national emergency declaration, survey data from 1,010 employed bartender and servers were analyzed to quantify rates of excessive or hazardous drinking along with regression predictors of alcohol use as assessed by the 10-item Alcohol Use Disorders Identification Test (AUDIT). Findings indicate that more than 2 out of 5 (44%) people surveyed reported moderate or high rates of alcohol problem severity (i.e., AUDIT scores of 8 or higher)-a rate 4 to 6 times that of the heavy alcohol use rate reported pre- or mid-pandemic by adults within and outside the industry. Person-level factors (gender, substance use, mood) along with the drinking habits of one's core social group were significantly associated with alcohol use. Bartenders and servers reported surprisingly high rates of alcohol problem severity and experienced risk factors for hazardous drinking at multiple ecological levels. Being a highly vulnerable and understudied population, more studies on bartenders and servers are needed to assess and manage the true toll of alcohol consumption for industry employees.

Background: Guidelines suggest that active surveillance (AS) may be considered for select patients with favorable intermediate-risk (fIR) prostate cancer. Objective: To compare the outcomes between fIR prostate cancer patients included by Gleason score (GS) or prostate-specific antigen (PSA). Most patients are classified with fIR disease due to either a 3 + 4 = 7 GS (fIR-GS) or a PSA level of 10–20 ng/ml (fIR-PSA). Previous research suggests that inclusion by GS 7 may be associated with worse outcomes. Design, setting, and participants: We conducted a retrospective cohort study of US veterans diagnosed with fIR prostate cancer from 2001 to 2015. Outcome measurements and statistical analysis: We compared the incidence of metastatic disease, prostate cancer–specific mortality (PCSM), all-cause mortality (ACM), and receipt of definitive treatment between fIR-PSA and fIR-GS patients managed with AS. Outcomes were compared with those of a previously published cohort of patients with unfavorable intermediate-risk disease using cumulative incidence function and Gray’s test for statistical significance. Results and limitations: The cohort included 663 men; 404 had fIR-GS (61%) and 249 fIR-PSA (39%). There was no evidence of difference in the incidence of metastatic disease (8.6% vs 5.8%, p = 0.77), receipt of definitive treatment (77.6% vs 81.5%, p = 0.43), PCSM (5.7% vs 2.5%, p = 0.274), and ACM (16.8% vs 19.1%, p = 0.14) between the fIR-PSA and fIR-GS groups at 10 yr. On multivariate regression, unfavorable intermediate-risk disease was associated with higher rates of metastatic disease, PCSM, and ACM. Limitations included varying surveillance protocols. Conclusions: There is no evidence of difference in oncological and survival outcomes between men with fIR-PSA and fIR-GS prostate cancer undergoing AS. Thus, presence of GS 7 disease alone should not exclude patients from consideration of AS. Shared decision-making should be utilized to optimize management for each patient. Patient summary: In this report, we compared the outcomes of men with favorable intermediate-risk prostate cancer in the Veterans Health Administration. We found no significant difference between survival and oncological outcomes.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Abstract Viral and host factors can shape SARS-CoV-2 evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within individuals. Here, we analysed deep sequencing data from 2,820 SARS-CoV-2 respiratory samples with different viral lineages to describe the patterns of within-host diversity under different conditions, including vaccine-breakthrough infections. In unvaccinated individuals, variant of Concern (VOC) Alpha, Delta, and Omicron respiratory samples were found to have higher within-host diversity and were under neutral to purifying selection at the full genome level compared to non-VOC SARS-CoV-2. Breakthrough infections in 2-dose or 3-dose Comirnaty and CoronaVac vaccinated individuals did not increase levels of non-synonymous mutations and did not change the direction of selection pressure. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 sequence diversification. Our findings suggest that vaccination does not increase exploration of SARS-CoV-2 protein sequence space and may not facilitate emergence of viral variants.

Quantum key distribution (QKD) can provide unconditional security to next-generation communication networks guaranteed by the laws of quantum physics. This article studies the secret key rate (SKR) of a continuous variable QKD (CV-QKD) system using multiple-input multiple-output (MIMO) transmission and operating at terahertz (THz) frequencies. Distinct from previous works, we consider a practical “restricted” eavesdropping scenario in which Eve can collect only a fraction of photons lost in the environment. We propose a system model for the MIMO THz CV-QKD system that accounts for restricted eavesdropping via a lossy wireless channel between Alice and Eve. We derive for this system new SKR expressions for both coherent-state-based and squeezed-state-based CV-QKD protocols. Our results show that previous analysis assuming unrestricted eavesdropping leads to overly pessimistic SKRs, and that in practice, the achievable SKR can be significantly increased under restricted eavesdropping. The increase in the SKR is quantified by the simplified SKR expansions derived in this article. Our results also reveal that squeezing is beneficial for improving the SKR only for unrestricted eavesdropping. However, in a practical setting with restricted eavesdropping, increased squeezing leads to a reduction in the SKR.

Abstract In recent decades, variability in the incidence and mortality of kidney cancer (KC) has been reported. This study aimed to compare trends in incidence, mortality, and disability-adjusted life years (DALY) of KC between the European Union (EU) 15 + countries and 6 World Health Organization (WHO) regions. The data of KC Age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and age-standardized DALYs were extracted from the Global Burden of Disease database. Joinpoint regression was employed to examine trends. From 1990 to 2019, the ASIR increased in most countries except for Luxembourg (males), the USA (females) and Austria and Sweden (both sexes). ASIR increased across all 6 WHO regions for both sexes except for females in Americas. The ASMR increased in 10/19 countries for males and 9/19 for females as well across most WHO regions. The mortality-to-incidence ratio (MIR) decreased in all countries and WHO regions. Trends in DALYs were variable across countries and WHO regions. While the incidence and mortality from KC rose in most EU15 + countries and WHO regions from 1990 to 2019, the universal drop in MIR suggests an overall improvement in KC outcomes. This is likely multifactorial, including earlier detection of KC and improved treatments.

As the therapeutic landscape for metastatic clear cell renal cell carcinoma (mccRCC) expands to include vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immunotherapies, new challenges are in place for evaluating and treating refractory disease. Assessing and managing refractory disease has several elements: (1) the mechanism(s) of front-line treatment, (2) timing of progressive disease, (3) rapidity and sites of progressing disease, (4) use of adjuvant therapy, and (5) incorporation of surgical and radiation techniques. These variables all have distinct impact on the biology of refractory or resistant mccRCC. A better understanding of the essential mechanisms of both primary and secondary immunotherapy resistance will inform biomarker development and therapeutic strategies in the refractory setting. This paper addresses the current understanding of treatment sequencing in refractory mccRCC, focusing on treatment options with prospective clinical trial data, considers refractory mccRCC after adjuvant immunotherapy, and incorporates radiation or surgical resection for oligoprogressive disease.

Introduction: The Brief Addiction Monitor-Revised (BAM-R) is a widely used, 17-item assessment of substance use, risk, and protective factors associated with recovery from substance use disorders. Despite wide adoption in the U.S. Department of Veterans Affairs (VA) and recommendations for use in measurement-based care (MBC), administration may not be feasible in many MBC settings due to time constraints. The purpose of this study was to derive a shortened version of the BAM-R for use in fast-paced healthcare settings. Methods: BAM-R data from 32,002 Veterans were obtained through the VA's Corporate Data Warehouse. We used logistic regression models to identify items for removal based on prediction of two clinical outcomes (90-day substance use disorder (SUD) treatment retention and 12-month mortality) and item-level sensitivity to change during substance use treatment. Results: Although no intake BAM-R items predicted SUD treatment retention or mortality, effect sizes for item-level sensitivity to change during substance use treatment varied from small to large. Seven items were judged as relevant for MBC of SUD. Among all BAM-R items, Heavy Alcohol Use, Self-Help, Drug Use, Craving, and Mood items demonstrated the greatest magnitude of sensitivity to change. Conclusions: Although additional research is recommended before a shortened BAM-R can be implemented in non-specialty MBC settings, we identified 5 BAM-R items with perceived clinical utility and scores that demonstrated evidence of sensitivity to change. Shortening the BAM-R increases feasibility of use, though more work is needed to optimize measurement for SUD MBC.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54–74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11–1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p

The SARS-CoV-2 Omicron sub-variants BA.2.86 and JN.1 contain multiple mutations in the spike protein that were not present in previous variants of concern and Omicron sub-variants. Preliminary research suggests that these variants reduce the neutralizing capability of antibodies induced by vaccines, which is particularly significant for JN.1. This raises concern as many widely deployed COVID-19 vaccines are based on the spike protein of the ancestral Wuhan strain of SARS-CoV-2. While T cell responses have been shown to be robust against previous SARS-CoV-2 variants, less is known about the impact of mutations in BA.2.86 and JN.1 on T cell responses. We evaluate the effect of mutations specific to BA.2.86 and JN.1 on experimentally determined T cell epitopes derived from the spike protein of the ancestral Wuhan strain and the spike protein of the XBB.1.5 strain that has been recommended as a booster vaccine. Our data suggest that BA.2.86 and JN.1 affect numerous T cell epitopes in spike compared to previous variants; however, the widespread loss of T cell recognition against these variants is unlikely.

Summary: Background: Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with poor 5-year overall survival (OS) at 14%. Patients with mRCC to endocrine organs historically have prolonged OS. Pancreatic metastases are uncommon overall, with mRCC being the most common etiology of pancreatic metastases. In this study, we report the long-term outcomes of patients with mRCC to the pancreas in two separate cohorts. Methods: We performed a multicenter, international retrospective cohort study of patients with mRCC to the pancreas at 15 academic centers. Cohort 1 included 91 patients with oligometastatic disease to the pancreas. Cohort 2 included 229 patients with multiples organ sites of metastases including the pancreas. The primary endpoint for Cohorts 1 and 2 was median OS from time of metastatic disease in the pancreas until death or last follow up. Findings: In Cohort 1, the median OS (mOS) was 121 months with a median follow up time of 42 months. Patients who underwent surgical resection of oligometastatic disease had mOS of 100 months with a median follow-up time of 52.5 months. The mOS for patients treated with systemic therapy was not reached. In Cohort 2, the mOS was 90.77 months. Patients treated with first-line (1L) VEGFR therapy had mOS of 90.77 months; patients treated with IL immunotherapy (IO) had mOS of 92 months; patients on 1L combination VEGFR/IO had mOS of 74.9 months. Interpretations: This is the largest retrospective cohort of mRCC involving the pancreas. We confirmed the previously reported long-term outcomes in patients with oligometastatic pancreas disease and demonstrated prolonged survival in patients with multiple RCC metastases that included the pancreas. In this retrospective study with heterogeneous population treated over 2 decades, mOS was similar when stratified by first-line therapy. Future research will be needed to determine whether mRCC patients with pancreatic metastases require a different initial treatment strategy. Funding: Statistical analyses for this study were supported in part by the University of Colorado Cancer Center Support Grant from the NIH/NCI, P30CA046934-30.

Abstract Objective To analyse the effect of age at diagnosis on clinical outcomes of localized prostate cancer (PCa) treated with radiation therapy. Subjects and methods We identified 12 784 patients with intermediate‐ or high‐risk localized PCa treated with radiation therapy (RT) and neoadjuvant androgen deprivation therapy (ADT) between 2000 and 2015 from nationwide Veterans Affairs data. Patients were grouped into three age categories (≤59, 60–69, and ≥70 years old). Outcomes included immediate PSA response (3‐month post‐RT PSA and 2‐year PSA nadir, grouped into

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.

Abstract Background CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan‐cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real‐world clinical‐grade sequencing. Methods This was a single‐center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. Results In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12‐altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow‐up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11–5.74). Ten patients with CDK12‐altered tumors received at least one immune checkpoint inhibitor‐containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression‐free survival for patients who had metastatic disease and received a checkpoint inhibitor‐containing regimen was 1.16 years (95% CI: 0.32–2.00). Conclusion CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12‐altered tumors.

In this article, we propose a machine-learning framework for parameter estimation of single-mode Gaussian quantum states. Under a Bayesian framework, our approach estimates parameters of suitable prior distributions from measured data. For phase-space displacement and squeezing parameter estimation, this is achieved by introducing expectation–maximization (EM)-based algorithms, while for phase parameter estimation, an empirical Bayes method is applied. The estimated prior distribution parameters along with the observed data are used for finding the optimal Bayesian estimate of the unknown displacement, squeezing, and phase parameters. Our simulation results show that the proposed algorithms have estimation performance that is very close to that of “Genie Aided” Bayesian estimators, which assume perfect knowledge of the prior parameters. In practical scenarios, when numerical values of the prior distribution parameters are not known beforehand, our proposed methods can be used to find optimal Bayesian estimates from the observed measurement data.

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.

PurposeWe hypothesized that two-tier re-classification of the “M” (metastasis) domain of the Tumor-Node-Metastasis (TNM) staging of Renal Cell Carcinoma (RCC) may improve staging accuracy than the current monolithic classification, as advancements in the understanding of tumor biology have led to increased recognition of the heterogeneous potential of metastatic RCC (mRCC).MethodsMulticenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. Patients were stratified by number of metastases into two groups, M1 (≤3, “Oligometastatic”) and M2 (>3, “Polymetastatic”). Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS). Cox-regression and Kaplan-Meier (KMA) analysis were utilized for outcomes, and receiver operating characteristic analysis (ROC) was utilized to assess diagnostic accuracy compared to current “M” staging.Results429 patients were stratified into proposed M1 and M2 groups (M1 = 286/M2 = 143; median follow-up 19.2 months). Cox-regression revealed M2 classification as an independent risk factor for worsened all-cause mortality (HR=1.67, p=0.001) and cancer-specific mortality (HR=1.74, p

Patients with cancer represent a particularly vulnerable population at risk of adverse outcomes related to COVID-19. Collectively, the initial studies, including patients with and without cancer, confirmed that patients with cancer had a higher risk of complications and death related to COVID-19. Subsequent studies on patients with COVID-19 and cancer investigated patient and disease-related factors associated with COVID-19 severity and morality. Multiple interconnected factors include demographics, comorbidities, cancer-associated variables, treatment side effects, and other parameters. However, there is a lack of clarity on the contributions of any one factor. In this commentary, we deconvolute the data of specific risk factors associated with worse outcomes due to COVID-19 in cancer patients and focus on understanding the recommended guidelines to mitigate COVID-19 risk in this vulnerable population. In the first section, we highlight the key parameters, including age and race, cancer status, type of malignancy, cancer therapy, smoking status and comorbidities that impact outcomes for cancer patients with COVID-19. Next, we discuss efforts made at the patient, health system, and population levels to mitigate the effects of the ongoing outbreak for patients with cancer, including (1) screening, barrier and isolation strategies (2), Masking/PPE (3), vaccination, and (4) systemic therapies (e.g., evusheld) to prevent disease onset in patients. In the last section, we discuss optimal treatment strategies for COVID-19, including additional therapies for patients with COVID-19 and cancer. Overall, this commentary focuses on articles with high yield and impact on understanding the evolving evidence of risk factors and management guidelines in detail. We also emphasize the ongoing collaboration between clinicians, researchers, health system administrators and policymakers and how its role will be important in optimizing care delivery strategies for patients with cancer. Creative patient-centered solutions will be critical in the coming years, post the pandemic.

Summary: Background: Breakthrough SARS-CoV-2 infections following vaccination against COVID-19 are of international concern. Patients with cancer have been observed to have worse outcomes associated with COVID-19 during the pandemic. We sought to evaluate the clinical characteristics and outcomes of patients with cancer who developed breakthrough SARS-CoV-2 infections after 2 or 3 doses of mRNA vaccines. Methods: We evaluated the clinical characteristics of patients with cancer who developed breakthrough infections using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19; NCT04354701). Analysis was restricted to patients with laboratory-confirmed SARS-CoV-2 diagnosed in 2021 or 2022, to allow for a contemporary unvaccinated control population; potential differences were evaluated using a multivariable logistic regression model after inverse probability of treatment weighting to adjust for potential baseline confounding variables. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported. The primary endpoint was 30-day mortality, with key secondary endpoints of hospitalization and ICU and/or mechanical ventilation (ICU/MV). Findings: The analysis included 2486 patients, of which 564 and 385 had received 2 or 3 doses of an mRNA vaccine prior to infection, respectively. Hematologic malignancies and recent receipt of systemic anti-neoplastic therapy were more frequent among vaccinated patients. Vaccination was associated with improved outcomes: in the primary analysis, 2 doses (aOR: 0.62, 95% CI: 0.44–0.88) and 3 doses (aOR: 0.20, 95% CI: 0.11–0.36) were associated with decreased 30-day mortality. There were similar findings for the key secondary endpoints of ICU/MV (aOR: 0.60, 95% CI: 0.45–0.82 and 0.37, 95% CI: 0.24–0.58) and hospitalization (aOR: 0.60, 95% CI: 0.48–0.75 and 0.35, 95% CI: 0.26–0.46) for 2 and 3 doses, respectively. Importantly, Black patients had higher rates of hospitalization (aOR: 1.47, 95% CI: 1.12–1.92), and Hispanic patients presented with higher rates of ICU/MV (aOR: 1.61, 95% CI: 1.06–2.44). Interpretation: Vaccination against COVID-19, especially with additional doses, is a fundamental strategy in the prevention of adverse outcomes including death, among patients with cancer. Funding: This study was partly supported by grants from the National Cancer Institute grant number P30 CA068485 to C-YH, YS, SM, JLW; T32-CA236621 and P30-CA046592 to C.R.F; CTSA 2UL1TR001425-05A1 to TMW-D; ACS/FHI Real-World Data Impact Award, P50 MD017341-01, R21 CA242044-01A1, Susan G. Komen Leadership Grant Hunt to MKA. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH).

Quantitative satellite observations only provide an assessment of ice sheet mass loss over the last four decades. To assess long-term drivers of ice sheet change, geological records are needed. Here we present the first millennial-scale reconstruction of David Glacier, the largest East Antarctic outlet glacier in Victoria Land. To reconstruct changes in ice thickness, we use surface exposure ages of glacial erratics deposited on nunataks adjacent to fast-flowing sections of David Glacier. We then use numerical modelling experiments to determine the drivers of glacial thinning. Thinning profiles derived from 45 10Be and 3He surface exposure ages show David Glacier experienced rapid thinning of up to 2 m/yr during the mid-Holocene (∼ 6.5 ka). Thinning slowed at 6 ka, suggesting the initial formation of the Drygalski Ice Tongue at this time. Our work, along with ice thinning records from adjacent glaciers, shows simultaneous glacier thinning in this sector of the Transantarctic Mountains occurred 4–7 kyr after the peak period of ice thinning indicated in a suite of published ice sheet models. The timing and rapidity of the reconstructed thinning at David Glacier is similar to reconstructions in the Amundsen and Weddell embayments. To identify the drivers of glacier thinning along the David Glacier, we use a glacier flowline model designed for calving glaciers and compare modelled results against our geological data. We show that glacier thinning and marine-based grounding-line retreat are controlled by either enhanced sub-ice-shelf melting, reduced lateral buttressing or a combination of the two, leading to marine ice sheet instability. Such rapid glacier thinning events during the mid-Holocene are not fully captured in continental- or catchment-scale numerical modelling reconstructions. Together, our chronology and modelling identify and constrain the drivers of a ∼ 2000-year period of dynamic glacier thinning in the recent geological past.

The application of induced pluripotent stem cells (iPSCs) in advanced therapies is increasing at pace, but concerns remain over their clinical safety profile. We report the first-ever application of doggybone DNA (dbDNA) vectors to generate human iPSCs. dbDNA vectors are closed-capped linear double-stranded DNA gene expression cassettes that contain no bacterial DNA and are amplified by a chemically defined, current good manufacturing practice (cGMP)-compliant methodology. We achieved comparable iPSC reprogramming efficiencies using transiently expressing dbDNA vectors with the same iPSC reprogramming coding sequences as the state-of-the-art OriP/EBNA1 episomal vectors but, crucially, in the absence of p53 shRNA repression. Moreover, persistent expression of EBNA1 from bacterially derived episomes resulted in stimulation of the interferon response, elevated DNA damage, and increased spontaneous differentiation. These cellular activities were diminished or absent in dbDNA-iPSCs, resulting in lines with a greater stability and safety potential for cell therapy.

Abstract Background Little is known regarding the rate and clinical outcomes of asymptomatic carriers of SARS‐CoV‐2 among patients with cancer. Detection of asymptomatic carriers is important in this population given the use of myelosuppressive and immunomodulating therapies. Understanding the asymptomatic carrier rate will help to develop mitigation strategies in this high‐risk cohort. Methods Retrospective cohort analysis of an asymptomatic screening protocol which required patients receiving infusional anti‐cancer therapy to undergo a symptom/exposure screen and SARS‐CoV‐2 PCR testing 24–96 h prior to their infusion. The primary outcome of this analysis was the rate of asymptomatic SARS‐CoV‐2 infection. Secondary outcomes included the rate of COVID‐19‐related hospitalization and mortality and delays in oncologic therapy. Results Among a cohort of 2691 cancer patients who underwent asymptomatic screening, 1.6% (N = 43/2691) of patients were found to be SARS‐CoV‐2 positive on asymptomatic screening. 11.6% (N = 5/43) of the cohort ultimately developed COVID‐19‐related symptoms. Four patients required hospitalization for complications of COVID‐19 infection. No patient died from COVID‐related complications. 97.7% (N = 42/43) had their anti‐cancer therapy delayed or deferred with a median delay of 21 days (range: 7–77 days). Conclusions Overall, among a cohort of active cancer patients receiving anti‐cancer therapy, an asymptomatic SARS‐CoV2 PCR‐based screening protocol detected a small cohort of asymptomatic carriers. The majority of these patients remained asymptomatic on long‐term follow‐up and outcomes were much more favorable compared to previously described outcomes of cancer patients with symptomatic COVID‐19 infection.

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care.

Abstract This debate paper asserts that implementation science needs to incorporate a key concept from entrepreneurship—market demand—and demonstrates how assessing an innovation’s potential market viability might advance the pace and success of innovation adoption and sustainment. We describe key concepts, language distinctions, and questions that entrepreneurs pose to implementation scientists—many of which implementation scientists appear ill-equipped to answer. The paper concludes with recommendations about how concepts from entrepreneurship, notably market viability assessment, can enhance the translation of research discoveries into real-world adoption, sustained use, and population health benefits. The paper further proposes activities that can advance implementation science’s capacity to draw from the field of entrepreneurship, along with the data foundations required to assess and cultivate market demand.