STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival.Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS  had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival .P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS  and PFS  but no good evidence of overall survival benefit . There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity.Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS , without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases. STAMPEDE’s “docetaxel comparison” previously showed a clear, clinically important overall survival advantage for adding upfront docetaxel across men with locally advanced or metastatic prostate cancer initiating long-term androgen deprivation therapy (ADT) . Trials International guidelines incorporate upfront docetaxel into recommendations for suitable patients with metastatic prostate cancer, particularly high-volume disease ,9. MetasWe report long-term analysis of patients with nonmetastatic disease, allowing in-depth assessment of outcomes of docetaxel in node-positive (N+) and node-negative (N0) populations and by use of standard-of-care (SOC) prostate radiotherapy. The nonmetastatic patients STAMPEDE’s docetaxel comparison control arm previously demonstrated 96% 2-year survival . With suSTAMPEDE uses a multi-arm multistage platform design to compare treatments against SOC . PatientAll patients were planned for long-term ADT as the basis for SOC. Here, the relevant patients were randomly assigned 2:1 to control (SOC) or research: SOC plus upfront docetaxel. Random assignment used minimization with a 20% random element, stratified by age at randomization (younger than 70 years vs 70 years and older), World Health Organization (WHO) performance score (0 vs 1 or 2), baseline metastases (yes or no) and nodal status , planned ADT type, use of aspirin or other nonsteroidal anti-inflammatory drugs, participating hospital/site, and from 2011, planned radiotherapy. This algorithm was developed and used centrally at MRC Clinical Trials Unit at University College London.2) 3 weekly plus 10 mg prednisolone daily in addition to SOC ADT. For patients without a contraindication, SOC could include prostate radiotherapy; before November 14, 2011, irrespective of nodal status, such SOC radiotherapy was optional but encouraged; from November 14, 2014, such SOC radiotherapy was mandated for patients with N0 disease and encouraged for N+ disease; this change was to implement the findings of the MRC PR07/NCIC PR.3 and SPCG-7 trials  or disease progression was reported at routine follow-up visits scheduled in the protocol to be 6 weekly in the first 6 months postrandomization, then 12 weekly until 2 years, 6 monthly until 5 years, and annually thereafter. AEs were classified and graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.The first findings of the docetaxel comparison were reported previously based on a May 13, 2015, data freeze . The maiCause of death was categorized algorithmically to differentiate prostate cancer and non-prostate cancer causes, with rules agreed to in 2018 by the Trial Management Group ; the docetaxel-safety group consisted of 212 research arm patients who reported starting trial treatment.P values are reported. Kaplan-Meier graphs have been presented using the KMunicate format , except for participating hospital. Time period was included as stratification in the models to delineate periods of STAMPEDE, where other trial arms were opened or closed to recruitment or with SOC change of practice. Nonparametric stratified log-rank tests were used to test differences between trial arms. Flexible parametric models ,17 were e format .Exploratory subgroup analyses are presented for the primary outcome to assess consistency of docetaxel treatment effect across baseline factors .Further exploratory analyses assessed the efficacy of SOC radiotherapy for each outcome measure. These analyses focused on patients with no contraindication to radiotherapy and with either N0 disease recruited before SOC November 14, 2011 (before SOC radiotherapy was mandated) or N+ disease recruited any time see . These aTo contextualize the findings, estimates of treatment effects on overall survival from relevant trials were combined using standard meta-analysis methods. The inclusion criteria were randomized trial; nonmetastatic prostate cancer; control treatment of long-term hormone therapy with or without prostate radiotherapy; and with survival data published.There were 690 nonmetastatic patients recruited to STAMPEDE’s docetaxel comparison between October 5, 2005, and March 31, 2013: 460 patients to the control group and 230 patients to the docetaxel group. P = .43; P = .23) of nonproportional hazards in the treatment effect on mPFS. The proportion event free at 5 years was 77% (95% CI = 73% to 81%) in the control and 82% (95% CI = 78% to 87%) in the docetaxel group.For the primary outcome measure for this long-term analysis, metastatic mPFS, there were 207 mPFS events reported: 142 of 460 (31%) control group and 65 of 230 (28%) docetaxel group. There was no good evidence that docetaxel improved survival  and found no evidence of inconsistency in the effect in the groups examined  was impacted by evidence of nonproportional hazards of treatment effect (P = .03). However, these earlier improvements did not translate into improvements in overall survival or PCSS. There were 182 deaths with 88 of 125 (70%) in the control group and 39 of 57 (68%) in the docetaxel group attributed to prostate cancer on review. The treatment effect for overall survival was estimated as a hazard ratio of 0.88  and in the N0 and N+ subgroups  patients, regardless of treatment allocation, for whom the use of SOC radiotherapy was optional , and theP = .08) with no evidence of heterogeneity of effect across the trials (I2 = 0.0).Three trials met the criteria for a combined analysis with these STAMPEDE data: GETUG-12, RTOG-0521, and ARTIC AOM 03108  and higher 5-year survival (81% vs 87%) with docetaxel. They may also argue there was insufficient patient numbers or that our dataset is still too immature to detect any potential benefit of docetaxel in a population with good outcomes. The trial team has closed out site follow-up for these patients, but most patients consented to access to data through national registries, which could allow for longer-term assessment.Sceptics may argue there was insufficient power on mPFS to detect a clinically meaningful benefit had there been one. They may also argue, from ICECaP’s surrogacy work , it is uWe previously reported higher rates of AEs in the docetaxel group. Here, we show the AE rate after the first year of follow-up, starting about 6 months after completion of chemotherapy, was similar between patients in the control and docetaxel groups of the safety population who had not already progressed; AE data collection stopped at disease progression. Quality of life is an important factor in treatment decisions; it is reassuring there was no evidence of persistent toxicity associated with worse quality of life. Our findings are consistent with studies that demonstrated quality of life can improve back to baseline after chemotherapy . The AEsOur analysis confirms the FFS benefit associated with this approach, with clear evidence that patients treated with upfront docetaxel lived longer without their disease relapsing. This would also mean that men could continue their lives for a longer period without the need for additional therapeutic intervention. This in turn may augment any psychological benefit arising from living without signs of disease progression, which is considered important for many patients. Participant-reported quality-of-life measures are an important contributor to quantifying treatment impact, although these data are typically less well recorded in clinical trials after disease progression. We previously demonstrated, consistent with this, how upfront docetaxel increased quality-adjusted life-years in this group of nonmetastatic patients . ExaminiOur findings align with results from other trials of docetaxel in nonmetastatic prostate cancer ,26,27. TDuring recruitment to STAMPEDE’s docetaxel comparison, recommendations for treating nonmetastatic patients with local radiotherapy were adapted in response to then emerging results from other trials ,15, whicOur exploratory analysis of this SOC radiotherapy’s impact in nonmetastatic patients, regardless of allocation to the control or docetaxel group, found good evidence radiotherapy improved FFS and some evidence of improved PFS. This was consistent across N0 and N+ patients, albeit more prominently for N0 patients. We could also explore any interaction between radiotherapy and docetaxel. There was some evidence that SOC radiotherapy’s benefit was apparent in the control group but not the docetaxel group . Clinicians should consider this information carefully when making treatment decisions with nonmetastatic patients.Overall, these long-term analyses of nonmetastatic patients in STAMPEDE did not demonstrate a benefit to using docetaxel chemotherapy in terms of metastasis-free survival or overall survival. There was good evidence that upfront docetaxel resulted in men living longer before their disease relapsed, and good evidence that there was no excess of long-term AEs for these patients. The findings are consistent with trials addressing the same broad question and provide some evidence of modest benefit in favor of chemotherapy. These points will be worth considering altogether for selected men in this population and interpreted in the context of more recent data reporting a large statistically significant and clinically meaningful benefit for adding abiraterone acetate and prednisolone in this population in the same STAMPEDE protocol . The benThis work was supported by Cancer Research UK (grant number CRUK_A12459); Medical Research Council ; Sanofi; Astellas; Clovis; Janssen; Novartis; Pfizer. NDJ, CCP, and DPD were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London.Role of the funders: The study funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.Disclosures: GA: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Astellas; Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Medivation; Advisory/Consultancy: Novartis; Advisory/Consultancy: Millennium Pharmaceuticals; Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Abbott Laboratories; Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Essa Pharmaceuticals; Advisory/Consultancy, Travel/Accommodation/Expenses, Nonremunerated activity/ies: Bayer Healthcare Pharmaceuticals; Speaker Bureau/Expert testimony: Takeda; Speaker Bureau/Expert testimony: Sanofi-Aventis; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Arno Therapeutics; Research grant/Funding (self): Innocrin Pharma; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Non-remunerated activity/ies: Janssen; Advisory/Consultancy: Veridex; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Roche/Ventana; Advisory/Consultancy, Non-remunerated activity/ies: Pfizer; Research grant/Funding (self), employee of the Institute of Cancer Research (ICR), where abiraterone acetate was developed, up to January 8, 2018, ICR. AJB: Speaker fees: Janssen. Support for attending meetings and/or travel: Janssen; SC: Honoraria, Speakers fee, Travel Grant- Janssen Pharmaceutical. NWC: Advisory/Consultancy: Janssen. WC: Dr Cross reports personal fees from Janssen and other from Bayer outside the submitted work. DPD: Research grant/Funding (institution), Financial Support for Trial Recruitment: UK National Institute for Health Research Clinical Research Network (NIHR CRN); Research grant/Funding (institution): ICR; Research grant/Funding (self), C46/A3976, C46/A10588 and C33589/A19727: Cancer Research UK; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Astellas; Advisory/Consultancy, Travel/Accommodation/Expenses: Sandoz; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Janssen. R. Jones: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Astellas; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Sanofi; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis. SG: Honorarium payments to hospital- Roche, Innocrin Pharmaceuticals, Sanofi, Novartis, Cell Search, Clovis and Bristol-Myers Squibb. Uncompensated advisory role- Nectar Therapeutic and ProteoMedix. NDJ: Advisory/Consultancy: Sanofi; Advisory/Consultancy: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Non-remunerated activity/ies: Janssen. RJJ: Grants or contracts paid to my institution from Bayer plc, Pfizer and Astellas. Consulting fees—Janssen Advisory board honoraria, Astellas Advisory board honoraria, consultancy, Bayer Advisory board honoraria, Pfizer Advisory board honoraria. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events- speakers fees from Janssen, Astellas, Bayer, Pfizer. AM: Research grants from Cancer Research UK’s Clinical Research Committee, from Medical Research Council, from Novartis, from Sanofi-Aventis, from Pfizer, from Janssen Pharma NV, from Astellas, from Clovis Oncology, during the conduct of the study. MDM: Honoraria (self), Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony: Bayer. ZIM: Advisory boards- Sanofi, Janssen and Pfizer. Assisted travel to Congress- Bayer. JOS: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; AAA, Astellas, Bayer, Janssen, Novartis, Sanofi. Participation on a Data Safety Monitoring Board or Advisory Board; AAA, Astellas, Bayer, Janssen, Novartis, Sanofi. CCP: Dr Parker reports grants, personal fees and other from Bayer, other from AAA and personal fees from Janssen, outside the submitted work. MKBP: Research grant/Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant/Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant/Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant/Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Research grant/Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Sanofi. SS: Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events, from Bayer, Clovis Oncology, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board; Bayer. Support for attending meetings and/or travel: BMS, Roche. MRC: Research grant/Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant/Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant/Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant/Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eli Lilly; Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Janssen; Research grant/Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Sanofi. JT: Participation on a Data Safety Monitoring Board or Advisory Board: Astra Zeneca, Astellas, Bayer. Support for attending meetings and/or travel: Jansen, Roche, Bayer; JW: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Eisai, Novartis. All other authors did not declare a conflict of interest.Author contributions: Conceptualization: MKBP, NDJ, MRS, REL, NWC, MDM, DPD. Data curation: All. Formal Analysis: FI, AC, MRS. Funding acquisition: MKBP, NDJ, MRS, NWC, MDM, DPD, SG. Investigation: All. Methodology: MKBP, FI, AC, MRC. Project administration: MKBP, CA, REL, MRS, HR. Resources: All. Software: FI, AC, MRC. Supervision: NDJ, FI, NWC, CA, GA, CDB, SC, WC, DPD, DCG, SG, RJJ, REL, ZIM, MDM, DJM, RM, CCP, HLR, JMR, MKBP, MRS. Validation: FI, AC, MRS. Visualization: FI, AC, MRS. Writing - original draft: NDJ, FI, HR, MRS. Writing - review & editing: All.Acknowledgements: We recognize the efforts of all trial team members at the trials units and hospitals who have supported and engaged with STAMPEDE. Investigators and oversight committee members are listed in the pkac043_Supplementary_DataClick here for additional data file.


The correct name is: Alex Junior Nunes da Silva. The correct citation is: Nunes da Silva AJ, Breve MM, Mena-Chalco JP, Lopes FM (2022) Analysis of co-authorship networks among Brazilian graduate programs in computer science. PLOS ONE 17(1): e0261200. The publisher apologizes for the error.


Dolutegravir/lamivudine (DTG/3TC) is indicated as a 2DR for both treatment-naïve and virally suppressed PLWH. The feasibility of DTG/3TC use in a Test & Treat (T&T) setting has been demonstrated in a clinical trial, but there is limited evidence with this approach in US real world clinical settings.TANDEM was a retrospective medical chart review conducted across 24 US sites. Eligible PLWH were adults initiated on DTG/3TC or DTG/rilpivirine (DTG/RPV) prior to Sept/30/2020 with a minimum clinical follow-up of six months. Treatment-naïve (TN) PLWH had no prior history of HIV therapy. Clinical characteristics, treatment history and outcomes were abstracted. Analyses were descriptive. Reported here are results for the sub-group of TN PLWH that were initiated DTG/3TC as part of a T&T strategy, defined as clinician attestation of treatment initiation shortly after diagnosis and in the absence of known lab values for HIV-1 RNA viral load, CD4 cell count and HIV-1 resistance mutations.From an overall sample of 469 PLWH on DTG-based 2DR, 318 received DTG/3TC, of whom, 126 were TN and 192 were stable switch. Almost half 48% of PLWH received DTG/3TC as part of a T&T paradigm. Characteristics of the cohort are described in Table 1. In the T&T sub-group, the most common reasons for initiating DTG/3TC were avoidance of long-term toxicities (n=26), followed by simplification/streamlining (n=8) and convenience (n=7). Overall, 114 (90.5%) of TN PLWH achieved the desired health outcome per clinician attestation. At data cut-off, 61 (94%) non T&T achieved virologic suppression, 57 (93%) of the T&T sub-group achieved virological suppression, 3 (5%) did not, and 1 (2%) was still unknown. Of the 3 who did not achieve suppression, 2 remained on DTG/3TC while 1 was switched to bictegravir/emtricitabine/tenofovir alafenamide. Virologic rebound occurred in 6 TN PLWH overall with only 1 occurring in the T&T sub-group.Baseline Characteristics and Virologic OutcomesReflecting results from clinical trials, DTG/3TC achieved its desired health outcomes in the majority of cases regardless of treatment paradigm, with virtually no difference in virological suppression rates across the two cohorts (93-94% achieving suppression in a median duration of 10-11 weeks).Cindy Donovan, PharmD, Johnson & Johnson: Stocks/Bonds|ViiV Healthcare: Employee/Salary|ViiV Healthcare: Stocks/Bonds Gavin Harper, BA, ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare.|ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare Deanna Merrill, PharmD, MBA, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds Katie L. Mycock, MChem, ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare|ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare Alan Oglesby, MPH, GlaxoSmithKline (GSK): Employment|GlaxoSmithKline (GSK): Stocks/Bonds Aimee Metzner, PharmD, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds Jimena Patarroyo, PharmD, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds|ViiV Healthcare: Stocks/Bonds.


Patients who develop AKI are at increased risk of adverse outcomes. The consequences of AKI are well-described in most therapeutic domains but there are scant data on the incidence of AKI among pts with CR-GNIs. This study sought to characterize the incidence of AKI and AKI-associated outcomes among adult, hospitalized pts with CR-GNIs who received early targeted tx with a newer BL, COL, or AG-containing regimen.CR) ≥2 mg/dL ± 2 d of index tx initiation day. Outcomes: on-tx AKI based on RIFLE criteria ; in-hospital mortality, and hospital LOS post-index culture day. Incidence of AKI was compared between tx groups and logistic regression (LR) was used to adjust for baseline differences. In-hospital mortality and hospital LOS post-index culture were compared between AKI groups.Design: multi-centered observational study using 2016-20 data from the PINC AI Healthcare Database. Inclusion criteria: hospitalized; age ≥ 18 yrs; diagnosis for pneumonia, complicated urinary tract infection (cUTI), or bloodstream infection; CR-GN on culture site consistent with diagnosis; receipt of a newer BL, COL, or AG within 3 days of index CR-GN culture; and ≥3 consecutive days of a newer BL, COL, or AG (first received for ≥3 d defined tx group). Exclusion criteria: receipt of any renal replacement therapy prior to index tx day; and serum creatinine . In the LR , receipt of COL was associated with a higher adjusted probability of AKI relative to BL and AG (p< 0.01). Occurrence of AKI was associated with higher mortality  and increased median [IQR] post-index culture LOS .Overall, 1,061 pts met criteria and the majority received BL (45%), followed by AG (36%), and COL (19%). We present baseline characteristics by treatment in Incidence of AKI among hospitalized pts with serious CR-GNIs was highest in pts who received an early-targeted COL-containing regimen. Occurrence of AKI was associated with increased in-hospital mortality and longer post-index culture hospital LOS.Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant Ryan J. Dillon, MSc, Merck: Employee|Merck: Stocks/Bonds Brian H. Nathanson, Ph.D., cidara: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support.


Hepatitis C virus (HCV) eradication is currently achieved in >98% of cases with oral direct-acting antivirals (DAA).Chronic Hepatitis C infection is considered a systemic disease with extrahepatic manifestations, mainly neuropsychiatric symptomsTo study potential clinical neuropsychiatric changes  in HCV-infected patients after HCV eradication with DAA.Design: Cohort study. Subjects: 37 HCV-infected patients, aged<55 years old, with non-advanced liver disease receiving DAA; free of current mental disorder. 24 healthy controls were included at baseline. Assessment: -Baseline (BL) , . Follow-up: End-of-treatment, 12weeks-after and 48weeks-after DAA: NRS. Analysis: Descriptive and bivariate non-parametrical analysis.NRS total score and dimensions where different between cases and controls (.000) at baseline. NRS total score (.000) and mood (.000), cognition (.000), sleep (.002), gastrointestinal (.017), and sickness (.003), except motor dimension score (.130) showed significant longitudinal improvement.HCV-infected patients with mild liver disease presented significantly worse scores for neurotoxicity symptomatology in all dimensions compared to healthy individuals. After HCV eradication with DAA, both at short and long follow-up a significant improvement of the NRS total score and each of the dimensions (except motor) were observed. However, they did not reach the values of healthy individuals, suggesting a not complete neuropsychiatric restoration in the period studied. Grant: ICIII-FIS:PI17/02297.(One way to make Europe) (RMS) and Gilead Fellowship-GLD17/00273 (ZM); and the support of SGR17/1798 (RMS)No significant relationships.


In the published article, there were two errors. The errors are in two of the equations,A correction has been made to Methods, Leptin Model Formulation, Paragraph 1, Equation (2). This sentence (equation) previously stated:The corrected sentence (equation) appears below:A correction has been made to Methods, Cortisol Model Formulation, Paragraph 1, Equation (6). This sentence (equation) previously stated:The corrected sentence (equation) appears below:The original article has been updated.


In the U.S., HIV transmission persists largely through sexual transmission in gender and sexual minorities. Transactional sex (TS) is a known risk factor for HIV transmission, yet risk behaviors and engagement in HIV treatment and other medical services among transgender (TG) individuals who have TS are poorly understood.PATCH is a natural history study of TG individuals in Washington, DC. Participants complete laboratory testing and surveys, including assessment of TS – defined as previous year sex in exchange for drugs, money or shelter. Fisher’s exact test was used for statistical analysis.Of 54 participants assigned male at birth (AMAB), 21(39%) endorsed TS, the majority of whom were female (81%), Black (95%), median age 35, and HIV+ . Of those with HIV, 12 (75%) were prescribed ART, though only 8 (50%) had HIV VL < 200.The majority of TG people with TS had sex weekly or more (75%), with > 5 partners/year (62%) and used their penis (80%) and anus (90%) during TS. A minority consistently used condoms in receptive anal sex (29%), penetrative anal sex (25%), penetrative vaginal sex (17%), and chem sex (8%).While 95% had ever taken gender affirming hormone therapy (GAHT), 62% were not prescribed GAHT at screening, of whom, 54% were interested in seeing a provider for GAHT.When compared to non-TS participants, TG individuals with TS were more likely to have chem sex (p< 0.01), use drugs daily or more (p=0.04), use amphetamines (p< 0.01) and cocaine (p< 0.01), and less likely to have GAHT prescribed by a provider (p=0.03). HIV+ patients with TS were less likely to have HIV VL< 200 (p=0.02).This cohort of AMAB TG individuals with TS had high rates of viremic HIV, and multiple risk factors for HIV transmission, including frequent condomless sex with multiple partners. Additionally, those with TS were more likely to have high risk drug use, indicating that novel strategies to decrease risk associated with chem sex, particularly stimulant use, should be prioritized. Further, nearly all TG participants with TS had taken GAHT, yet were less likely to get GAHT from a provider. As many had interest in seeing a provider for GAHT, co-locating GAHT with HIV treatment and prevention services could help providers engage this population and address HIV-related risks.Shyam Kottilil, MD, PhD, Arbutus Pharmaceuticals: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support|Regeneron Pharmaceuticals: Advisor/Consultant|Silverback Therapeutics: Advisor/Consultant|The Liver Company: Advisor/Consultant|Yufan Biotechnologies: Advisor/Consultant Sarah Kattakuzhy, MD, Gilead: Grant/Research Support Elana S. Rosenthal, MD, Gilead: Grant/Research Support|Merck: Grant/Research Support.


Correction: J Exp Clin Cancer Res 41, 112 (2022)https://doi.org/10.1186/s13046-022-02320-6Following publication of the original article , author Incorrect Funding:This research was funded by Fondazione AIRC under 5 per Mille 2018 – ID 21052 program - PI: Comoglio PM, GL: Vigna E; by FPRC 5xmille 2014 Ministero Salute to PMC, and by Ministero Salute, Ricerca Corrente 2018–2020. The studies performed by Accelera Srl. were sponsored by Metis Precision Medicine B-Corp.Correct Funding:by Italian Association for Cancer Research (AIRC), IG 20210 to S. Giordano, and IG 21770 to S. Corso; by FPRC 5xmille 2014 Ministero Salute to PMC, and by Ministero Salute, Ricerca Corrente 2018-2020. The studies performed by Accelera Srl. were sponsored by Metis Precision Medicine B-Corp.This research was funded by Fondazione AIRC under 5 per Mille 2018 - ID 21052 program - PI: Comoglio PM, GL: Vigna E; The correction does not have any effect on the final conclusions of the paper. The original article has been corrected.


Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the safety and pharmacokinetics of XERU following multiple doses alone and in combination with meropenem.Twenty-four healthy subjects were enrolled into one of 3 cohorts with XERU alone. XERU was administered as a 500 mg loading dose followed by 250 mg q8h or 1000 mg loading dose followed by 500 mg q8h. 15 healthy subjects were enrolled in a single cohort of meropenem alone administered as a 4000 mg loading dose followed by 2000 mg q8h or meropenem in combination with XERU administered as a 500 mg loading dose followed by 250 mg q8h for 10 days. Intensive plasma sampling was obtained after dosing and assayed for drug content using validated LC-MS/MS methods.XERU and Meropenem Steady State pharmacokinetic parameters are shown in the table below.No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild or moderate in severity.XERU was safe and well-tolerated when administered alone and in combination with meropenem. XERU has unique PK properties that includes a long elimination half-life that provides sustained plasma concentrations. The loading dose of XERU allows for rapid achievement of steady state plasma levels of XERU within the first day of treatment. XERU plasma PK properties, along with a broad spectrum of inhibitory activity, facilitates its use with multiple beta-lactam antibiotics including meropenem.David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Shawnee Gehrke, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.


Respiratory syncytial virus (RSV) can cause severe respiratory disease in older adults (OAs). However, there is no approved vaccine against RSV disease in OAs. Co-administration of vaccines against RSV and influenza could be considered given their overlapping seasonality. Here, we assessed the immunogenicity, reactogenicity and safety of an RSV prefusion F Older Adult (RSVPreF3 OA) investigational vaccine when co-administered with the seasonal quadrivalent influenza vaccine (FLU-QIV) in OAs.In this Phase 3, open-label, controlled, multi-country study (NCT04841577), OAs aged ≥ 60 years recruited in New Zealand, Panama and South Africa were randomized 1:1 to receive either RSVPreF3 OA and FLU-QIV simultaneously on day 1 (Co-Ad group), or FLU-QIV on day 1 and RSVPreF3 OA on day 31 (Control group). The co-primary objectives were to demonstrate the non-inferiority of i) RSVPreF3 OA in terms of RSV-A neutralizing antibody geometric mean titers (GMT) ratio and ii) FLU-QIV in terms of hemagglutinin inhibition antibody GMT ratio for each Flu strain when co-administered versus when administered alone. Blood samples were collected from all participants pre vaccination and 1 month post vaccination. Non-inferiority was demonstrated if the upper limit (UL) of the 95% confidence interval (CI) of the group GMT ratio (Control/Co-Ad) was ≤ 1.5. Secondary descriptive outcomes included reactogenicity and safety.885 participants received at least 1 dose of the study interventions. Of these, 838 were included in the per protocol set at 1 month post vaccination. The demographic characteristics of the participants were similar across groups. The study co-primary objectives were met; for both vaccines, the UL of the 95% CI of the GMT ratio was ≤ 1.5 (Table 1). The observed safety events were balanced between Co-Ad and Control groups (Table 2). The reactogenicity profile of the Co-ad group compared with the Control group was driven by the RSVPreF3 OA investigational vaccine.Our results support simultaneous seasonal vaccination with RSVPreF3 OA and FLU-QIV in adults ≥ 60 years, as co-administration elicits a statistically non-inferior immune response to the administration of each vaccine alone, with no safety concerns identified.Nathali Montenegro, MD, GSK: Support for the present abstract/study Lorena Noriega-Aguirre, MD, ScD, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Astra Zeneca: Support for attending meetings and/or travel|Boehringer Ingelheim: Honoraria|Boehringer Ingelheim: Support for attending meetings and/or travel|GSK: Advisor/Consultant|GSK: Support for the present abstract/study|Novartis: Honoraria Mohammed Bensellam, PhD, GlaxoSmithKline Biologicals SA: Agency worker on assignment at GSK Nathalie De Schrevel, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Ownership Interest Sherine Kuriyakose, MSc, GSK: GSK Employee Axel Lambert, MSc, GSK: GSK Employee Aurélie Olivier, PhD, GlaxoSmithKline Biologicals SA: I’m an employee of GSK Biologicals|GlaxoSmithKline Biologicals SA: Ownership Interest Veronica Hulstrøm, PhD MD, GlaxoSmithKline Biologicals SA: Employee.


Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in non-hospitalized and hospitalized adult as well as pediatric patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 ACTT-1 placebo-controlled clinical trial in hospitalized adults.th and 50% of participants with < 20th percentile of cumulative viral shedding underwent resistance analysis in both the RDV and placebo arm. The SARS-CoV-2 genome was sequenced using next generation sequencing. Phenotyping was conducted using virus isolation from clinical samples or generation of select site-directed mutants (SDMs) in a SARS-CoV-2 replicon system.Oro- or nasopharyngeal swab samples in ACTT-1 study were collected on Day 1, 3, 5, 8, 11, 15, and 29. All participants with >80th percentile of cumulative viral shedding from the RDV and placebo arms as shown in Table 1. Among participants with both baseline and postbaseline sequencing data, emergent substitutions in nsp12 were observed in 12 of 31 participants (38.7%) treated with RDV and 12 of 30 participants (40.0%) in the placebo arm. The nsp12 substitutions that emerged in the RDV arm were only observed in one participant each, and the majority were present as mixtures with wildtype sequence. The following nsp12 mutations emerged in the RDV treatment group and were successfully phenotyped as clinical isolates or SDMs with low to no fold change in RDV susceptibility: A16V (0.8-fold), P323L+V792I (2.2-fold), C799F (2.5-fold), K59N (1.0-fold), and K59N+V792I (3.4-fold). V792I and C799F were identified previously in vitro in resistance selection experiments (Stevens Sci Transl Med 2022). In addition, for D684N and V764L identified in the RDV arm, the recovery of neither clinical isolates nor SDMs for phenotypic analysis were successful.The majority of the sequencing data were obtained from participants with 80The similar rate of emerging nsp12 substitutions in participants treated with RDV compared to placebo and the minimal to no change in RDV susceptibility among the treatment-emergent nsp12 substitutions support a high barrier to RDV resistance development in COVID-19 patients.Charlotte Hedskog, PhD, Gilead Sciences: Stocks/Bonds Lauren Rodriguez, PhD, Gilead: Stocks/Bonds Alexander L. Greninger, MD, PhD, Abbott: Contract Testing|Cepheid: Contract Testing|Gilead: Grant/Research Support|Gilead: Contract Testing|Hologic: Contract Testing|Merck: Grant/Research Support|Novavax: Contract Testing|Pfizer: Contract Testing Jiani Li, PhD, Gilead Sciences: Stocks/Bonds Jason Perry, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Dong Han, MS, Gilead Sciences: Stocks/Bonds Gregory Camus, PhD, Gilead Sciences: Employee and shareholder|Gilead Sciences: Stocks/Bonds Danielle P. Porter, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds|Gilead Sciences: Stocks/Bonds.


Mucorales (MCR) and Gram-negative rods (GNR) commonly infect patients (pts) with hematological malignancies (HM); however, their co-occurrence is understudied.We retrospectively reviewed the records of 63 pts with HM and sinopulmonary MCR  at MD Anderson Cancer Center  from 2008-2016. Co-occurrence was defined as a culture positive for GNR taken from sinuses or the lungs within 90 days (d) of a positive Mucorales culture or histology demonstrating Mucorales spp.Ninety percent of the 63 pts with MCR had leukemia or myelodysplastic syndrome (54% AML) and 10% had lymphoma/myeloma. Sixty-eight percent had undergone hematopoietic stem cell transplant. Sixty-seven percent were neutropenic at the time of MCR diagnosis. Thirty-five percent had received > 600mg of prednisone within 30 days (d) prior to MCR diagnosis. Thirty-five percent were admitted to the ICU during the time of MCR treatment. MCR pts had sinusitis (42.9%), pneumonia (38.1%) and disseminated sinopulmonary disease (19.0%). Nearly all pts (92%) received empiric antimicrobials with activity against Pseudomonas prior to collection of their positive fungal cultures. Twenty-three pts (37%) had concurrent detection of GNRs  in samples from the sinopulmonary tract. Eight of 23 co-isolations of GNRs and Mucorales (35%) were found in same-day samples. Demographic and clinical characteristics of pts with and without co-occurrence of GNR were comparable. Pts with co-occurrence had less frequently received antibiotics with activity against Stenotrophomonas 7 (30.4%) vs 23 . Ninety-day all-cause mortality was high and comparable in pts with (83%) and without (78%) GNR detection (p = 0.75).Over a third of heavily immunosuppressed pts with sinopulmonary MCR harbor GNRs in their respiratory tract, most commonly Pseudomonas. Although no impact on survival outcomes was seen in a background of high mortality, pathogenesis studies are needed to understand the mutualistic interplay of GNR and Mucorales spp. and their influence on host responses.William R. Miller, MD, Entasis Therapeutics: Grant/Research Support|UpToDate: Royalties - Topic Contributor Dimiitrios P. Kontoyiannis, MD, ScD, PhD (hon), AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Advisor/Consultant.


Article title: Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a reviewAuthors: Bingqian Li, Huili Shao, Lei Gao, Huan Li, Huagang Sheng, and Liqiao ZhuJournal:Drug DeliveryBibliometrics: Volume 29, Number 1, pages 2130–2161DOI:https://doi.org/10.1080/10717544.2022.2094498As per author’s request, the captions of figure 6 and 8 should be revised as shown below.International Journal of Nanomedicine 2020; 15: 10285–10304’ Originally published by and used with permission from Dove Medical Press Ltd.Figure 6. Illustration of the preparation, dual-drugs loading, pH-responsive intracellular release of MSNCA@GODOX-HA nanoparticles and the apoptosis induction in MCF-7 cells. International Journal of Nanomedicine 2021; 16: 1775–1787’ Originally published by and used with permission from Dove Medical Press Ltd.Figure 8. Schematic representation of the carrier-free nanoparticles (NPs) via co-assembly between UA and MTX.


Cytomegalovirus (CMV) infection is a frequent complication after allogeneic hematopoietic cell transplant  and may increase the risk of other viral infections through its immunomodulatory effects. Donor CMV serology (seropositive [D+] or seronegative donor [D-]) in CMV-seropositive (R+) or seronegative recipients (R-) may impact outcomes post allo-HCT. We analyzed the significance of donor CMV serostatus in a large cohort of alloHCT recipients.This is a single-center, retrospective cohort study of 651 allo-HCT recipients cared for at our institution between March 2016 and December 2018. Data on baseline demographics, transplant characteristics, preventive strategies, CMV infection characteristics, and transplant-related outcomes (development of graft versus host disease (GVHD), all-cause mortality, and non-relapse mortality) were collected. A univariate analysis was performed for outcomes of interest using CMV serostatus D-/R- as a control group.Out of the 651 allo-HCT recipients, 77 were D-/R-, 43 D+/R-, 290 D+/R+, and 241 D-/R+ (table 1). Most patients underwent HCT for AML (40%), received myeloablative conditioning (51%), and had a matched unrelated donor (MUD) HCT (46%). In 2018, letermovir was used in 27% of the D+/R+, 18% of the D-/R+ allo-HCT recipients (table 1) for a total of 116 (55%) allo-HCT recipients. Compared to the CMV D-/R- group, D+/R+ and D-/R+ groups (table 2) had a greater incidence of clinically signicant CMV infections (CS-CMVi) , CMV end organ disease , and refractory/resistant (R/R) CMV infections  with 48 weeks of allo-HCT. CS-CMVi and R/R CMV was more common in D-/R+ allo-HCT when compared to D+/R+ group . D-/R+ allo-HCT had worse non-relapse mortality at day 100 compared to D-/R- .Allo-HCT recipients with CMV seronegative donor and recipient had less CMV related complications and a trend towards better survival when compared to D-/R+ allo-HCT. CMV D-/R+ HCT recipients had greater CMV related complications when compared to CMV D+/R+ HCT recipients, possibly due to the protective affect of donor seropositivity.Terri Lynn Shigle, PharmD, BCOP, Takeda: Advisor/Consultant Gabriella Rondon, MD, Omeros: Advisor/Consultant Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.


Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes.In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts.DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings.We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.The online version contains supplementary material available at 10.1186/s13045-022-01283-7 To the editorIn the past decades, neoadjuvant therapy has provided extra treatment opportunities for lung cancer patients and prolonged their survival . For exaTP53 (92.9%), MUC16 (42.9%), CSMD3 (35.7%) and MUC4 (35.7%) most frequently mutated  genes on genome instability, the chromosome and arm-level copy number variation (CNV) burden  escalateWe next inspected TMB and ITH considering their recognized impacts on immunotherapy efficacy . Non-aneAdditionally, MPR group generated more neoantigens with higher clonal proportion  Regimen combinations of the 14 NSCLC patients. (B) Chemotherapeutic drugs and immunotherapy agents used by each patient. (C) Neoadjuvant immunotherapy duration time distribution between MPR and Non-MPR groups. (D) Correlation between PD-L1 expression and percentage of viable tumor cells in patients. (E) Mutation number retained after filtrations. (F) Mutation number distribution on MPR/Non-MPR and FFPE/Frozen specimen. (G) Six substitution type spectrum plot in two patient groups. P-values were shown above each substitution category. (H) Exposures of three types of mutation signature to known database. SBS: single base substitution; ID: InDel; DBS: double base substitution. Either sum or log2 fold change of the absolute exposures was addedly depicted. (I) Percentage of altered tumor suppressor genes enriched in multiple DNA repair-related pathways in MPR and Non-MPR group. Figure S2. SCNA statistical and signature analyses results in groups with distinct therapeutic response. (A) Chromosome level CNV burden between MPR/Non-MPR groups. (B) Arm level CNV burden in two groups. (C) Chromosome level CNV burden between squamous cell carcinoma (SCC) MPR/Non-MPR patients. (D) Arm level CNV burden in two SCC patient groups. (E) Correlation between chromosome level CNV burden and percentage of viable tumor cells. (F) Correlation between arm level CNV burden and percentage of viable tumor cells. (G) Percentage of genome amplified in two groups. (H) Percentage of genome deleted in two groups. (I) Percentage of genome amplified in SCC patients. (J) Percentage of genome deleted in SCC patients. (K) SCNA heatmap only plotting copy number alternations exceeding the threshold +/-0.2. Two aneuploid samples were marked by pink circles. (L) Contributions of three SCNA signatures in all samples. Adenocarcinoma samples were marked with pink triangles. (M) Proportion of SCNA Signature 1 in patients. (N) Proportion of SCNA Signature 7 in patients. (O) Proportion of SCNA Signature 5 in patients. (P) Proportion of SCNA Signature 1 in SCC patients. (Q) Proportion of SCNA Signature 7 in SCC patients. (R) Proportion of SCNA Signature 5 in SCC patients. Figure S3. HRDscore in non-aneuploid SCC samples. (A) HRDscore calculated on non-aneuploid SCC samples. (B) Correlation between HRDscore and percentage of viable tumor cells in all non-aneuploid SCC samples. Figure S4. Multidimensional ITH comparison results between MPR/Non-MPR groups. (A) TMB value distribution in SCC samples. (B) Correlation between TMB and percentage of viable tumor cells in SCC samples. (C) Clonal TMB value in two groups, only selecting SCC patients. (D) Correlation between clonal TMB and percentage of viable tumor cells on SCC samples. (E) Germline HR pathway gene mutation number in MPR/Non-MPR groups. (F) Subclonal SCNA fragment number in two groups, only selecting SCC samples. (G) Correlation between subclonal SCNA fragment number and percentage of viable tumor cells, only selecting SCC samples. Figure S5. Investigation on the neoantigen load difference between patients with distinct outcomes. (A) TNB in two groups. (B) Correlation between TNB values and percentage of viable tumor cells. (C) TNB in two groups, only selecting SCC samples. (D) Correlation between TNB values and percentage of viable tumor cells, only selecting SCC samples. (E) Clonal TNB value distribution in two groups, only selecting SCC samples. (F) Correlation between clonal TNB and percentage of viable tumor cells, only selecting SCC samples. (G) HLA LOH frequency in MPR/Non-MPR groups. (H) TNB value on kept HLA alleles. (I) Correlation between TNB on kept HLA alleles and percentage of viable tumor cells. (J) TNB value on kept HLA alleles, only selecting SCC samples. (K) Correlation between TNB on kept HLA alleles and percentage of viable tumor cells, only selecting SCC samples. (L) Clonal TNB value on kept HLA alleles. (M) Correlation between clonal TNB on kept HLA alleles and percentage of viable tumor cells. (N) Clonal TNB value on kept HLA alleles, only selecting SCC samples. (O) Correlation between clonal TNB on kept HLA alleles and percentage of viable tumor cells, only selecting SCC samples. Figure S6. Comprehensive analysis on clonal neoantigen and SCNA bring insights to the function of SCNA on neoantigen generation. (A) Percentage of kept clonal neoantigens on SCNA regions in two groups. (B) Correlation between CNV-related neoantigen proportion and percentage of viable tumor cells. (C) Percentage of kept clonal neoantigens on SCNA regions in two groups, only selecting SCC samples. (D) Correlation between CNV-related neoantigen proportion and percentage of viable tumor cells, only selecting SCC samples. (E) Number of clonal neoantigen on kept HLA alleles and their distribution on 3 types of SCNAs. Adenocarcinoma samples were marked with pink triangles. The sample with ATR mutation was marked with arrow. (F) Correlation between clonal neoantigen number on amplified segments and percentage of viable tumor cells. (G) Correlation between clonal neoantigen number on amplified segments and percentage of viable tumor cells, only selecting SCC samples. (H) Correlation values on all 11 non-aneuploid and high purity samples, calculated by Spearman Correlation Coefficient (SCC). (I) Similar with (H), the correlation values were on MPR samples. (J) Similar with (H), the correlation values were on Non-MPR samples. Figure S7. Investigation on HR pathway gene alternation frequency in patients with distinct response from public cohorts. (A) HR pathway gene mutation frequency in J Immunother Cancer. 2020 neoadjuvant dataset. Left: in pCR patients. Middle: in other patients. Right: percentage of distinct mutant reads for each HR gene mutation detected. Mutations from pCR patients were marked with red color. (B) HR pathway gene mutation frequency in N Engl J Med. 2018 neoadjuvant dataset. Left: in MPR patients. Middle: in Non-MPR patients. Right: percentage of distinct mutant reads for each HR gene mutation detected. Mutations from MPR patients were marked with red color. (C) HR pathway gene mutation frequency in DCB patients from Nat Genet. 2018 dataset. Left: all and clonal HR gene mutations. Right: all and clonal HR core pathway mutations. (D) Similar with (C), but using non-DCB patients. (E) Similar with (C), but using J Clin Oncol. 2018 dataset. (F) Similar with (C), but using NDB patients. (G) HR pathway gene mutation frequency in patients achieved DCB in chemotherapy from Cancer Discov. 2017 dataset. (H) Similar with (G), but in NDB patients. (I) HR pathway gene SCNA frequency in patients achieved DCB in chemotherapy from Cancer Discov. 2017 dataset. Left: HR gene SCNAs. Right: HR core pathway gene SCNAs. (J) Similar with (I), but in NDB patients. (K) HR pathway gene mutation frequency in patients achieved CR and PR in chemotherapy from Nat Med. 2018 dataset. Left: all and clonal HR gene mutations. Right: all and clonal HR core pathway mutations. (L) Similar with (K), but in other patients. (M) Similar with (K), but using patients received immunotherapy. (N) Similar with (M), but in other patients. Figure S8. Comparisons on TMB values stratified by therapeutic response and HR pathway gene status from public cohorts. (A) TMB and clonal TMB value distribution between DCB and other patients in non-squamous population from Nat Genet. 2018 dataset. Left: TMB. Right: clonal TMB. (B) Similar with (A) but using HR pathway gene clonal mutations as the stratification strategy. (C) TMB value distribution between DCB and NDB patients in J Clin Oncol. 2018. (D) Similar with (C) but focusing on different histological subtypes. Left: in adenocarcinoma subgroup. Right: in squamous subgroup. (E) Similar with (D) but using HR pathway gene mutation as the classification strategy. (F) Clonal TMB value distribution between patients stratified by HRD event in J Clin Oncol. 2018 dataset. Left: between patients with and without HR pathway gene mutation. Right: between patients with and without HR pathway gene clonal mutation. (G) TMB value distribution between CR+PR and other immunotherapy patients in Nat Med. 2018 dataset. (H) Similar with (G) but focusing on different histological subtypes. Left: in non-squamous subgroup. Right: in squamous subgroup. (I) TMB value distribution between CR+PR patients with HRD and other CR+PR patients in Nat Med. 2018. (J) Similar with (F), but in Nat Med. 2018 dataset. Figure S9. Survival analyses and TMB comparisons on HRD event-stratified patients in multiple public cohorts. (A) PFS of patients stratified by HR gene mutational condition in Nat Genet. 2018 dataset. Left: between patients with and without HR gene mutation. Right: between patients with and without HR gene clonal mutation. (B) Similar with (A), but on OS data. (C) Similar with (A) but in all patients from J Clin Oncol. 2018 cohort. (D) Similar with (C) but in adenocarcinoma patients. (E) Similar with (C), but in squamous patients. (F) PFS and TMB of all DCB patients with and without HR gene mutations in Nat Genet. 2018 cohort. (G) Similar with (F) but on OS data. (H) Similar with (F) but using HR pathway gene clonal mutations as the classification strategy. (I) Similar with (H) but on OS data. (J) Similar with (F) but in patients from J Clin Oncol. 2018 cohort. Figure S10. Survival analyses and TMB comparisons conducted on Nat Med. 2018 blood cohort. (A) Survival and TMB of all chemo-treated non-squamous patients with and without HR gene mutations. Left: OS. Middle: PFS. Right: TMB distribution. (B) Similar with (A) but on squamous patients. (C) Similar with (A) but on patients received immunotherapy. (D) Similar with (C) but on squamous patients. (E) Survival and TMB of all HR pathway-mutant patients treated with immunotherapy and chemotherapy. Left: OS. Middle: PFS. Right: TMB distribution. (F) Similar with (E) but among patients with HR gene clonal mutations. Figure S11. Investigation on HR pathway gene alternation frequency and HRD events in multiracial untreated patients. (A) HR pathway gene mutation frequency in Sci Rep. 2015 dataset. Left: all and clonal HR gene mutations. Right: all and clonal HR core pathway mutations. (B) Similar with (A), but in J Thorac Oncol. 2020 cohort. (C) Similar with (A), but in TCGA-LUAD dataset. (D) Similar with (A), but in TCGA-LUSC dataset. (E) HR pathway gene alternation frequency in TCGA-LUAD dataset. (F) Similar with (E), but in TCGA-LUSC dataset. (G) Correlation between CNV burden and HRDscore in TCGA-LUAD dataset. (H) Similar with (G), but in TCGA-LUSC dataset.Additional file 4: Supplementary Materials and methods.


In-vitro neutralizing antibody (Ab) titers correlated with ∼250 IU/mL Spike Ig Ab level for the Delta COVID-19 variant, establishing the 2021 French and Swiss cutoff for booster guidance. In a New York City healthcare clinic where those guidelines were adopted, we aimed to quantify vaccination responses in HIV+ and HIV- individuals to assess the utility of quantifying antibodies to guide booster timing.Adults who were fully vaccinated against SARS-CoV-2 virus  were included if >1 Roche SARS-CoV-2 Semi-Quant Spike Ig Ab test was performed >21 days after vaccination and before any booster (through 03DEC2021). Vaccine response was assessed at the first Ab test and considered adequate (>250 IU/mL) or inadequate . The rate of Ab decline was estimated with linear regression, using all sequential Ab tests over the first 6 months between vaccination and boosting. Analyses were stratified by vaccine type, HIV status and CD4 count in HIV+ ( >200 cells/µL cutoff).Out of 1979 patients, 869 completed their primary vaccinations, of whom 825 (95%) had ≥1 eligible Ab test . Overall, 83% had an adequate immune response to vaccination , with similar findings regardless of HIV status and CD4 count . In those with ≥2 Ab tests within six months between vaccination and boosting, Ab levels declined at a rate of 91 IU/mL per month . While some variation was observed, rates of Ab decay were generally consistent across vaccine, HIV status and CD4 count strata . Only 1/7 breakthrough COVID-19 infections occurred post booster (6 days later).In the pre-omicron era, primary COVID immunization with a mRNA vaccine generally yielded adequate Ab responses, although inadequate responses were observed in 19% of Pfizer, 6% of Moderna, and 49% of J&J vaccine recipients. Ab levels decreased at an average rate of 91 IU/mL per month after primary immunization. Variability in vaccine responses and Ab declines show the utility of measuring spike Ig Ab levels rather than using empiric time frames for booster guidance. Omicron-specific quantitative IgG neutralization levels must be established to inform preventative care.Ricky K. Hsu, MD, Gilead: Honoraria|Merck: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria Laurence Brunet, PhD, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck & Co: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Jennifer S. Fusco, BS, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck & Co.: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer.


The shift to antiretroviral single-tablet regimens (STR) from multiple-tablet regimens (MTR) has lagged for people living with HIV (PLWH) covered by Medicaid. This study examines STR and MTR utilization and pharmacy costs over a 5-year period for PLWH enrolled in Medicaid.This retrospective study used IQVIA’s Prescription Claims (Rx) data to identify two mutually exclusive cohorts based on STR or MTR use within each of 5 calendar years (2016-2020). For the STR cohort, the date of the first STR claim in each calendar year was termed the index date. For the MTR cohort, the date of the first MTR drug in the first observed complete MTR regimen in each calendar year was termed the index date; a window of 5 days between prescription fills for the agents used in an MTR regimen was allowed. The regimen received on the index date was used to assign the study cohort for each year and study measures were reported for each of the 5 calendar years. Additional eligibility criteria are provided in Table 1.The final STR cohort was 47,140  in 2016 and 73,111 (13.5%) in 2020 (Table 1). The final MTR cohort was 36,007 (15.5%) in 2016 and 20,264 (13.5%) in 2020. The distribution of PLWH with Medicaid Fee-For-Service (FFS) or Medicaid managed care was generally similar by year for both STR and MTR cohorts from 2016 to 2019 ; Medicaid managed care enrollment for both cohorts increased in 2020 (62.4-62.9%). Among PLWH, STR use increased annually from 56.7% in 2016 to 78.3% in 2020 . Conversely, MTR use decreased from 43.3% to 21.7% over the same time period. The increase in STR utilization over time was consistent for both plan types. Mean HIV-specific per member per month (PMPM) pharmacy costs were similar across years for both STR and MTR cohorts, ranging from $2,016-$2,342 for STR cohorts and $2,247-$2,380 for MTR cohorts .Between 2019 and 2020, PLWH enrolled in Medicaid shifted from FFS towards managed care. STR use among PLWH enrolled in Medicaid increased from 2016 to 2020 with minimal differences in PMPM pharmacy costs compared with PLWH enrolled in Medicaid receiving MTR.Andrew P. Brogan, PhD, ViiV Healthcare: Employee, Salary|ViiV Healthcare: Stocks/Bonds Cindy Garris, MS, ViiV Healthcare: Employee|ViiV Healthcare: Stocks/Bonds Julie Priest, MSPH, ViiV Healthcare: Employee, Salary|ViiV Healthcare: Stocks/Bonds Victoria Divino, BA, IQVIA: Employee, Salary|ViiV Healthcare: Grant/Research Support Jing He, PhD, IQVIA: Employee, Salary|ViiV Healthcare: Grant/Research Support Justin Chen, MHS, IQVIA: Employee, Salary|ViiV Healthcare: Grant/Research Support Mitch DeKoven, MHSA, IQVIA: Employee, Salary|ViiV Healthcare: Grant/Research Support.


Epetraborole (EBO) — an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria — is under clinical development for treatment of MAC lung disease. We conducted a Phase 1b dose-ranging study of EBO tablets in healthy adult volunteers, to inform dose selection in the treatment of MAC lung disease.In this double-blind, placebo-controlled trial, EBO or placebo tablets were administered  at dosages of 250-1000 mg q24h or 500 mg or 1000 mg q48h for up to 28 days. Standard Ph1 clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Based on prior human studies using significantly higher EBO daily doses, gastrointestinal (GI) events and anemia were predetermined AEs of special interest (AESIs). Plasma concentrations of EBO were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods.max and AUC0-∞ of EBO increased in a linear, dose-proportional manner across cohorts. Tmax was observed at ∼1 h post dose; mean t1/2 ranged from 7.63 to 11.1 h.A total of 43 subjects were enrolled; the 1000 mg q24h cohort was terminated early due to local COVID restrictions. Overall, 80.6% EBO subjects and 83.3% placebo subjects experienced ≥1 TEAE, none of which was serious or severe (Table). Most TEAEs were mild in severity (90%), and the remainder were moderate (10%). No TEAE leading to withdrawal from study was reported. The most frequent types of TEAEs were GI events , the most common being mild nausea. Two subjects had premature discontinuation of EBO due to a TEAE (asymptomatic liver enzyme elevations in a 250 mg q24h subject and mild nausea in a 1000 mg q48h subject). One 1000mg q24h subject had a TEAE of anemia. No clinically significant findings or TEAEs were observed for physical examinations, ECGs, or urine laboratory tests. Plasma COral EBO administered for 28-day dosing was generally well tolerated at the predicted therapeutic dose (500mg q24h)Predictable PK characteristics facilitate its use in MAC lung diseaseFurther evaluation in a Phase 2/3 treatment-refractory MAC lung disease study is plannedPaul B. Eckburg, MD, Paratek Pharmaceuticals, Inc.: Safety Review Board|Spero Therapeutics, Inc.: Advisor/Consultant Sanjay Chanda, PhD, AN2 Therapeutics: Stocks/Bonds George Talbot, MD, AN2 Therapeutics, Inc.: Advisor/Consultant|AN2 Therapeutics, Inc.: Co-founder Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support.


Hospitalized COVID-19 patients with severe pneumonia are commonly treated for secondary bacterial pneumonia. The Biofire pneumonia panel, a rapid molecular diagnostic tool with 18 bacterial, 8 viral and 7 resistance gene targets, was made available to critical care and infectious disease clinicians in May 2020 at our institution. We sought to describe its utilization and influence on antibiotic use in patients hospitalized with COVID-19 lower respiratory tract infection (LRTI).Eligible patients with COVID-19 LRTI  had sputum or bronchoalveolar lavage pneumonia panel (PNP) paired with a respiratory tract culture between May 4 and Dec. 8, 2020, were included. Demographics, comorbidities, clinical data including microbiologic testing, PNP indication(s), and antibiotic use after testing were abstracted through chart review. Descriptive statistics were utilized.Staphylococcus aureus was the most common bacterial isolate identified  with culture growth in 21 specimens. More than 1 target was identified in 29 patients (22%). Empiric antibiotics and subsequent modifications within 24h hours of pneumonia panel are provided in Table 3. Vancomycin and cefepime were most frequently prescribed. Antibiotic modifications were made in 71/133 patients. Cessation of the anti-MRSA agent occurred in 39/72 (54%) of eligible patients and the anti-Pseudomonal agent in 21/78 (27%).Characteristics of 133 patients are provided in Table 1. Median age was 61 years, 93 (70%) were male, 93 (70%) were mechanically ventilated, and 68 (51%) died within 30 days on PNP testing. PNP results, including culture results are listed in Table 2. No target was identified in 63 (47%) patients. The PNP is a useful tool to evaluate secondary bacterial pneumonia in critically ill COVID-19 patients and may assist clinicians and antimicrobial stewardship programs in expedited antibiotic discontinuation or de-escalation particularly where rates of secondary bacterial infection are low, such as COVID-19 LRTI.Erica J. Stohs, MD, MPH, bioMerieux: Grant/Research Support Paul D. Fey, PhD, BioFire: Advisor/Consultant|BioFire: Grant/Research Support|Merck: Grant/Research Support Trevor C. Van Schooneveld, MD, bioMerieux: Advisor/Consultant|bioMerieux: Grant/Research Support|Insmed: Grant/Research Support|Merck: Grant/Research Support|Thermo-Fischer: Advisor/Consultant.


Escherichia coli, most commonly due to production of an extended spectrum beta-lactamase (ESBL), and lead to increased morbidity and mortality. Pulsed Xenon Ultraviolet light (PX-UV), in combination with terminal cleaning, has been shown to improve disinfection and has the potential to lower HAIs by reducing the horizontal spread of infections in hospitals. Here, we assess the effect of PX-UV on the clonal recovery pattern of several E. coli sequence types (STs) using Whole Genome Sequencing (WGS).Healthcare-associated infections (HAIs) can be caused by some multidrug-resistant E. coli samples were collected. WGS of the isolates was performed using the Nextseq 550 (Illumina). After de novo assembly, BioNumerics calculation engine (v7.6) was used to complete Whole Genome Multilocus Sequence Type (wgMLST) analysis, assembly free and assembly-based call, and construction of minimum spanning tree (MST).A prospective, sham-controlled, double-blinded, interventional, crossover trial was conducted to compare standard terminal cleaning with PX-UV  and standard terminal cleaning with sham UV  in 2 Detroit hospitals from 2017 to 2020. Treatments lasted 12 months before crossover, with a 6-month washout period in between (Group R) during which UV was not used. A total of 67 The total number of different STs found for the intervention UV device group (Q) and the sham UV device group (W) was 6 while the washout group (R) was 5. Out of the 9 total STs obtained, the most common was ST131 (Table 1). In Group Q, 11 of ST131 were found; 15 were found in Group W. During the washout period (R) 17 of ST131 were found. All other STs had 3 or less circulating clusters. After UV treatment ST1193, ST399, and ST7394 were not recovered.E. coli ST found in Detroit, which is consistent with previously published data stating ST131 as the predominant strain. While PX-UV has previously demonstrated effectiveness on decreasing bioburden, our data does not indicate any remarkable change in clonality and prevalence of E. coli STs after PX-UV use.During UV intervention 3 different STs  were not recovered, but there were negligible changes to the frequency of recovery of the other 6 STs as compared to sham UV treatment. ST131 was the dominant Piyali Chatterjee, PhD, AHRQ Grant # 1R03HS027667-01: Grant/Research Support|AHRQ Grant # 1R03HS027667-01: Central Texas Veterans Health Care System Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|GlaxoSmithKline plc.: Receiving symposia honoraria|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502|Merck: Advisor/Consultant|qpex: Advisor/Consultant|Shionogi: Grant/Research Support|Spero: Advisor/Consultant Chetan Jinadatha, MD, MPH, AHRQ R01 Grant-5R01HS025598: Grant/Research Support|EOS Surfaces: Copper Coupons and materials for testing.


We previously demonstrated frequent detection of HHV-6B DNA in bronchoalveolar lavage fluid (BALF) and its positive association with mortality in HCT recipients from 1992-2015 with lower respiratory tract disease (LRTD). Whether these findings remain pertinent in contemporary patients, the additive value of testing for viral gene transcription, and the correlation of HHV-6 detection in blood and BALF, are unknown.We conducted a prospective study of allogeneic HCT recipients undergoing BAL for LRTD within 120 days of HCT at three cancer centers from 2015-2019. We collected and tested paired blood and BALF for HHV-6B DNA by qPCR and HHV-6B mRNA (U38 and U90 gene transcripts) among DNA positive samples using RT-qPCR. We described the detection of HHV-6B DNA and mRNA in blood and BALF, generated receiver operating characteristic (ROC) curves to determine the ability of BALF HHV-6B DNA detection to predict HHV-6B mRNA detection, and analyzed the association of HHV-6B DNA detection with mortality.Figure 1). BALF HHV-6B DNA ≥ 218 copies/ml had an area under the curve of 0.93 for predicting detection of BALF viral mRNA . In turn, patients with BALF HHV-6B DNA ≥ 218 copies/mL had increased risk for mortality and death due to LRTD within 60 days after the BAL . This association remained after adjustment for age, oxygen use, and steroid use at the time of BAL in a multivariable Cox model .We enrolled 116 allogeneic HCT recipients who underwent 125 BALs. HHV-6B DNA was detected in 45 of 122 BALF (37%) compared to 19 of 124 (15%) plasma samples. Among the 45 BALF samples with HHV-6B DNA detected, either HHV-6B mRNA transcript was detected in 22 (49%) (HHV-6B was detected more frequently in BALF than plasma, suggesting compartment-specific reactivation. BALF HHV-6B DNA ≥ 218 copies/mL had high sensitivity and specificity for detection of viral gene transcription in BALF and was associated with increased mortality; this viral load is strikingly similar to the BALF viral load threshold of 251 copies/mL associated with mortality in our prior retrospective study. Together, these data suggest transcriptionally active HHV-6B is a clinically impactful pulmonary pathogen in contemporary HCT recipients.Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Alpana waghmare, MD, Allovir: Grant/Research Support|Ansun BioPharma: Grant/Research Support|Kyorin Pharmaceutical: Advisor/Consultant|Pfizer: Grant/Research Support|Vir/GSK: Grant/Research Support Geoffrey Hill, M.D., FRACP, FRCPA, Applied Molecular Transport: Grant/Research Support|Compass Therapeutics: Grant/Research Support|Generon Corporation: Advisor/Consultant|Heat Biologics: Grant/Research Support|iTeos Therapeutics: Advisor/Consultant|iTeos Therapeutics: Grant/Research Support|Laevoroc Oncology: Grant/Research Support|NapaJen Pharma: Advisor/Consultant|Neoleukin Therapeutics: Advisor/Consultant|Serplus Technology: Grant/Research Support|Syndax Pharmaceuticals: Grant/Research Support Danielle M. Zerr, MD MPH, AlloVir: Advisor/Consultant Sanjeet S. Dadwal, MD, FACP, FIDSA, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope: Advisor/Consultant|Aseptiscope: Stocks/Bonds|Astellas: Speaker's Bureau|Cidara: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Speaker's Bureau|Takeda: Speaker's Bureau Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support.


Beta-lactam therapeutic drug monitoring  can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM.This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands , and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks.Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety . Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics . Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development.We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM.Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Allecra: Grant/Research Support|Merck: Advisor/Consultant|Nevakar: Advisor/Consultant|Nevakar: Grant/Research Support|Premier Healthcare Solutions: Honoraria|Spero: Advisor/Consultant|SuperTrans Medical: Advisor/Consultant|SuperTrans Medical: Grant/Research Support|Takeda: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant.


The proportion of older adults living with HIV is growing, increasing the focus of managing age-related comorbidities and polypharmacy while maintaining virologic suppression. DTG/3TC is an international guidelines–recommended 2-drug regimen demonstrating high and durable efficacy, high barrier to resistance, and good safety and tolerability. We present pooled TANGO and SALSA efficacy and safety results analyzed by age .Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily DTG/3TC fixed-dose combination or continuing current antiretroviral regimen  were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 c/mL  and safety were analyzed by age.Of 1234 participants , 71% were aged < 50 years, 26% aged 50 to < 65 years, and 3% aged ≥ 65 years. At Week 48, in participants aged 50 to < 65 years, 1 (< 1%) and 3 (2%) participants in the DTG/3TC and CAR groups, respectively, had HIV-1 RNA ≥ 50 c/mL, comparable to results in the overall population (Table 1). No participants aged ≥65 years had HIV-1 RNA ≥ 50 c/mL. Proportions with HIV-1 RNA < 50 c/mL were high regardless of age group. Adjusted mean change from baseline in CD4+ cell count and CD4+/CD8+ ratio was also consistent with overall results regardless of age (< 50 vs ≥ 50 years). No participants in the DTG/3TC group had confirmed virologic withdrawal (CVW); 1 participant in the CAR group had CVW . Proportions of participants with baseline non-ART medication use and comorbidities increased with age in both treatment groups (Table 2). Across all age groups, proportions of any AEs were similar between the DTG/3TC and CAR groups, with few AEs leading to withdrawal and higher proportions of drug-related AEs with DTG/3TC vs CAR; similar results were observed in the overall population.Among PLWH, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile across all age groups, including those aged ≥65 years. As non-ART medication use and comorbidities increased with age, a well-tolerated 2-drug regimen may help older PLWH avoid drug interactions.Manyu Prakash, PhD, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare: Employee Richard Grove, MSc, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Brian R. Wynne, M.D., ViiV Healthcare: I am an employee|ViiV Healthcare: Stocks/Bonds Choy Man, BSc, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare: Employee Jean A. van Wyk, MBChB, MFPM, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare: Employee Clifford B. Jones, BSc MSc MB ChB, GSK: Stocks/Bonds|viiv healthcare: Employee Chinyere Okoli, MSc, DIP, ViiV Healthcare: I am an employee of ViiV healthcare|ViiV Healthcare: Stocks/Bonds Emilio Letang, MD, MPH, PhD, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare: Employee Mounir Ait-Khaled, PhD, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare: Employee Andrew Clark, MD, ViiV Healthcare: Employee|ViiV Healthcare: Stocks/Bonds.


Candida spp., with ∼7% of the bloodstream isolates tested at CDC resistant to fluconazole. We sought to determine if our targeted antifungal px in LT recipients remained effective in the era of rising azole resistance.Antifungal prophylaxis (px) in liver transplant (LT) recipients reduces invasive candidiasis (IC) and its associated mortality. Studies from our institution (UPMC) and others have shown that targeted px was as effective as universal px. Antifungal resistance has emerged among We performed a retrospective study of patients undergoing LT at UPMC between 11/2010 and 06/2021. IC episodes were included if they occurred within 6 months of transplant. IC was defined using EORTC/MSGERC criteria, 2020. CLSI’s M60 2nd edition was used for antifungal susceptibility interpretation. Px was with fluconazole or voriconazole, based on risk factors for yeast or mold infection, respectively .C. albicans and C. glabrata were the most common species . Sixteen isolates underwent susceptibility testing: 12% and 44% were resistant and S-DD to fluconazole ; none were resistant to voriconazole. Attributable mortality of IC was 8%.1065 patients (pts) underwent LT over the study period. The most common indications for LT were HCC and NASH cirrhosis. Thirty-four pts (3%) developed IC within six months. 74% and 65% of these pts had risk factors for yeast or mold infection at some point, respectively (Table 1). Twenty-five of 34 (73.5%) pts received antifungal px, with voriconazole most commonly. Sixteen pts with IC (47%) had living donor transplant, and 11 (32%) had Roux-en-Y anastomosis. Types of IC were intra-abdominal candidiasis in 19 (56%), fungemia in 11 (32%), and intra-abdominal IC with secondary fungemia in 4 (12%). Seventeen (50%) episodes were breakthrough (BT) IC (most BT occurred in the voriconazole group), eight (24%) developed after stopping px, and nine (26%) occurred in those without px (Table 2). Candida spp. We recommend antifungal susceptibility testing for Candida spp. obtained from infected sites to guide antifungal therapy.Targeted antifungal px in LT recipients with fluconazole or voriconazole effectively prevented IC, even in the era of rising azole resistance among Fernanda P. Silveira, MD, Ansun: Grant/Research Support|Janssen: Honoraria|Merck: Grant/Research Support|Novartis: Grant/Research Support|Regeneron: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Grant/Research Support.


The correct name is: Phunchai Charatcharoenwitthaya. The correct citation is: Pausawasdi N, Hongsrisuwan P, Chalermwai WV, Butt AS, Maipang K, Charatcharoenwitthaya P (2022) The diagnostic performance of combined conventional cytology with smears and cell block preparation obtained from endoscopic ultrasound-guided fine needle aspiration for intra-abdominal mass lesions. PLoS ONE 17(3): e0263982.


The primary driver of costs for C/IC pts is hospital length of stay. Studies across multiple infections demonstrate that most clinically stable pts with modest diagnostic & therapeutic requirements can be safely discharged prior to actual HD day. Few studies have assessed if there is an opportunity to accelerate time to HD in pts with C/IC. This study sought to determine the proportion of US hospitalized adult pts with C/IC who received an EC near HD & was potentially eligible for an earlier HD.Candida sp. on a culture consistent with C/IC; ≥3 days of an EC for C/IC; discharged alive; & received an EC near HD (-2 day to HD day). Pts were considerable potentially dischargeable if they met the following 3 criteria & maintained these 3 criteria until HD: resided on a non-ICU hospital ward, taking oral medications, & had no receipt of any diagnostic/therapeutic interventions (insertion of PICC lines were permitted). The difference in hospital days between first potentially eligible HD day & actual HD day was quantified. The proportion of pts that was potentially eligible for an earlier HD was examined overall & by Charlson Comorbidity index (CCI), C/IC, & Candida sp.Design: Retrospective, multi-centered observational study using Premier Healthcare Database (1/2016-4/2019). Study criteria: hospitalized; age ≥ 18 years; C. glabrata (31%) & C. albicans (31%) were the most frequent Candida. sp. Of the 1,008 pts on an EC near HD, 14%, 21%, 29%, & 38% were potentially dischargeable 4, 3, 2, & 1 day(s), respectively, prior to the actual HD day . The proportion of pts who were potentially eligible for HD at least 2 days prior to actual HD day did not vary by CCI score, C/IC, & Candida sp.During study period, 1,599 pts received an EC ≥ 3 days for C/IC & were discharged alive. Of the 1,599 pts, 1,008 (63%) were on an EC near HD. For the 1,008 pts on an EC near HD, the mean (SD) age was 59 (16) years, 52% were male, 40% had a CCI ≥4, 35% were in the ICU on index C/IC culture day, & 64% had C vs IC. Candida sp.Our findings suggest that a high proportion of hospitalized pts with C/IC receiving an EC near the time of HD, had modest diagnostic/therapeutic requirements prior to actual HD day & were potentially eligible for an earlier HD regardless of CCI, infection type, or Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Brian H. Nathanson, Ph.D., cidara: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support.


Eravacycline, a novel synthetic fluorocycline, is structurally similar to tigecycline. Cases of tigecycline associated hyperfibrinogenemia have been reported in the literature, however the mechanism is not currently well described. At this time it is unknown if this is a class effect.Mycobacterium abscessus (M.abscessus) who received regular fibrinogen monitoring are described.Two cases of patients on eravacycline for treatment of M.abscessus with positive cultures from the lung and blood. Eravacycline 1 mg/kg BID (80 mg) was started on D1 and continued through D24. Fibrinogen levels on D1 was 448 mg/dl and on D23 were 120 mg/dl. Eravacycline was stopped and fibrinogen returned to normal range (228 mg/dl) in 5 days. Eravacycline was re-trialed at 80 mg BID and fibrinogen level on D1 was 310 mg/dl and 147 mg/dl on D8. No repeat fibrinogen levels were obtained. Patient 2 was a lung transplant recipient (2019) admitted for treatment of M.abscessus skin and soft tissue infection. The patient was started on eravacycline 1 mg/kg BID (90 mg) due to concerns of hypofibrinogenemia from tigecycline. On D1 of eravacycline fibrinogen was 167 mg/dl , on D19 of therapy fibrinogen was 64 mg/dl and eravacycline was stopped. Fibrinogen level returned to normal 3 days after eravacycline discontinuation (212 mg/dl).Patient 1 received a kidney transplant (2010) and was admitted for acute hypoxic respiratory failure secondary to COVID-19. Their course was complicated by multiple infections including disseminated Similar to tigecycline, we observed eravacycline related hypofibrinogenemia. Time to onset was variable in the two cases presented. Hypofibrinogenemia was readily reversible, within 3-5 days, with drug withdrawal and reproducible in one patient with re-challenge of eravacycline. Further analysis into eravacycline related hypofibrinogenemia and its impact on coagulation outcomes are warranted based on these reports.David van Duin, MD, PhD, Achaogen: Advisor/Consultant|Allergan: Advisor/Consultant|Astellas: Advisor/Consultant|MedImmune: Advisor/Consultant|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|NeuMedicine: Advisor/Consultant|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|T2 Biosystems: Advisor/Consultant|Tetraphase: Advisor/Consultant.


Science. 2019; 363:288). To characterize the nature of antibody protection against CMV after HCT, we tested pre-HCT sera in a cohort of CMV D-R+ allogeneic HCT recipients from the pre-letermovir era using VirScan, a technology that measures pathogen-specific humoral immunity (IgG) at the epitope level.There is renewed interest in CMV-specific humoral immune protection due to recent murine data suggesting that strain-specific antibodies may inhibit CMV cell-to-cell spread  in the first 8 weeks post-HCT.Patients (age 0-70 years) who received 1Figure 1) and the effect appeared more pronounced in adults . High (≥ 4th quartile vs. 1st quartile), pre-HCT CMV antibody epitopes were associated with an increased risk of any CMV reactivation  and at >150 IU/mL  after adjusting for age, HLA-matching, and pre-HCT T-cell depletion ( >150 IU/mL only).170 CMV D-R+ HCT recipients were tested a median of 26 days (range 7-37 days) prior to HCT and had a median of 37 CMV antibody epitopes . The cumulative incidence of CMV reactivation was higher in patients with greater pre-HCT CMV antibody epitopes at each evaluated PCR threshold (We observed a paradoxically increased risk of CMV reactivation in patients with high pre-HCT CMV VirScan scores. It is possible that pre-HCT CMV-specific humoral immunity as measured by VirScan is reflective of the burden of latent CMV or that CMV-specific antibodies may mediate antibody-dependent enhancement after HCT and thus facilitate reactivation. Future studies are needed to validate our findings in diverse cohorts and to elucidate the underlying mechanism of increased VirScan scores and associated risks of CMV reactivation.Rachel A. Bender Ignacio, MD, MPH, Abbvie: Advisor/Consultant|SeaGen: Advisor/Consultant Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Geoffrey Hill, M.D., FRACP, FRCPA, Applied Molecular Transport: Grant/Research Support|Compass Therapeutics: Grant/Research Support|Generon Corporation: Advisor/Consultant|Heat Biologics: Grant/Research Support|iTeos Therapeutics: Advisor/Consultant|iTeos Therapeutics: Grant/Research Support|Laevoroc Oncology: Grant/Research Support|NapaJen Pharma: Advisor/Consultant|Neoleukin Therapeutics: Advisor/Consultant|Serplus Technology: Grant/Research Support|Syndax Pharmaceuticals: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support.


During the COVID-19 pandemic, social interventions such as social distancing and mask wearing have been encouraged. Social risk factors for SARS-CoV-2 infection and subsequent hospitalization remain uncertain.Adult patients were eligible if admitted to Emory University Hospital or Emory University Hospital Midtown with acute respiratory infection (ARI) symptoms (≤ 14 days) or an admitting ARI diagnosis from May 2021 – Feb 2022. After enrollment, an in-depth interview identified demographic and social factors , household characteristics, and pandemic social behaviors. All patients were tested for SARS-CoV-2 using PCR. We evaluated whether these demographic and social factors were related to a positive SARS-CoV-2 test upon admission to hospital with ARI using a logistic regression model.1141 subjects were enrolled and had SARS-CoV-2 PCR results available (700 positive and 441 negative). The median age was greater in the SARS-CoV-2 negative cohort than in the positive cohort . Those who tested positive were more likely to have had at least some college education compared to those who tested negative . Compared to those who tested negative, those who were SARS-CoV-2 positive were also more likely to be employed , have children 5-17 yo at home . Those with COVID-19 were less likely to receive home healthcare  and to be a current or previous smoker .Among adults admitted to the hospital for ARI, those who tested positive for SARS-CoV-2 were typically younger, more likely to care for school-aged children, more likely to work outside the home, but were less likely to receive home healthcare or smoke. Personal and public health strategies to mitigate COVID-19 should take into consideration modifiable social risk factors.Laura A. Puzniak, PhD. MPH, Merck & Co., Inc.: Stocks/Bonds|Pfizer, Inc.: Stocks/Bonds Robin Hubler, MS, Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds Srinivas Valluri, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Benjamin Lopman, PhD, Epidemiological Research and Methods, LLC: Advisor/Consultant Satoshi Kamidani, MD, NIH: His institution (Emory University) receives funds from Pfizer for his work as a co-investigator on clinical trials of Pfizer COVID-19 vaccine.|Pfizer: His institution (Emory University) receives funds from Pfizer for his work as a co-investigator on clinical trials of Pfizer COVID-19 vaccine. Christina A. Rostad, MD, BioFire Inc, GSK, MedImmune, Micron, Merck, Novavax, PaxVax, Pfizer, Regeneron, Sanofi-Pasteur.: Grant/Research Support|Meissa Vaccines, Inc.: Co-inventor of RSV vaccine technology licensed to Meissa Vaccines, Inc.|NIH : Grant/Research Support John M. McLaughlin, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Evan J. Anderson, MD, GSK: Advisor/Consultant|GSK: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kentucky Bioprocessing, Inc: Data Safety Monitoring Board|MedImmune: Grant/Research Support|Medscape: Advisor/Consultant|Merck: Grant/Research Support|Micron: Grant/Research Support|NIH: Funding from NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines|PaxVax: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support|Sanofi Pasteur: Data Adjudication and Data Safety Monitoring Boards|WCG and ACI Clinical: Data Adjudication Board.