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LINE-1 (L1) is a parasitic retrotransposable DNA element, active in primates for the last 80-120 Myr. L1 has generated nearly one-third of the human genome by copying its transcripts, and those of other genetic elements (e.g. Alu and SVA), into genomic DNA by target site-primed reverse transcription (TPRT) and remains active in modern humans. L1 encodes two proteins that bind their encoding transcript (cis preference) to form an L1 ribonucleoprotein (RNP) that mediates retrotransposition. ORF2p provides reverse transcriptase and endonuclease activity. ORF1p, its major component, is a homo-trimeric phospho-protein that binds single-stranded nucleic acid (ssNA) with high affinity and exhibits nucleic acid (NA) chaperone activity. We used optical tweezers to examine ORF1p binding to individual single-stranded DNA (ssDNA) molecules and found that the arrangement of ORF1p on the ssDNA depends on their molar ratio. When the concentration of ORF1p is just sufficient to saturate the entire NA molecule, the nucleoprotein (NP) is compact and stable. However, additional ORF1p binds and destabilizes the compacted NP, allowing it to engage a second ssDNA. Our results suggest that ORF1p displaced from its RNA template during TPRT could bind and destabilize remaining downstream L1 RNP, making them susceptible to hijacking by non-L1 templates, and thereby enable retrotransposition of non-L1 transcripts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Moderate secondary mitral regurgitation (SMR) represents a subgroup of heart failure (HF) patients with treatment restricted to medical therapy. Outcomes in patients with moderate SMR treated with mitral transcatheter edge-to-edge repair (M-TEER) are less well known., Objectives: The aim of this study was to assess the safety and effectiveness of M-TEER in subjects with moderate SMR using the EXPANDed studies., Methods: One-year outcomes in subjects from the EXPANDed studies (EXPAND [A Contemporary, Prospective Study Evaluating Real-world Experience of Performance and Safety for the Next Generation of MitraClip Devices] and EXPAND G4 [A Post-Market Study Assessment of the Safety and Performance of the MitraClip G4 System] MitraClip studies) with baseline moderate SMR (2+), per echocardiographic core laboratory (ECL) assessment, were compared with subjects with baseline severe SMR (≥3+)., Results: There were 335 subjects with moderate SMR and 525 with severe SMR at baseline per ECL review. Baseline characteristics were similar between the 2 subgroups. After treatment with M-TEER, significant MR reduction was achieved in both groups. Significant left ventricular (LV) reverse remodeling was observed through 1 year, with a >20 mL decrease in LV end-diastolic and end-systolic volumes on average in the moderate SMR group. Significant 1-year improvements in NYHA functional class (>78% NYHA functional class I or II) and quality of life (>20 points on the Kansas City Cardiomyopathy Questionnaire-Overall Summary) were observed in subjects with moderate SMR. Similarly, low rates of major adverse events, all-cause mortality, and HF hospitalizations were observed between the 2 subgroups through 1 year., Conclusions: In the EXPANDed studies, subjects with moderate SMR treated with M-TEER had improvements similar to subjects with severe SMR in quality of life and positive LV remodeling at 1 year. Future studies are needed to evaluate if M-TEER would be beneficial for HF patients with moderate SMR., Competing Interests: Funding Support and Author Disclosures The EXPAND (NCT03502811) and EXPAND G4 (NCT04177394) studies were funded and sponsored by Abbott. Dr Asgar is a consultant to Abbott Structural Heart, Medtronic, Edwards Lifesciences, W.L. Gore, and Anteris Technologies. Dr Tang has received speaker honoraria and served as a physician proctor, consultant, advisory board member, TAVR publications committee member, APOLLO trial screening committee member, and IMPACT MR steering committee member for Medtronic; has received speaker honoraria and served as a physician proctor, consultant, advisory board member, and TRILUMINATE trial anatomic eligibility and publications committee member for Abbott Structural Heart; has served as an advisory board member for Boston Scientific and JenaValve; has served as a consultant and physician screening committee member for Shockwave Medical; has served as a consultant for NeoChord, Peija Medical, and Shenqi Medical Technology; and has received speaker honoraria from Siemens Healthineers. Dr Rogers is a consultant to Abbott Structural Heart, Biosense Webster, and Boston Scientific. Dr Rottbauer has received consulting fees/speaker honoraria from Abbott, Bayer Healthcare, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, and Medtronic; and is a member of the steering committee of the EXPAND G4 study for Abbott and Encourage AF study for Daiichi Sankyo. Dr Morse is a consultant for Edwards Lifesciences. Dr Denti has received speaker honoraria from Abbott and Edwards Lifesciences; and has been a consultant to InnovHeart, Artiness, and Pi-Cardia. Dr Mahoney is a consultant and proctor for Medtronic, Edwards Lifesciences, and Boston Scientific; is a consultant for Abbott; and has been awarded research grants from Edwards Lifesciences, Medtronic Abbott, and Boston Scientific. Dr Rinaldi has been awarded honoraria and/or consulting fees from Abbott, Boston Scientific, and Edwards Lifesciences. Dr Asch’s work as an academic core laboratory director is performed through institutional research grants (MedStar Health) with Abbott, Boston Scientific, Medtronic, Edwards Lifesciences, Neovasc, Ancora Heart, LivaNova, MVRx, InnovHeart, Polares Medical, and Aria CV. Dr Zamorano has received speaker honoraria from Pfizer, Amgen, and Daiichi Sankyo; and research grants from Abbott and Edwards Lifesciences. Dr Dong and Ms Huang are employees of Abbott Structural Heart. Dr Lindenfeld has been a consultant for Abbott, Alleviant, AstraZeneca, Biotronik, Boston Scientific, CVRx, Edwards Lifesciences, Merck, Medtronic, V-Wave, Vascular Dynamics, WhiteSwell, and Vectorious; and receives research funding from AstraZeneca. Dr Maisano has received grants and/or institutional research support from Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific, NVT, and Terumo; has received honoraria and consulting fees (personal and institutional) from Abbott, Medtronic, Edwards Lifesciences, Xeltis, and Cardiovalve; has received royalty income and intellectual property rights from Edwards Lifesciences; and is a shareholder (including stock options) of CardioGard, Magenta, SwissVortex, Transseptal Solutions, Occlufit, 4Tech, and Perifect. Dr von Bardeleben has performed nonpaid trial activities for Abbott, Edwards Lifesciences, Medtronic, and the University of Göttingen (IIT); and serves as an advisory board or speaker bureau member for Abbott Cardiovascular Edwards Lifesciences, Medtronic, and NeoChord. Dr Kar has received grants and institutional research support from Abbott, Boston Scientific, and Edwards Lifesciences; has received consulting fees/honoraria from Abbott, Boston Scientific, W.L. Gore, and Medtronic; served as a steering committee member of the TRILUMINATE study (Abbott) and as national principal investigator of the EXPAND study and the REPAIR MR study for Abbott. Dr Rodriguez has been awarded grants and support for research from Abbott, Edwards Lifesciences, Boston Scientific, AtriCure, and CardioMech; and has received honoraria or consulting fees from Abbott, Edwards Lifesciences, Philips, Teleflex, and CardioMech., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL)., Patients/methods: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4 + T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification., Results: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4 + T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4 + cells/µL (P = .95)., Conclusion: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL., Competing Interests: Disclosure KL and RR: Bristol Myers Squibb-Celgene, Merck, EMD-Serono, Eli Lilly, Janssen, Lentigen, and CTI BioPharma research support through CRADAs with the NCI. DBJ: BMS, Catalyst Biopharma, Iovance, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko—advisory boards or consultancy; BMS and Incyte—research funding. NAW: ChemoCentryx—consultancy and speaker honoraria CK: Ad board/Consulting fee: Novartis, Regeneron, Janssen, Eisai, Daiichi Sankyo, Jazz Pharmaceuticals, Arcus Biosciences, Mirati Therapeutics, Sanofi, Diffuse Pharmaceuticals; Grant Support: Blueprint Medicines, Bristol-Myers Squibb, Daiichi Sankyo, Inc., Debiopharm, Genentech, Inc., Janssen, Karyopharm, Lyell, Novartis Pharmaceuticals, Regeneron, Spectrum TF: ADC therapeutics—speakers bureau; Astrazeneca—Consultancy and Speakers Bureau; Daiichi—Speakers Bureau; Sankyo—Speakers Bureau; Genmab—Consultancy and Speakers Bureau; Karyopharm—Speakers Bureau; Kite/Gilead—Honoraria and Speakers Bureau; MorphoSys—Speakers Bureau; Secura Bio—Speakers Bureau; Juno/Bristol Myers Squibb (BMS)—Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Celgene Corporation—Membership on an entity's Board of Directors or advisory committees; Janssen—Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC/Janssen—Honoraria and Membership on an entity's Board of Directors or advisory committees; Seattle Genetics—Membership on an entity's Board of Directors or advisory committees and Research Funding; Takeda—Honoraria, Membership on an entity's Board of Directors or advisory committees and travel expenses; Abbvie—Consultancy and Honoraria; Seagen—Consultancy, Honoraria, travel expenses, and Speakers Bureau; Bayer—honoraria; Portola Pharmaceuticals—research funding; Eisai—research funding; Kyowa Kirin—research funding; Amgen—research funding; Viracta Therapeutics—research funding; Cell Medica—research funding; Roche—research funding; Trillium Therapeutics—research funding; Pfizer—research funding AD: Athos Therapeutics—Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees and Patents & Royalties; Attica Sciences—Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees and Patents & Royalties; Dyania Health—Consultancy, Current Employment and stocks; Urogen Pharma- Stocks; Alimera Sciences—stocks; Kyn Therapeutics—stocks; Moderna Therapeutics—stocks; Proteas Bioanalystics—stocks and patents and royalties; BMS—consultancy and research funding; AstraZeneca—Consultancy, Other: Travel, accommodations, expenses and Research Funding; Radmetric—consultancy; Seagen—Consultancy and travel, accommodations, expenses; Janssen—consultancy; PACT Pharma—consultancy; Merck—Consultancy and Research Funding; Roche/Genentech—Consultancy and Research Funding; Exelixis—consultancy; Aveo—consultancy; Kite/Gilead—research funding; Jounce Therapeutics—Research funding; Infinity Pharmaceutics—research funding; Seattle Genetics/Astellas—research funding; Immunomedics/Gilead—research funding; Harvard Medical School—patents and royalties to spouse; UCLA—patents and royalties to spouse; Eli Lilly—travel, accommodations, expenses MM: Genentech/Roche—honoraria and speakers bureau, Novartis—honoraria, Sanofi—honoraria, Lexicon—honoraria and Research Funding, Ipsen—Honoraria and Speakers Bureau, Bayer—honoraria, Taiho Pharmaceutical—Honoraria and speakers bureau, Boehringer Ingelheim—honoraria, Eisai—Honoraria, Research Funding and Speakers Bureau, Merck—Honoraria and Research Funding, Exelixis—Honoraria and Speakers Bureau, AstraZeneca/Daiichi Sankyo—Honoraria and Speakers Bureau, Servier—Honoraria and Speakers Bureau, Tersera—Honoraria, QED Therapeutics—Honoraria, Precision Biologics—Research Funding, BMS—research funding, Onyx—research funding, Advanced Accelerator Applciations—research funding, AlphaVax—Research Funding, Duke University—Patents and Royalities DBJ: Advisory boards/consultancy: BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko; Research funding: BMS and Incyte AM: Research funding: Nektar, Tracon Pharma, Regeneron, Tempu slabs; Consultancy and research funding: SpringWorks Therapeutics; Honoraria: Targeted Oncology CD: Advisory Board: GenMab; BeiGene; ADC Pharmaceuticals Research funding: Genentech; Seagen; Astrazeneca AL: Advisory Board—Seagen, Kite Pharma; Consultancy—Research to Practice GS: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma; Consultant/Scientific Advisory Board (SAB): Suba Therapeutics, Syapse, Servier, Merck Research Support to institution: Sanofi (iaward), Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics; Speaker: BIO—INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer; Data safety monitoring committee honorarium: Mereo; Employment: Spouse employed by Myriad; Writing/Editor fees: Uptodate, Onviv PR: research funding (to institution)—Lilly, Bayer, Telix; speaker's fees—OncLive ARN: Funding to Institution for Trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals; Consultant Editor Compensation: JCO Precision Oncology; Travel Compensation from: SITC/ AACR/ Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences; Advisory Board : Foundation Med AFH: Bristol Myers Squibb—research funding, consultancy; Genentech—research funding, consultancy; Merck—research funding, consultancy; Seattle Genetics—research funding, consultancy; KiTE Pharma—research funding; Gilead Sciences—research funding; AstraZeneca—research funding, consultancy; Karyopharm—consultancy; ADC Therapeutics—research funding, consultancy; Takeda—consultancy; Tubulis—consultancy; Regeneron—consultancy; Genmab—consultancy; Pfizer—consultancy; Caribou Biosciences—consultancy; Adicet Bio—consultancy; Abbvie—consultancy; Allogene Therapeutics—consultancy All other authors have nothing to disclose., (Published by Elsevier Inc.)

The HIV-1 nucleocapsid protein (NC) is a multifunctional viral protein necessary for HIV-1 replication. Recent studies have demonstrated that reverse transcription (RT) completes in the intact viral capsid, and the timing of RT and uncoating are correlated. How the small viral core stably contains the ~10 kbp double stranded (ds) DNA product of RT, and the role of NC in this process, are not well understood. We showed previously that NC binds and saturates dsDNA in a non-specific electrostatic binding mode that triggers uniform DNA self-attraction, condensing dsDNA into a tight globule against extending forces up to 10 pN. In this study, we use optical tweezers and atomic force microscopy to characterize the role of NC's basic residues in dsDNA condensation. Basic residue mutations of NC lead to defective interaction with the dsDNA substrate, with the constant force plateau condensation observed with wild-type (WT) NC missing or diminished. These results suggest that NC's high positive charge is essential to its dsDNA condensing activity, and electrostatic interactions involving NC's basic residues are responsible in large part for the conformation, size, and stability of the dsDNA-protein complex inside the viral core. We observe DNA re-solubilization and charge reversal in the presence of excess NC, consistent with the electrostatic nature of NC-induced DNA condensation. Previous studies of HIV-1 replication in the presence of the same cationic residue mutations in NC showed significant defects in both single- and multiple-round viral infectivity. Although NC participates in many stages of viral replication, our results are consistent with the hypothesis that cationic residue mutations inhibit genomic DNA condensation, resulting in increased premature capsid uncoating and contributing to viral replication defects.

Bacteriophage T4 gene 32 protein (gp32) is a single-stranded DNA (ssDNA) binding protein essential for DNA replication. gp32 forms stable protein filaments on ssDNA through cooperative interactions between its core and N-terminal domain. gp32's C-terminal domain (CTD) is believed to primarily help coordinate DNA replication via direct interactions with constituents of the replisome. However, the exact mechanisms of these interactions are not known, and it is unclear how tightly-bound gp32 filaments are readily displaced from ssDNA as required for genomic processing. Here, we utilized truncated gp32 variants to demonstrate a key role of the CTD in regulating gp32 dissociation. Using optical tweezers, we probed the binding and dissociation dynamics of CTD-truncated gp32, *I, to an 8.1 knt ssDNA molecule and compared these measurements with those for full-length gp32. The *I-ssDNA helical filament becomes progressively unwound with increased protein concentration but remains significantly more stable than that of full-length, wild-type gp32. Protein oversaturation, concomitant with filament unwinding, facilitates rapid dissociation of full-length gp32 from across the entire ssDNA segment. In contrast, *I primarily unbinds slowly from only the ends of the cooperative clusters, regardless of the protein density and degree of DNA unwinding. Our results suggest that the CTD may constrain the relative twist angle of proteins within the ssDNA filament such that upon critical unwinding the cooperative interprotein interactions largely vanish, facilitating prompt removal of gp32. We propose a model of CTD-mediated gp32 displacement via internal restructuring of its filament, providing a mechanism for rapid ssDNA clearing during genomic processing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

HIV-1 cores, which contain the viral genome and replication machinery, must disassemble (uncoat) during viral replication. However, the viral and host factors that trigger uncoating remain unidentified. Recent studies show that infectious cores enter the nucleus and uncoat near the site of integration. Here, we show that efficient uncoating of nuclear cores requires synthesis of a double-stranded DNA (dsDNA) genome >3.5 kb and that the efficiency of uncoating correlates with genome size. Core disruption by capsid inhibitors releases viral DNA, some of which integrates. However, most of the viral DNA is degraded, indicating that the intact core safeguards viral DNA. Atomic force microscopy and core content estimation reveal that synthesis of full-length genomic dsDNA induces substantial internal strain on the core to promote uncoating. We conclude that HIV-1 cores protect viral DNA from degradation by host factors and that synthesis of long double-stranded reverse transcription products is required to trigger efficient HIV-1 uncoating.

Purpose: Hypomagnesemia is a common side effect of platinum-based chemotherapy and predicts poor overall survival in some cancers. Standard magnesium replacement strategies are often inadequate for maintaining magnesium levels. We hypothesized that a daily dietary magnesium replacement approach through magnesium-rich foods would help maintain adequate magnesium levels during platinum-based treatment., Materials and Methods: We conducted a prospective feasibility study of magnesium-rich diets in patients 18 years and older with previously untreated ovarian cancer scheduled to receive carboplatin-containing chemotherapy of at least six consecutive cycles. Education about magnesium-rich diets was provided at enrollment and then weekly during chemotherapy. Feasibility was defined as ≥60% completion of dietary recalls and ≥280 mg average daily dietary magnesium intake across all patients., Results: Twenty-one of 26 patients enrolled completed at least five chemotherapy cycles and were included in the analysis. Adherence to the study diet was 76%. Daily dietary magnesium intake was 100.5 mg at baseline and increased throughout each cycle: 6% of patients at baseline, 24% after the first cycle, and 67% after the fifth cycle reached ≥280-mg/day magnesium intake. Seven (33%) of 21 had at least one incident of hypomagnesemia. Patients who were adherent had significantly lower incidence of hypomagnesemia (19% v 80%, P = .03) and less need for intravenous magnesium (6% v 60%, P = .03) than those who were nonadherent., Conclusion: The study achieved primary feasibility objectives of retention and adherence to the study intervention. Weekly education about magnesium-rich diets was effective in increasing dietary magnesium intake. Adequate dietary magnesium appeared to be protective against hypomagnesemia.

Legionnaires' disease (LD) is a severe form of pneumonia (∼10-25% fatality rate) caused by inhalation of aerosols containing Legionella , a pathogenic gram-negative bacteria. These bacteria can grow, spread, and aerosolize through building water systems. A recent dramatic increase in LD incidence has been observed globally, with a 9-fold increase in the United States from 2000 to 2018, and with disproportionately higher burden for socioeconomically vulnerable subgroups. Despite the focus of decades of research since the infamous 1976 outbreak, substantial knowledge gaps remain with regard to source of exposure and the reason(s) for the dramatic increase in LD incidence. Here, we rule out factors indicated in literature to contribute to its long-term increases and identify a hitherto unexplored explanatory factor. We also provide an epidemiological demonstration that the occurrence of LD is linked with exposure to cooling towers (CTs). Our results suggest that declining sulfur dioxide air pollution, which has many well-established health benefits, results in reduced acidity of aerosols emitted from CTs, which may prolong the survival duration of Legionella in contaminated CT droplets and contribute to the increase in LD incidence. Mechanistically associating decreasing aerosol acidity with this respiratory disease has implications for better understanding its transmission, predicting future risks, and informed design of preventive and interventional strategies that consider the complex impacts of continued sulfur dioxide changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Purpose of Review: After a cancer diagnosis, patients ask what they can do in addition to the recommended treatments to increase their survival. Many turn to integrative medicine modalities and lifestyle changes to improve their chances of survival. Numerous studies have demonstrated that lifestyle changes can significantly improve survival rates for cancer patients. Less support exists for the use of natural products or supplements to improve cancer survival. In this manuscript, we review key findings and evidence in the areas of healthy eating habits, physical activity, stress management and social support, and sleep quality, as well as natural products and supplements as they relate to the cancer recurrence and survival., Recent Findings: While more research is needed to fully understand the mechanisms underlying the associations between lifestyle changes and cancer survival, findings suggest that lifestyle modifications in the areas of diet, physical activity, stress management and social support, and sleep quality improve clinical cancer outcomes. This is especially true for programs that modify more than one lifestyle habit. To date, outside of supplementing with vitamin D to maintain adequate levels, conflicting conclusion within the research remain regarding the efficacy of using natural products or supplement to improve cancer recurrence of disease or cancer survival. A call for further research is warranted. Lifestyle screening and counseling should be incorporated into cancer treatment plans to help improve patient outcomes. While the scientific community strives for the pursuit of high-quality research on natural products to enhance cancer survival, transparency, dialogue, and psychological safety between patients and clinicians must continue to be emphasized. Proactive inquiry by clinicians regarding patients' supplement use will allow for an informed discussion of the benefits and risks of natural products and supplements, as well as a re-emphasis of the evidence supporting diet and other lifestyle habits to increase survival., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chloroquine has been used as a potent antimalarial, anticancer drug, and prophylactic. While chloroquine is known to interact with DNA, the details of DNA-ligand interactions have remained unclear. Here we characterize chloroquine-double-stranded DNA binding with four complementary approaches, including optical tweezers, atomic force microscopy, duplex DNA melting measurements, and isothermal titration calorimetry. We show that chloroquine intercalates into double stranded DNA (dsDNA) with a K D ~ 200 µM, and this binding is entropically driven. We propose that chloroquine-induced dsDNA intercalation, which happens in the same concentration range as its observed toxic effects on cells, is responsible for the drug's cytotoxicity.

Purpose: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited., Methods: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated., Results: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI., Conclusion: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Single-stranded DNA-binding proteins (SSBs) are essential cellular components, binding to transiently exposed regions of single-stranded DNA (ssDNA) with high affinity and sequence non-specificity to coordinate DNA repair and replication. Escherichia coli SSB (EcSSB) is a homotetramer that wraps variable lengths of ssDNA in multiple conformations (typically occupying either 65 or 35 nt), which is well studied across experimental conditions of substrate length, salt, pH, temperature, etc. In this work, we use atomic force microscopy to investigate the binding of SSB to individual ssDNA molecules. We introduce non-canonical DNA bases that mimic naturally occurring DNA damage, synthetic abasic sites, as well as a non-DNA linker into our experimental constructs at sites predicted to interact with EcSSB. By measuring the fraction of DNA molecules with EcSSB bound as well as the volume of protein bound per DNA molecule, we determine the protein binding affinity, cooperativity, and conformation. We find that, with only one damaged nucleotide, the binding of EcSSB is unchanged relative to its binding to undamaged DNA. In the presence of either two tandem abasic sites or a non-DNA spacer, however, the binding affinity associated with a single EcSSB tetramer occupying the full substrate in the 65-nt mode is greatly reduced. In contrast, the binding of two EcSSB tetramers, each in the 35-nt mode, is preserved. Changes in the binding and cooperative behaviors of EcSSB across these constructs can inform how genomic repair and replication processes may change as environmental damage accumulates in DNA., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Bacteriophage T4 gene 32 protein (gp32) is a model single-stranded DNA (ssDNA) binding protein, essential for DNA replication. gp32 forms cooperative filaments on ssDNA through interprotein interactions between its core and N-terminus. However, detailed understanding of gp32 filament structure and organization remains incomplete, particularly for longer, biologically-relevant DNA lengths. Moreover, it is unclear how these tightly-bound filaments dissociate from ssDNA during complementary strand synthesis. We use optical tweezers and atomic force microscopy to probe the structure and binding dynamics of gp32 on long (∼8 knt) ssDNA substrates. We find that cooperative binding of gp32 rigidifies ssDNA while also reducing its contour length, consistent with the ssDNA helically winding around the gp32 filament. While measured rates of gp32 binding and dissociation indicate nM binding affinity, at ∼1000-fold higher protein concentrations gp32 continues to bind into and restructure the gp32-ssDNA filament, leading to an increase in its helical pitch and elongation of the substrate. Furthermore, the oversaturated gp32-ssDNA filament becomes progressively unwound and unstable as observed by the appearance of a rapid, noncooperative protein dissociation phase not seen at lower complex saturation, suggesting a possible mechanism for prompt removal of gp32 from the overcrowded ssDNA in front of the polymerase during replication., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This Viewpoint considers the implications of incorporating two interdisciplinary and burgeoning fields of study, settler colonialism and racial capitalism, as prominent frameworks within academic global health. We describe these two modes of domination and their historical and ongoing roles in creating accumulated advantage for some groups and disadvantage for others, highlighting their relevance for decolonial health approaches. We argue that widespread epistemic and material injustice, long noted by marginalised communities, is more apparent and challengeable with the consistent application of these two frameworks. With examples from the USA, Brazil, and Zimbabwe, we describe the health effects of settler colonial erasure and racial capitalist exploitation, also revealing the rich legacies of resistance that highlight potential paths towards health equity. Because much of the global health knowledge production is constructed from unregenerate contexts of settler colonialism and racial capitalism and yet focused transnationally, we offer instead an approach of bidirectional decoloniality. Recognising the broader colonial world system at work, bidirectional decoloniality entails a truly global health community that confronts Global North settler colonialism and racial injustice as forcefully as the various colonialisms perpetrated in the Global South., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Public health measures adopted to contain the spread of COVID-19 included restrictions on activities and mobility as people were asked to stay at home and schools moved to online learning. This may have increased risk of non-communicable disease by limiting recreational and transport-related physical activity. Building on an existing study, we assessed changes in self-reported and device-measured physical activity and travel behaviour before, during and after the peak of local COVID-19 outbreak and restrictions (March-July 2020). We examined beliefs in effectiveness of strategies to increase active and public transport after restrictions were reduced., Methods: A longitudinal study of adult infrequent bus users (average ≤ 2 trips per week; n = 70; 67% women) in Hobart, Australia. One-week assessment periods at four separate timepoints (before, during, 0-3 months after, and 3-6 months after the peak restrictions period) involved wearing an accelerometer, daily transport diaries, online surveys and tracking bus smartcard boardings., Results: Physical activity (especially among older participants), bus use and private motor vehicle use declined significantly during or 0-3 months after the peak restrictions period and returned to pre-restrictions levels by 3-6 months after the peak restrictions period, except bus use which remained significantly lower. Retrospective surveys overstated declines in bus use and active transport and self-reports understated declines in physical activity. Social distancing and improving service efficiency and frequency were seen as effective strategies for increasing bus use after restrictions but belief in effectiveness of distancing decreased over time., Conclusions: When restrictions on mobility are increased, supportive health promotion measures are needed to prevent declines in physical activity, particularly for older adults. Public transport systems need capacity to implement temporary distancing measures to prevent communicable disease transmission. Providing convenient, flexible, and efficient options for public transport may help to replenish public transport use after restrictions are reduced., Competing Interests: The authors declare the following financial interests or personal relationships which may be considered as potential competing interests. KC is, and MM was, an employee of Metro Tasmania and as such KC is, and MM was, involved in making policy decisions and funding allocations for the provision of public transport by Metro Tasmania. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Purpose: Tension band wiring (TBW) is the most widely accepted method for patella fracture fixation. The purpose of our study was to compare the biomechanical efficacy of a novel cable construct to TBW for the fixation of transverse patella fractures. The tensioned cable construct was hypothesized to have less fracture gapping after cyclic flexion-extension loading and greater ultimate load to failure as compared to TBW., Methods: Transverse patellar osteotomies (AO/OTA 34C1.1) were performed on nine pairs of fresh-frozen human cadaveric whole legs (mean age 82.2 years, range 71-101). Treatment with TBW or tensioned cable construct was randomized within each specimen pair. Fracture site displacement was measured after 5000 flexion-extension cycles from 0° to 90° at 0.5 Hz. In load to failure testing, the knee was fixed at 45° of flexion and the quadriceps tendon was pulled proximally at 0.5 mm/sec until patella fixation failure. Comparisons were made using paired t-tests with alpha values of 0.05., Results: Eight paired specimens completed the cyclic loading. The tensioned cable construct had significantly less fracture gapping than TBW (2.9 vs 10.9 mm; p = 0.020). Seven paired limbs underwent load to failure testing, which revealed no significant difference between the tensioned cable construct and TBW (1551.6 N vs 1664.0 N; p = 0.26)., Conclusion: In this study of transverse patella fracture fixation, a tensioned cable construct demonstrated significantly less fracture gapping compared to TBW in response to cyclic loading with no significant difference in load at failure., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

A recent trend in the design of liquid chromatography (LC) instrumentation is the move towards miniaturized and portable systems. These smaller platforms provide wider flexibility in operation, with the opportunity for conducting analysis directly at the point of sample collection rather than transporting the sample to a centralized laboratory facility. For the manufacturing of pharmaceutical and biopharmaceutical products, these platforms can be implemented for process monitoring and product characterization directly in manufacturing environments. This article describes a portable, miniaturized LC instrument coupled to a mass spectrometer (MS) for characterization of a biopharmaceutical monoclonal antibody (mAb).

Objective/background: Retinoblastoma is an ocular cancer diagnosed in early childhood. Previous research has indicated the impact of cancer treatment on sleep, but little is known about how sleep is impacted among survivors of retinoblastoma. The current study aimed to describe sleep habits of school-age survivors of retinoblastoma, to examine associations between sleep and quality of life, and to examine concordance between parent and child reports of sleep habits., Patients/methods: Sixty-nine survivors of retinoblastoma (Mage = 10.89, SD = 1.07, 50.7% female; 56.5% unilateral disease) and their caregivers participated, providing information on both self- and parent-reported sleep habits, quality of life, and demographic data., Results: Greater sleep concerns than national norms were reported by parents (bedtime resistance (t(58) = 2.69, p = .009), greater sleep onset delay (t(66) = 2.46, p = .017), shorter sleep duration (t(57) = 2.12, p = .038), increased daytime sleepiness (t(53) = 6.45, p= <.001)) and children (sleep location (t(61) = 2.39, p = .02), restless legs syndrome (t(62) = -2.21, p = .03), parasomnias (t(64) = 19.19, p=<.001)) . Both children and parents of children who received enucleation endorsed greater sleep concerns across several domains (e.g., electronic use before bed, sleep-disordered breathing). Child- and parent-reported sleep concerns were generally associated with decreased quality of life. Finally, child- and parent-report of sleep habits appeared generally consistent., Conclusions: Survivors of retinoblastoma experience sleep difficulties. As such, assessment and targeted intervention is important to mitigate any effects on quality of life. Future research should examine sleep habits of survivors of retinoblastoma across cultures and developmental periods., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Retinoblastoma is the most common intraocular childhood cancer and is typically diagnosed in young children. With increasing number of survivors and improved medical outcomes, long-term psychosocial impacts need to be explored. Thus, the current study sought to assess functioning in school-aged survivors of retinoblastoma., Procedure: Sixty-nine survivors of retinoblastoma underwent a one-time evaluation of psychosocial functioning. Survivors (M age = 10.89 years, SD = 1.07 years; 49.3% male; 56.5% unilateral disease) and parents completed measures of quality of life (QoL; PedsQL) and emotional, behavioral, and social functioning (PROMIS [patient-reported outcome measurement information system] Pediatric Profile, BASC-2 parent report). Demographic and medical variables were also obtained., Results: On the whole, both survivors and caregivers indicated QoL and behavioral and emotional health within the typical range of functioning. Survivors reported better physical QoL compared to both parent report and a national healthy comparison sample, whereas caregivers reported that survivors experienced lower social, school, and physical QoL than a healthy comparison. Regarding behavioral and emotional health, survivors indicated more anxiety than a nationally representative sample. Parents of female survivors endorsed lower adaptive scores than parents of male survivors., Conclusions: Results indicated that survivors of retinoblastoma reported QoL and behavioral and emotional health within normal limits, although parents appear to perceive greater impairment across several assessed domains. Understanding both survivor and parent reports remains important for this population. Future research should explore psychosocial functioning of these survivors as they transition to adolescence and early adulthood, given the increased independence and behavioral and emotional concerns during these developmental periods., (© 2022 Wiley Periodicals LLC.)

The SARS-CoV-2 nucleocapsid (N) protein performs several functions including binding, compacting, and packaging the ∼30 kb viral genome into the viral particle. N protein consists of two ordered domains, with the N terminal domain (NTD) primarily associated with RNA binding and the C terminal domain (CTD) primarily associated with dimerization/oligomerization, and three intrinsically disordered regions, an N-arm, a C-tail, and a linker that connects the NTD and CTD. We utilize an optical tweezers system to isolate a long single-stranded nucleic acid substrate to measure directly the binding and packaging function of N protein at a single molecule level in real time. We find that N protein binds the nucleic acid substrate with high affinity before oligomerizing and forming a highly compact structure. By comparing the activities of truncated protein variants missing the NTD, CTD, and/or linker, we attribute specific steps in this process to the structural domains of N protein, with the NTD driving initial binding to the substrate and ensuring high localized protein density that triggers interprotein interactions mediated by the CTD, which forms a compact and stable protein-nucleic acid complex suitable for packaging into the virion., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The histone chaperone FACT (facilitates chromatin transcription) enhances transcription in eukaryotic cells, targeting DNA-protein interactions. FACT, a heterodimer in humans, comprises SPT16 and SSRP1 subunits. We measure nucleosome stability and dynamics in the presence of FACT and critical component domains. Optical tweezers quantify FACT/subdomain binding to nucleosomes, displacing the outer wrap of DNA, disrupting direct DNA-histone (core site) interactions, altering the energy landscape of unwrapping, and increasing the kinetics of DNA-histone disruption. Atomic force microscopy reveals nucleosome remodeling, while single-molecule fluorescence quantifies kinetics of histone loss for disrupted nucleosomes, a process accelerated by FACT. Furthermore, two isolated domains exhibit contradictory functions; while the SSRP1 HMGB domain displaces DNA, SPT16 MD/CTD stabilizes DNA-H2A/H2B dimer interactions. However, only intact FACT tethers disrupted DNA to the histones and supports rapid nucleosome reformation over several cycles of force disruption/release. These results demonstrate that key FACT domains combine to catalyze both nucleosome disassembly and reassembly., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) ( p = 0.0328) and tended to improve overall survival compared to the no-treatment control ( p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 ( p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway.

Importance: In the US, Black individuals die younger than White individuals and have less household wealth, a legacy of slavery, ongoing discrimination, and discriminatory public policies. The role of wealth inequality in mediating racial health inequities is unclear., Objective: To assess the contribution of wealth inequities to the longevity gap that exists between Black and White individuals in the US and to model the potential effects of reparations payments on this gap., Design, Setting, and Participants: This cohort study analyzed the association between wealth and survival among participants in the Health and Retirement Study, a nationally representative panel study of community-dwelling noninstitutionalized US adults 50 years or older that assessed data collected from April 1992 to July 2019. Participants included 7339 non-Hispanic Black (hereinafter Black) and 26 162 non-Hispanic White (hereinafter White) respondents. Data were analyzed from January 1 to September 17, 2022., Exposures: Household wealth, the sum of all assets (including real estate, vehicles, and investments), minus the value of debts., Main Outcomes and Measures: The primary outcome was all-cause mortality by the end of survey follow-up in 2018. Using parametric survival models, the associations among household wealth, race, and survival were evaluated, adjusting for age, sex, number of household members, and marital status. Additional models controlled for educational level and income. The survival effects of eliminating the current mean wealth gap with reparations payments ($828 055 per household) were simulated., Results: Of the 33 501 individuals in the sample, a weighted 50.1% were women, and weighted mean (SD) age at study entry was 59.3 (11.1) years. Black participants' median life expectancy was 77.5 (95% CI, 77.0-78.2) years, 4 years shorter than the median life expectancy for White participants (81.5 [95% CI, 81.2-81.8] years). Adjusting for demographic variables, Black participants had a hazard ratio for death of 1.26 (95% CI, 1.18-1.34) compared with White participants. After adjusting for differences in wealth, survival did not differ significantly by race (hazard ratio, 1.00 [95% CI, 0.92-1.08]). In simulations, reparations to close the mean racial wealth gap were associated with reductions in the longevity gap by 65.0% to 102.5%., Conclusions and Relevance: The findings of this cohort study suggest that differences in wealth are associated with the longevity gap that exists between Black and White individuals in the US. Reparations payments to eliminate the racial wealth gap might substantially narrow racial inequities in mortality.

Background: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients., Patients and Methods: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1)., Results: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation., Conclusions: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals., Competing Interests: Disclosure TA reports support for the present manuscript from Bristol Myers Squibb; consulting roles for Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Merck & Co., Pierre Fabre, Seagen, and Servier; honoraria from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck & Co., Pierre Fabre, Roche/Ventana, Sanofi, and Servier; travel/meetings funding from Bristol Myers Squibb and Roche; and participation in advisory boards for Amgen, Astellas Pharma, Bristol Myers Squibb, Gritstone Oncology, Haliodx, Kaleido Biosciences, Merck & Co., Pierre Fabre, and Servier. SL reports research funding from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, and Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, and Amgen; and participation in advisory boards for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and Merck Sharp & Dohme. KYMW reports consulting roles for Merck & Co., Novartis, Ipsen, and Sirtex. FG reports honoraria for speaker/advisory roles from Servier, Eli Lilly, IQVIA, Merck Serono, Amgen, and Bristol Myers Squibb, outside the present work. HJL reports consulting roles for Bayer, Merck & Co., Roche, Bristol Myers Squibb, Merck KGaA, Oncocyte, Fulgent, Jazz Therapeutics, and 3T Bioscience. MAM reports support for the present manuscript from Bristol Myers Squibb; grants from Merck & Co. and Amal; and honoraria from Genentech/Roche. EVC reports participation in advisory boards for AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Helsinn, Incyte, Ipsen, Janssen Research, Eli Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, and Zymeworks; and research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier, paid to his institution. RMD reports personal fees and non-financial support from Pfizer and Janssen; grants from Amgen, Bristol Myers Squibb, and Merck; grants and personal fees from Bayer; non-financial support from Celgene; and personal fees from Clovis. MBS reports support for the present manuscript from Bristol Myers Squibb; grants from AstraZeneca, Alberta Cancer Foundation, Alberta Health Services Strategic Network (Seed Grant Competition), Rexahn, Eli Lilly, Canadian Institutes of Health Research, Bristol Myers Squibb, and Celgene; consulting fees from Ipsen, Bristol Myers Squibb, and Merck & Co.; honoraria from Mylan, Ipsen, Bristol Myers Squibb, and AstraZeneca; support for meetings and travel from Novartis; and holds a patent (number 61/406,856). BN reports support for the present manuscript from Bristol Myers Squibb. SA reports owning stocks and being an employee of Bristol Myers Squibb. AM and MD report being employees of Bristol Myers Squibb. ML reports being an employee of, owning stock in, and being an inventor of patents filed/owned by Bristol Myers Squibb. SK reports consulting or advisory role from Genentech, Merck, Amal Therpeutics, Holy Stone, Novartis, Eli Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, EMD Serono, Redx Pharma, Jacobio, Natera, Repare Therapeutics, Daiichi Sankyo, Lutris, Pfizer, Ipsen, HalioDx, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therapeutics, Endeavor BioMedicines, Numab Pharma, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, and Taiho Pharmaceutical; research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Eli Lilly, and Daiichi Sankyo; and stock and other ownership interests from MolecularMatch, Lutris, Iylon, and Frontier Medicines. MJO reports consulting fees from Merck Sharp & Dohme, AbbVie, Agilvax, Takeda, Acrotech Biopharma, and Novartis. All other authors have declared no conflicts of interest. Data sharing BMS policy on data sharing can be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Acute pulmonary embolism (PE) is a leading cause of morbidity and mortality worldwide. Systemic anticoagulation remains the recommended treatment for low-risk PE. Systemic thrombolysis is the recommended treatment for PE with hemodynamic compromise (massive/high-risk PE). A significant number of patients are not candidates for systemic thrombolysis due to the bleeding risk associated with thrombolytics. Historically, surgical pulmonary embolectomy (SPE) was recommended for massive PE with hemodynamic compromise for these patients. In the last decade, catheter-directed thrombolysis (CDT) has largely replaced SPE in the patient population with intermediate risk PE (submassive), defined as right heart strain (as evidenced by right ventricle enlargement on echocardiogram and/or computed tomography, usually along with elevation of troponin or B-type natriuretic peptide). Use of CDT increased in the last few years due to high incidence of PE in hospitalized patients with coronavirus disease 2019 pneumonia, and the use of mechanical thrombectomy (initially reserved for those with contraindications to thrombolysis) has also grown. In this article, we discuss the value of the PE response team, our approach to management of submassive (intermediate risk) and massive (high risk) PE with systemic thrombolytics, CDT, mechanical thrombectomy, and surgical embolectomy., Competing Interests: Conflict of Interest E.H. reports consulting fees from iSchemaView, Inc (research consulting), and Teleflex, Inc.; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Teleflex, Inc. J.K. reports consulting fees from Biotronik, Cordis, Ischemaview inc, Osprey Medical, and Philips; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abiomed, Asahi, Penumbra, Teleflex., (International College of Angiology. This article is published by Thieme.)

Long interspersed nuclear element 1 (L1) parasitized most vertebrates and constitutes ∼20% of the human genome. It encodes ORF1p and ORF2p which form an L1-ribonucleoprotein (RNP) with their encoding transcript that is copied into genomic DNA (retrotransposition). ORF1p binds single-stranded nucleic acid (ssNA) and exhibits NA chaperone activity. All vertebrate ORF1ps contain a coiled coil (CC) domain and we previously showed that a CC-retrotransposition null mutant prevented formation of stably bound ORF1p complexes on ssNA. Here, we compared CC variants using our recently improved method that measures ORF1p binding to ssDNA at different forces. Bound proteins decrease ssDNA contour length and at low force, retrotransposition-competent ORF1ps (111p and m14p) exhibit two shortening phases: the first is rapid, coincident with ORF1p binding; the second is slower, consistent with formation of tightly compacted complexes by NA-bound ORF1p. In contrast, two retrotransposition-null CC variants (151p and m15p) did not attain the second tightly compacted state. The C-terminal half of the ORF1p trimer (not the CC) contains the residues that mediate NA-binding. Our demonstrating that the CC governs the ability of NA-bound retrotransposition-competent trimers to form tightly compacted complexes reveals the biochemical phenotype of these coiled coil mutants., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objective: The Peer Engaged Empowered Recovery (PEER) program is a county collaboration between specialty behavioral health and probation departments to address substance use and related problems by providing team-based peer recovery specialist (PRS) services. The study aimed to assess the feasibility and potential effectiveness of PEER and propose recommendations., Method: Eligible clients released from jail had suspected substance use disorder and were assigned to the local drug court, on pretrial probation, or considered of high risk of recidivism. Clients were offered PRS support for 6 months. Client-reported data, administrative data on services, and survey data from program stakeholders were assessed., Result: The program successfully identified clients with substance use disorder who had high to very high levels of need for social determinants of health, comorbid mental illness and other chronic conditions, and a high recidivism risk. Clients were served predominantly by phone despite complex needs. The sustainability of the PEER program was rated as stable along many dimensions except funding stability., Conclusion: The PEER pilot program was well targeted. The average level of health and social need among clients was high, and many were difficult for PRS to contact. PRS services, which are currently undifferentiated in the state, may need to be risk-stratified in the future to take into account health and social factors and to align caseloads, reimbursement, and training., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2022 International Nurses Society on Addictions.)

Predator-prey interactions shape ecosystems and can help maintain biodiversity. However, for many of the earth's most biodiverse and abundant organisms, including terrestrial arthropods, these interactions are difficult or impossible to observe directly with traditional approaches. Based on previous theory, it is likely that predator-prey interactions for these organisms are shaped by a combination of predator traits, including body size and species-specific hunting strategies. In this study, we combined diet DNA metabarcoding data of 173 individual invertebrate predators from nine species (a total of 305 individual predator-prey interactions) with an extensive community body size data set of a well-described invertebrate community to explore how predator traits and identity shape interactions. We found that (1) mean size of prey families in the field usually scaled with predator size, with species-specific variation to a general size-scaling relationship (exceptions likely indicating scavenging or feeding on smaller life stages). We also found that (2) although predator hunting traits, including web and venom use, are thought to shape predator-prey interaction outcomes, predator identity more strongly influenced our indirect measure of the relative size of predators and prey (predator:prey size ratios) than either of these hunting traits. Our findings indicate that predator body size and species identity are important in shaping trophic interactions in invertebrate food webs and could help predict how anthropogenic biodiversity change will influence terrestrial invertebrates, the earth's most diverse animal taxonomic group., (© 2022 The Ecological Society of America.)

Background: Faculty development for nurse and physician educators has a limited evidence base in high income countries, and very little research from low- and middle-income countries. Health professions educators in many global settings do not receive training on how to educate effectively., Objective: To pilot and assess a faculty development program aimed at nurse and physician educators at a teaching hospital in rural Haiti., Methods: We developed a program covering a total of 22 topics in health professions education, including applied learning theory as well as nurse and physician targeted topics. We assessed impact through participant assessment of personal growth, participant evaluation of the program, knowledge testing pre and post program, and structured observations of program participants providing teaching during the program., Findings: Nineteen out of 37 participants completed the program. While participant reviews were uniformly positive, a pre- and post-test on general educational topics showed no significant change, and the effort to institute observation and feedback of teaching did not succeed., Conclusions: Our project showcases some benefits of faculty development, while also demonstrating the challenges of instituting faculty development in situations where participants have limited time and resources. We suspect more benefits may emerge as the program evolves to fit the learners and setting., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Background: Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored., Methods: We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions., Results: NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value., Conclusion: Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Insomnia is common in Tourette syndrome (TS) and chronic tic disorder (CTD), but precise prevalence estimates are lacking., Objective: In this Swedish register-based cohort study, we estimated the prevalence of insomnia in TS/CTD and quantified the magnitude of this association, accounting for familial confounders and relevant somatic and psychiatric comorbidities., Methods: Of 10,444,702 individuals living in Sweden during the period from 1997 to 2013, 5877 had a diagnosis of TS/CTD and were compared to unexposed individuals from the general population on the presence of insomnia using logistic regression models., Results: Individuals with TS/CTD had a period prevalence of insomnia of 32.16%, compared to 13.70% of the unexposed population. This translated into a 6.7-fold increased likelihood of insomnia in TS/CTD (odds ratio adjusted [aOR] for sex, birth year, birth country, and somatic disorders = 6.74; 95% confidence interval [CI], 6.37-7.15). A full sibling comparison, designed to adjust for shared familial factors, attenuated the estimates (aOR = 5.41; 95% CI, 4.65-6.30). When individuals with attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders were excluded, the association was also attenuated, whereas exclusion of other psychiatric comorbidities had minimal impact. Having persistent TS/CTD, comorbid ADHD, and taking ADHD medication greatly increased the likelihood of insomnia., Conclusions: Insomnia is significantly associated with TS/CTD, independently from somatic disorders, familial factors or psychiatric comorbidities, although familial factors, neurodevelopmental comorbidities, and ADHD/ADHD medication may explain part of the association. Insomnia should be routinely assessed and managed in TS/CTD, particularly in chronic patients and in those with comorbid ADHD. Other sleep disorders require further study. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Chronic kidney disease is an important clinical condition beset with racial and ethnic disparities that are associated with social inequities. Many medical schools and health centres across the USA have raised concerns about the use of race - a socio-political construct that mediates the effect of structural racism - as a fixed, measurable biological variable in the assessment of kidney disease. We discuss the role of race and racism in medicine and outline many of the concerns that have been raised by the medical and social justice communities regarding the use of race in estimated glomerular filtration rate equations, including its relationship with structural racism and racial inequities. Although race can be used to identify populations who experience racism and subsequent differential treatment, ignoring the biological and social heterogeneity within any racial group and inferring innate individual-level attributes is methodologically flawed. Therefore, although more accurate measures for estimating kidney function are under investigation, we support the use of biomarkers for determining estimated glomerular filtration rate without adjustments for race. Clinicians have a duty to recognize and elucidate the nuances of racism and its effects on health and disease. Otherwise, we risk perpetuating historical racist concepts in medicine that exacerbate health inequities and impact marginalized patient populations., (© 2021. Springer Nature Limited.)

The HIV-1 nucleocapsid protein (NC) is a multi-functional protein necessary for viral replication. Recent studies have demonstrated reverse transcription occurs inside the fully intact viral capsid and that the timing of reverse transcription and uncoating are correlated. How a nearly 10 kbp viral DNA genome is stably contained within a narrow capsid with diameter similar to the persistence length of double-stranded (ds) DNA, and the role of NC in this process, are not well understood. In this study, we use optical tweezers, fluorescence imaging, and atomic force microscopy to observe NC binding a single long DNA substrate in multiple modes. We find that NC binds and saturates the DNA substrate in a non-specific binding mode that triggers uniform DNA self-attraction, condensing the DNA into a tight globule at a constant force up to 10 pN. When NC is removed from solution, the globule dissipates over time, but specifically-bound NC maintains long-range DNA looping that is less compact but highly stable. Both binding modes are additionally observed using AFM imaging. These results suggest multiple binding modes of NC compact DNA into a conformation compatible with reverse transcription, regulating the genomic pressure on the capsid and preventing premature uncoating.