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  • Microsoft gave Perfect Dark’s developers a chance to save the game — after it was already canceled

    Microsoft gave Perfect Dark’s developers a chance to save the game — after it was already canceled

    Here’s where it gets potentially confusing: Microsoft doesn’t own Crystal Dynamics — that studio belongs to the Embracer Group, which has had many troubles of its own. So Embracer was trying to cut a deal with yet another publisher, the giant Take-Two, to buy, fund, and publish the game. But, Schreier reports:

    the talks collapsed at least in part because the companies involved were unable to come to terms over long-term ownership of the Perfect Dark franchise, said the people, who requested anonymity because they were not authorized to speak about sensitive negotiations.

    When that deal fell through, it reportedly led to the new round of layoffs at Crystal Dynamics that IGN reported last week, and Schreier writes that Crystal Dynamics has now “fully” abandoned the game.

    Seems Microsoft didn’t want to give up the rights to Perfect Dark, which it presumably obtained when it bought Rare in 2002. (For the uninitiated, Perfect Dark was a spiritual successor to Rare’s hit Goldeneye 007 on the Nintendo 64, a game that itself went many decades without a revival because of a complicated licensing situation.) That feels like a crummy reason for the game to stay canceled, but we don’t know the details.

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  • Diagnostic value of Serum Amyloid A (SAA) in HIV-associated pulmonary infections and its correlation with inflammatory markers | BMC Infectious Diseases

    Diagnostic value of Serum Amyloid A (SAA) in HIV-associated pulmonary infections and its correlation with inflammatory markers | BMC Infectious Diseases

    The hallmark of HIV infection is progressive CD4+ T lymphocyte depletion, resulting in persistent immunodeficiency that markedly increases susceptibility to opportunistic infections, particularly pulmonary complications [8]. Our findings demonstrate significantly reduced CD4+ T cell count in HIV-infected patients compared to controls (P < 0.05), confirming this immunopathological basis. Notably, even with effective ART, HIV infection sustains chronic immune activation and inflammatory responses involving T cells, B cells, and monocytes, accompanied by elevated pro-inflammatory cytokines including TNF-α, IL-6, and acute-phase proteins such as CRP [9,10,11,12,13,14]. This persistent inflammatory state not only contributes to non-AIDS-related morbidity and mortality [13, 14], but may also fundamentally alter inflammatory responses to acute secondary infections, such as the pulmonary infections central to this investigation.

    As a key acute-phase protein, SAA rapidly escalates following inflammatory stimuli and orchestrates pathogen clearance by recruiting monocytes, neutrophils, dendritic cells, and T cells to sites of inflammation [15]. In chronic inflammatory states, circulating SAA levels—though lower than acute-phase peaks—remain elevated above baseline [16]. However, there is limited research on the dynamic changes of SAA in HIV-infected individuals, particularly in cases of concurrent acute infections (e.g.pulmonary infections), and its diagnostic value remains underexplored [17]. This study therefore addresses a critical gap by examining how chronic HIV infection modulates SAA responsiveness to acute pulmonary inflammation.

    A pivotal observation was the markedly higher acute-phase SAA and CRP levels in HIV-positive patients with lung infections versus non-HIV controls (P < 0.05), aligning with Hussbekk et al. [18]. We propose two mechanistic explanations: (1) The compounding effects of chronic immune activation: HIV-induced low-grade inflammation may hypersensitize the immune system to secondary lung infections, amplifying acute-phase protein release; (2) Increased pathogen burden: Immunodeficiency likely predisposes HIV patients to heavier or polymicrobial infections, intensifying the acute-phase response. Moreover, this study demonstrated significantly elevated serum LDH levels in HIV-infected patients compared to controls (P < 0.05), indicating exacerbated tissue damage during concurrent pulmonary infection. Given the well-documented sensitivity of LDH in HIV-associated Pneumocystis pneumonia (PJP) [19], these findings further corroborate that pulmonary infection intensifies histopathological injury in HIV-positive individuals. Together, the data explain the prolonged hospitalization observed in these patients (P < 0.05).

    In analyzing inflammatory markers, we observed that SAA levels in HIV patients with pulmonary infections showed significant positive correlations with CRP, PCT, LDH, and PLT. This finding holds important clinical implications. As CRP and SAA are among the most sensitive acute-phase proteins, their concentrations are strongly associated during inflammation, with SAA typically exhibiting a more pronounced increase [20,21,22]. PCT, driven by endotoxin and cytokines, signals bacterial involvement. LDH serves as a highly sensitive biomarker for tissue injury, reflecting cellular damage with remarkable precision. Beyond its well-known role in hemostasis, emerging evidence highlights PLT as pivotal “first responders” in infection immunity. They actively combat pathogens through direct microbicidal action and by orchestrating immune cell-mediated pathogen clearance [23, 24]. These linkages position SAA as a integrative biomarker reflecting inflammatory intensity, tissue injury, and immune engagement in HIV-lung coinfection. In clinical practice, this approach offers a more effective predictive tool for early diagnosis of acute infections in patients with prolonged chronic infections. Furthermore, the study revealed no significant correlation between SAA levels in HIV patients with pulmonary infections and either CD4+ T cell counts or hospitalization duration. This may be attributed to SAA’s nature as a highly sensitive but short-lived inflammatory marker—it surges rapidly within 24 h of stimulation and declines swiftly post-acute phase. Consequently, while it detects inflammation effectively, it shows minimal association with long-term clinical outcomes such as hospital stay [25, 26].

    Beyond acute-phase roles, SAA participates in tissue remodeling, atherosclerosis, and cancer metastasis via receptor interactions and metalloproteinase modulation [1, 27], suggesting potential implications for HIV-related chronic complications—a avenue warranting further study.

    This study has several potential limitations. First, as a retrospective analysis, it inherently carries a lower level of evidence compared to prospective studies. Second, although all enrolled patients presented with pulmonary infections, the causative pathogens varied substantially, leading to significant microbial heterogeneity. Third, incomplete viral nucleic acid data in the HIV group precluded further analysis of the relationship between infection and viral load. Fourth, the modest sample size (approximately 50 patients) may limit the robustness of the key findings. Despite these limitations, this study represents the first investigation into the role of SAA in HIV patients with acute lung infections, providing a foundation for future research. Addressing these shortcomings will be a priority in subsequent, more in-depth studies.

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  • NASA Spaceline Current Awareness List #1,164 29 August 2025 (Space Life Science Research Results)

    NASA Spaceline Current Awareness List #1,164 29 August 2025 (Space Life Science Research Results)

    The abstract in PubMed or at the publisher’s site is linked when available and will open in a new window.

  • McGregor HR, Hupfeld KE, Pasternak O, Beltran NE, De Dios YE, Bloomberg JJ, Wood SJ, Riascos RF, Reuter-Lorenz PA, Seidler RD.Crewmember demographic factors and their association with brain and ocular changes following spaceflight.npj Microgravity. 2025 Aug 28;11:59.PI: R.D. SeidlerNote: ISS results. This article may be obtained online without charge.

    Journal Impact Factor: 5.1

    Funding: “This study was supported by NASA grant #NNX11AR02G awarded to RDS, SJW, PARL, and JJB. HRM was supported by an NSERC postdoctoral fellowship, a Translational Research Institute for Space Health Postdoctoral Fellowship, and a NASA Human Research Program augmentation grant. KEH was supported by National Institute on Aging fellowships F99AG068440 and K00AG068440.”

  • Friedman MA, Zeineddine Y, Tuyambaze O, Elhawabri W, Al Shammary A, Stodieck L, Ferguson VL, Donahue H.Simulated microgravity accurately models long-duration spaceflight effects on bone and skeletal muscle in skeletally immature mice.Bone Rep. 2025 Sep;26:101871.PI: M.A. FriedmanNote: Hindlimb unloading study.

    Journal Impact Factor: 2.6

    Funding: “This work is supported by the Translational Research Institute for Space Health Postdoctoral Fellowship (NASA Cooperative Agreement NNX16AO69A), Center for the Advancement of Science in Space User Agreement UA-2019-888, and National Institutes of Health 3UM1TR004360-02S2.”

  • Lonner TL, Austin CR, Blake JS, Gupta P, Katz JM, Gopinath AR, Clark TK.Impact of sickness induced by centrifugation on tilt perception.Front Neurol. 2025 Aug 12;16:1628938.PI: T.K. ClarkNote: This article is part of Research Topic “Impact of Vestibular Dysfunction Studies on Space Flight Health Challenges” (https://genelab.nasa.gov). The Research Topic also includes articles from previous Current Awareness Lists #1,075 https://doi.org/10.3389/fneur.2023.1284029 and #1,139 https://doi.org/10.3389/fneur.2025.1556553. This article may be obtained online without charge.

    Journal Impact Factor: 2.8

    Funding: “This work was supported by the National Aeronautics and Space Administration Human Research Program under Grant No. 80NSSC23K0449.”

  • Hughes AM, Jenkins BE, Bauer LV, Kiss JZ.Performance and accuracy of the automated measurement software: Simple Online Automated Plant Phenomics (SOAPP).Gravit Space Res. 2025 Aug 7;13(1):51-64.PI: J.Z. KissNote: This article may be obtained online without charge.

    Journal Impact Factor: 2.0

    Funding: PI reports past NASA funding.

  • Johns S, Wiegman E, Bakshi A, Gilroy S.The cyclic nucleotide-gated channels CNGC2 and CNGC4 support systemic wound responses in Arabidopsis thaliana.Front Plant Sci. 2025 Aug 21;16:1545065.PI: S. GilroyNote: This article may be obtained online without charge.

    Journal Impact Factor: 4.8

    Funding: “The authors are grateful for funding for this work from NSF MCB2016177, NASA 80NSSC21K0577 and 80NSSC19K0126, and the Wisconsin Space Grant Consortium.”

  • Evans MA, Walsh K.Clonal hematopoiesis in cancer and cardiovascular disease: JACC: CardioOncology state-of-the-art review.JACC: CardioOncology. 2025 Aug;7(5):470-95.PI: K. WalshNote: This article may be obtained online without charge.

    Journal Impact Factor: 12.8

    Funding: “These studies were supported by National Institutes of Health grants AG073249 and AG086508, Department of Defense grant CA210887, and National Aeronautics and Space Administration grant 80NSSC21K0549 to Dr Walsh.”

  • Walsh RFL, Smith LT, Bisgay A, Stephenson AR, Goel N, Alloy LB.Sleep duration as a mediator of the association between caffeine intake and mood symptoms: An intensive longitudinal study of young adults with and without bipolar spectrum disorders.Chronobiology International. 2025 Aug 18;1-11. Online ahead of print.PI: N. GoelJournal Impact Factor: 1.7

    Funding: “This study was supported in part by the National Science Foundation’s Graduate Research Fellowship to Rachel Walsh and by National Institute of Mental Health R01 grants [MH077908, MH102310, and MH126911] to Lauren B. Alloy. Namni Goel was supported in part by National Aeronautics and Space Administration (NASA) grants [NNX14AN49G] and [80NSSC20K0243] and National Institutes of Health grant [R01DK117488].”

  • Bouvet P, Bevilacqua C, Ambekar Y, Antonacci G, Au J, Caponi S, Chagnon-Lessard S, Czarske J, Dehoux T, Fioretto D, Fu Y, Guck J, Hamann T, Heinemann D, Jähnke T, Jean-Ruel H, Kabakova I, Koski K, Koukourakis N, Krause D, La Cavera S, Landes T, Li J, Mahmodi H, Margueritat J, Mattarelli M, Monaghan M, Overby DR, Perez-Cota F, Pontecorvo E, Prevedel R, Ruocco G, Sandercock J, Scarcelli G, Scarponi F, Testi C, Török P, Vovard L, Weninger WJ, Yakovlev V, Yun S-H, Zhang J, Palombo F, Bilenca A, Elsayad K.Consensus statement on Brillouin light scattering microscopy of biological materials.Nat Photon. 2025 Jul 3;19(7):681-91.Note: This article may be obtained online without charge.

    Journal Impact Factor: 32.9

    Funding: “…support from NASA, BARDA, the NIH and USFDA under contract/agreement no. 80ARC023CA002.”

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  • Adria Arjona on ‘Splitsville,’ monogamy and Wonder Woman rumors

    Adria Arjona on ‘Splitsville,’ monogamy and Wonder Woman rumors

    Forget Carmen Sandiego. Where in the world is Adria Arjona?

    On any given day, the Puerto Rican actress might be traveling. “Frequent flyer miles are off the chart. If you ever need a flight, I got you,” she says, laughing. On this particular Sunday, Arjona has parked herself for a Zoom interview in an airport lounge in Budapest – a couple of weeks after walking a red carpet in Hawaii with her boyfriend Jason Momoa – and waiting for a flight to London to film “The Thomas Crown Affair” with co-star/director Michael B. Jordan.

    This is the life of an in-demand movie star, who jokes she’s become an expert in napping “just out of desperation, or survival.” After breakthrough roles in “Hit Man” and “Blink Twice,” this year Arjona appeared in the Emmy-nominated Season 2 of the “Star Wars” show “Andor” and stars (and executive produces) in the unconventional screwball comedy “Splitsville” (in select theaters now, nationwide Sept. 5).

    She plays Ashley, a life coach who admits to her husband Carey (co-writer Kyle Marvin) that she’s cheated on him and wants a divorce. Carey turns to married friends Julie (Dakota Johnson) and Paul (director Michael Angelo Corvino) and learns that they have an open marriage, which sounds like a good idea for everybody until the situation turns into a love trapezoid.

    She couldn’t relate “at all” to Ashley (“I am as monogamous and as boring as you get”), but Arjona confesses she’s had the most fun in her career playing “kooky” characters, “things that are a little bit off center and not 100% common for a Latin American woman to play.” She next stars as a trailer park “mama bear” keeping her kids safe from a threat that escapes from a military base in the upcoming horror flick “Onslaught.”

    Arjona, 33, talks about “Splitsville,” those Wonder Woman rumors, and her secret to a happy romance.

    Conversation edited for length and clarity.

    Q: The opening scene of “Splitsville” is wild, where Ashley and Carey are enjoying a pleasant drive until they witness a gnarly accident. When you read the script, did it stop you in your tracks or did you dig it?

    Adria Arjona: I loved it. It’s one of the best opening sequences I’ve ever read, to be honest. In the first 10 minutes, the movie just slaps you in the face and it’s like, ‘All right, are you going to jump on this roller coaster or what?” It’s funny, it’s dramatic, and then there’s like an action element to it.

    But you can easily imagine someone weighing their life decisions, as Ashley does, after something this bonkers.

    Ashley is with such a wonderful human being, and for some reason it’s not working for her. She has no real excuse of why she needs to leave, and in a way she takes him for granted. She wants to experience other stuff and it’s heartbreaking, but it’s also so truthful. I’ve had girlfriends and we’ve had conversations like this. There’s nothing wrong. There’s just nothing right, either. And those are sometimes the hardest relationships to say goodbye to. You can stay with that person forever, but no one’s growing. 

    You’ve enjoyed this really interesting breakthrough period in Hollywood. Are you seeing the results of that now?

    I’m still a human, so there’s times you get a little bit overwhelmed, but 90% of the time I just feel so grateful. Everything that I’ve worked so hard for is now accessible to me. I’m so grateful to be in “Thomas Crown” and reimagine that movie that we all love so much with a brown woman and Michael at the center of it. I’m really grateful to those filmmakers that took a chance on me early on. And because of them, I’m seeing the fruits of their belief in me.

    Is it joyful or annoying that you’ve gotten to the level of stardom where James Gunn follows you on Instagram and all off a sudden you’re being fan-cast as Wonder Woman? He does admit you’d be “great.”

    I really take it as a beautiful honor that audiences are saying that it’s me. I look really cool to my 15-year-old brother. He’s been calling me way more often, so please keep it going! And James Gunn is family. I’ve known him for so long. (His film) “The Belko Experiment” was my first big thing.

    Jason’s a guy familiar with the DC universe. What have you found is the key to having a healthy, loving relationship in the year 2025 and avoiding actual Splitsville?

    I mean, being monogamous (laughs). I guess that’s my answer.

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  • Breakthrough discovery reveals treatable form of familial mesothelioma

    Breakthrough discovery reveals treatable form of familial mesothelioma

    Researchers working independently at the University of Hawaii Cancer Center and the National Cancer Institute have discovered, and validated, a new variant of mesothelioma that may lead to more successful treatments. The studies have been published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer.

    Mesothelioma is a rare and aggressive type of cancer that develops in the mesothelium, the thin layer of tissue that lines the lungs, heart, and abdomen. Asbestos exposure is the primary risk factor. Median survival time after diagnosis is typically 6 to 18 months.

    In these new manuscripts, Dr. Michele Carbone of the University of Hawaii Cancer Center, and Dr. David Schrump of the National Cancer Institute, report that mesotheliomas caused by inherited germline BAP1 mutations are a different and much less aggressive compared to sporadic mesotheliomas and they discovered how to identify and diagnose these patients and how to best treat them.

    They found that in addition to mesothelioma, these patients develop multiple tumors and therefore it is critical that they are enrolled in screening programs for early cancer detection. They propose to re-name these tumors as “low-grade-BAP1-associated-mesotheliomas”, L-BAM- to distinguish them from the very aggressive sporadic asbestos-induced mesotheliomas which are resistant to therapy.

    The research team of Dr. Michele Carbone at the University of Hawaii Cancer Center discovered this variant of mesothelioma responds to therapy and these patient’s lives can be saved when these tumors are detected early on. Their new manuscript titled Clinical and Pathologic Phenotyping of mesotheliomas developing in carriers of Germline BAP1 Mutations Michele Carbone et al is in press in the JTO) https://www.sciencedirect.com/journal/journal-of-thoracic-oncology/articles-in-press.

    During 1999-2024, the researchers studied 47 families carrying BAP1+/- transmitted in a Mendelian fashion. We characterized these mutations, collected family history, clinical records, prepared family pedigrees and diagnosed their mesotheliomas.

    Dr. Carbone’s research team identified 34 different germline inactivating mutations. Among 238 BAP1+/- carriers aged 27-81, 84 were diagnosed with mesothelioma (35%), 1/84 had evidence of asbestos exposure. No mesothelioma was recorded among 123 siblings/relatives who did not inherit BAP1+/- p<0.0001. The 84 BAP1+/- patients developed mesothelioma at a relatively young age; 45.2% developed multiple cancers. BAP1+/- patients had a florid, diffuse mesothelial hyperplasia often present in both pleural cavities, peritoneum and pericardium. Thoracoscopy and laparoscopy showed several multi-cavity ∼1-3 mm whitish flat lesions, imaging was usually negative for cancer. Histology revealed epithelioid cells lacking BAP1 nuclear staining arranged in tubulo-papillary and trabecular architectures, focally invading sub-mesothelial adipose tissue. These findings may lead to the diagnosis of stage IV metastatic mesothelioma. However, Carbone et al found that these tumors may remain indolent for years and, at this early stage, patients do not require aggressive therapy.

    We refer to these tumors as “Low-grade-germline-mutant-BAP1-associated-mesotheliomas, L-BAM” to distinguish them from aggressive, therapy-resistant, sporadic mesotheliomas. For the 1/3 of patients who develop lesions visible by imaging, surgery and/or chemotherapy leads to survival of several years,may be cured. Deep invasion by mesothelioma cells with a solid architecture is rare: these cases have poor survival.” 


    Dr. Michele Carbone, University of Hawaii Cancer Center

    In an independent study conducted by the research team of Dr. David Schrump at the National Cancer Institute, National Institutes of Health, Bethesda, Md., 50 subjects with 32 germline BAP1 mutations underwent state-of-the-art computed tomographic imaging followed by video assisted thoracoscopies and diagnostic laparoscopies. Dr. Schrump and his team identified clinically occult mesotheliomas in 39 of 45 (87%) subjects affecting 63 of 81 (78%) hemi-thoraces and 27 of 32 (84%) peritoneal cavities. These mesotheliomas exhibited histological features distinct from sporadic mesotheliomas and slow clinical progression without therapeutic interventions (median follow-up: 21.8 months; range: 1.7 – 41.1 months). Laboratory experiments identified common as well as mutation-specific, cancer-associated epigenomic alterations in normal fibroblasts and peripheral blood mononuclear cells (PBMC) which correlated with cancer predilection in subjects with BAP1 Cancer Syndrome.

    Overall, this prospective study demonstrated that subjects with germline BAP1 mutations have a strikingly high prevalence of subclinical mesotheliomas with unique histologic features and clinical characteristics. Furthermore, mesothelioma risk in subjects with BAP1 Cancer Syndrome may be a reflection of potentially quantifiable epigenetic changes in normal cells. These findings have already led to two ongoing protocols at the NCI (NCT05960773 and NCT06654050) to determine if oral epigenetic agents can abort progression of mesotheliomas to life threatening disease states in subjects with BAP1 Cancer Syndrome. The NCI experience is detailed in a comprehensive manuscript entitled Prospective Analysis of Mesotheliomas in Subjects with BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease which is also in press in JTO.

    https://www.jto.org/article/S1556-0864(25)00984-0/fulltext

    “This is a major step in the fight against mesothelioma, one of the most aggressive human cancers. It is also great relief to these families, who are now aware that their tumors can be treated and therefore most of them can live a normal life span,” said Dr. Carbone.

    Dr. Carbone’s research progressed over years. Initially, studying a mesothelioma epidemic in 3 small villages in Cappadocia, Dr. Carbone proposed that familial mesothelioma was caused by genetics (Roushdy-Hammady et al. The Lancet 2001); next his team discovered the first gene responsible for familial mesothelioma (Testa et al Nature Genetics 2011); then they identified the mechanisms responsible for the potent tumor suppressor activity of BAP1 (Bononi et al Nature 2017; PNAS 2023) and discovered additional genes that when mutated in the germline may cause mesothelioma (Bononi et al PNAS 2020; Novelli et al., PNAS 2024).

    The latest discovery is therefore the result of over 25 years of working with families affected by multiple cases of mesothelioma, he stated.

    Source:

    International Association for the Study of Lung Cancer

    Journal reference:

    Wu, X., et al. (2021). Prospective Analysis of Mesotheliomas in Subjects with BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease. Journal of Thoracic Oncology0(0). doi.org/10.1016/j.jtho.2025.07.132

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  • APA Publishes Comprehensive Practice Guidelines for the Prevention and Treatment of Delirium

    APA Publishes Comprehensive Practice Guidelines for the Prevention and Treatment of Delirium

    The American Psychiatric Association (APA) has published the updated comprehensive “Practice Guideline for the Prevention and Treatment of Delirium.” This new guideline is designed to assist any clinician who may encounter patients with delirium and includes evidence-based recommendations to improve its detection, prevention, and treatment.1

    Delirium is expected to affect about 23% of adults in inpatient medical units, 31% of adults in intensive care units (ICUs), and 75% of patients who are mechanically ventilated in ICUs. Despite this prevalence, delirium is frequently not recognized, which can lead to longer hospital stays, greater risk of complications, increased strain on patients and caregivers, and significant additional health care costs.

    The goal of the guideline is to prevent at-risk individuals from developing delirium and to improve the quality of care and treatment outcomes for those who have it. The practice guideline includes 12 clinical recommendations and 3 suggestions, depending on the level of scientific evidence.

    The guideline was developed by the APA Practice Guideline Writing Group, which is chaired by Catherine Crone, MD. The Writing Group conducted an extensive review of research evidence and used a process consistent with the recommendations of the Institute of Medicine (2011) and the Council of Medical Specialty Societies (2017) in developing the guideline. A detailed description of the process and research evidence are included in the guideline and accompanying appendices. Members of the multidisciplinary writing group included experts from psychiatry, internal medicine, family medicine, and critical care nursing.

    “All too often, clinical guidelines come across as 2-dimensional documents that are intellectual exercises rather than what they truly are: carefully considered, evidence-based guides that can be applied to direct patient care, quality improvement efforts, as well as the education of colleagues and trainees in psychiatry and other disciplines, with the end result being improvement in patient care,” said Crone.

    Mark A. Oldham, MD, an associate professor of psychiatry at the University of Rochester Medical Center and the immediate past presidents of the American Delirium Society, recently shared with Psychiatric Times that prevention is a key differentiator from the last guidelines, which were published in 1999. Most guidelines are considered out of date after 5 years and the lack of newer treatments may have delayed these revisions.2 Watch the exclusive interview with Oldham here.

    The full “Practice Guideline for the Prevention and Treatment of Delirium,” executive summary and appendices are available free online and as a printed copy for purchase from APA Publishing. The APA is also developing related resources to facilitate understanding of the guideline and its implementation, including training slides, clinician guide, patient/family guide, webinar and case vignettes. All materials will be available to practitioners and the public.

    References

    1. American Psychiatric Association publishes updated comprehensive Guideline for the Prevention and Treatment of Delirium. American Psychiatric Association. September 2, 2025. Accessed September 2, 2025. https://www.psychiatry.org/News-room/News-Releases/APA-Published-Updated-Guideline-for-Delirium

    2. Oldham MA, Miller JJ. New delirium guidelines discussed at APA Annual Meeting. Psychiatric Times. May 20, 2025. https://www.psychiatrictimes.com/view/new-delirium-guidelines-discussed-at-apa-annual-meeting

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  • Pakistan: 11 killed, 40 injured after suicide bombing at political rally in Balochistan; probe on

    Pakistan: 11 killed, 40 injured after suicide bombing at political rally in Balochistan; probe on

    At least 11 people were killed and 40 others injured in a suicide bombing at a political rally in Quetta, the capital of Pakistan’s restive Balochistan province, officials told news agency AFP on Tuesday.The blast occurred in the parking lot of a stadium where hundreds of supporters of the Balochistan National Party (BNP) had gathered. Two provincial officials, speaking on condition of anonymity, confirmed the death toll to AFP.Emergency services rushed to the scene as authorities launched an investigation into the attack.According to Dawn, Advocate Sajid Tareen, acting president of the BNP-M the attack took place shortly after a party rally marking the death anniversary of BNP founder Attaullah Mengal.A statement from the Balochistan Home Department confirmed that rescue teams had reached the site and that the wounded were being treated in local hospitals. Security forces swiftly cordoned off the area and have begun collecting evidence.Balochistan chief minister Sarfraz Bugti strongly condemned the attack, calling it a “cowardly act of enemies of humanity.” He said “malicious elements” were targeting innocent civilians and vowed that the “evil intentions of terrorists” would be defeated. No group has yet claimed responsibility.Pakistani forces have battled an insurgency in Balochistan for over a decade, with violence escalating in 2024 as 782 people were killed. In March, the Baloch Liberation Army seized a train, taking passengers hostage and killing off-duty troops in a three-day siege. Since January 1, over 430 people, mostly security forces, have died in attacks by armed groups in Balochistan and Khyber Pakhtunkhwa. On Tuesday, six soldiers died in Bannu after “a suicide bomber rammed an explosives-laden vehicle into the gate.”


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  • Partnerships Power Highland Electric’s Expanding Fleet of School Buses

    Partnerships Power Highland Electric’s Expanding Fleet of School Buses

    BRIAN KENNY: Welcome to Cold Call, the podcast where we dive deep into the stories behind groundbreaking Harvard Business School case studies. As we sit down to record today’s episode, there’s a hint of autumn in the air in Boston, and children across the US are getting ready to start the new school year, which, for many begins by climbing aboard a big yellow school bus, the largest transportation fleet in the country. Today we’re diving into a case that explores how one organization is attempting to transform that fleet from diesel to electric. It’s a story as much about reimagining American infrastructure as it is about leadership, and complex partnerships. We’ll talk about innovation, public-private collaboration, policy incentives, and the immense logistical challenges of scaling a climate-friendly solution that affects the lives of millions of children.

    And we’ll hear what it takes to maintain momentum, and customer trust when the road to change gets bumpy. Today on Cold Call, we welcome Professor Rosabeth Moss Kanter, and case protagonist Duncan McIntyre to discuss the case “’The Wheels on the Bus’ Go Electric: Highland Electric Fleets and Partners.” I’m your host Brian Kenney, and you’re listening to Cold Call on the HBR Podcast Network. Rosabeth Moss Kanter studies, and writes about strategy, innovation, and leadership for change. She has written innumerable articles, cases, and books on those topics, including her book, Think Outside the Building: How Advanced Leaders Can Change the World One Smart Innovation at a Time. Rosabeth, great to have you back on Cold Call.

    ROSABETH MOSS KANTER: Thanks Brian. It’s a total pleasure.

    BRIAN KENNY: Duncan McIntyre is the founder and CEO of Highland Electric Fleets. He’s the protagonist in today’s case. Duncan, thanks for joining us. This has got to be a very busy time for you.

    DUNCAN MCINTYRE: It is, Brian, thanks for having me. I love being the protagonist. Appreciate it.

    BRIAN KENNY: It’s a good title to have the protagonist as opposed to the antagonist. We don’t invite them on the show, so it’s great to have you here. Obviously, I hinted about the fact the school year’s about to start, those buses are going to be all over the roads pretty soon. Most of us remember them as big, bumpy, uncomfortable lurching vehicles. So, I think what you’re attempting to do, Duncan, is really improve that experience in a multitude of ways. So, why don’t we just dive right in. Rosabeth, I’m going to start with you and ask you what drew you to write the case, and why do you see Highland as a compelling study for business leaders? And importantly, what is your cold call when you start the discussion in class?

    ROSABETH MOSS KANTER: So, I’m very interested in innovations that can make a huge difference, not just a small difference. And so I was looking for climate solutions with very big potential for scaling, and that also would not meet with public antagonism that would delight people rather than scare people, which has been one of the change problems around a very big existential threat we face. And so Highland popped up in a conversation with one of the investors who had been in an HBS program, whom I knew, who was telling me about this. And I got incredibly excited because of the potential for not only being a scalable climate solution that could be a profitable business at scale, or even before scale, and could impact the lives of so many children. And I thought of children as change agents we never tap who tell their parents, whose parents get delighted and can therefore build a future that’s the future they want.

    We know that young people are most interested in climate more than older generations. And so I love the idea of Highland, which is built on a lot of complex partnerships and getting those school systems who are getting ready to have the buses, and by the way, Duncan’s buses had to be in place months ago in order for the school districts to be ready for back to school day. And so the cold call is a crisis that faced Highland when one of the largest customers and largest school districts in the US wasn’t getting the buses in time and had to quickly buy 80 diesel-fueled buses. Oh, my gosh. And were saying they had to look at alternatives, and maybe they would not go forward with the contract with Highland. So, I say to the students, You’re Duncan McIntyre. What do you do?

    BRIAN KENNY: That’s a leadership crisis in the works right there. So, I’m sure we’re going to talk a little bit about that. Duncan, let me turn to you. The case, I think, quotes you as saying something to the effect of, one of the motivators for starting Highland was that your child was at about eye level with the exhaust pipe of a school bus, and that made you think about this. Maybe you can talk a little bit about the motivation behind what you’re doing and what you’re trying to achieve with Highland.

    DUNCAN MCINTYRE: I’m happy to. Yeah, you’re spot on. I think the journey started for me when I recognized that our son, a second grader at the time, his mouth was literally at the same height as the tailpipe on a diesel school bus. The source of poor air quality in urban areas in our country and globally is not from power plants anymore. It’s from tailpipes, it’s from our transportation infrastructure, and predominantly it’s from diesel tailpipes. The reality is I recognized that we had the technology to fix this and shift it. Battery electric vehicles were getting more mature. The technology was being adopted by big bus and truck manufacturers, global companies like Daimler and Navistar.

    But it was really complex, expensive, and the implementation and the services needed were extensive, and the average public transportation department just isn’t staffed or resourced to do that independently. So, to me it was a problem worth solving, worthy of our time to solve, and a really interesting opportunity to stitch together a whole bunch of services and structured capital that makes it affordable and reliable to make this transition. As Rosabath very elegantly teed up early on, when you really get into building out the business plan and running the math, that’s an exciting business opportunity because these buses operate much cheaper than a diesel bus. The fuel’s cheaper, there’s less maintenance. And not only does it have a public health benefit, but long run has the promise of just being a cheaper, better alternative for cities, and towns alike. And so it became really exciting on paper, and it was compelling enough that I said, I got to leave my job. I got to go run at this, which I did.

    BRIAN KENNY: Yeah, that’s great. Rosabeth, you talked about change at scale in your opening remarks there. This certainly would be change at scale. I mentioned in the introduction this is the largest public transportation fleet in the country. I have no idea—you might know Duncan better than I do—how many school buses there are on the road, but it’s big. So, the opportunity is big. Rosabeth, how does that affect the way that Duncan and Highland need to think about scaling their business to meet this kind of a demand?

    ROSABETH MOSS KANTER: Well, so first of all, there is likely to be even more demand in the future because as this works, more and more school districts, cities will want this more, and more areas will want this, and it’ll be a demand for more buses. And so here’s Highland, which is really a services company, and yet works in incredibly closely with the bus manufacturers, then with the school district and with the utilities and so forth. Highland doesn’t have any control over the manufacturing of buses, but this really could be big. I can imagine this is one of the moves that will help increase demand for public transportation. So, that creates an enormous opportunity for electric buses in the regular fleet, but certainly for the schools. And I think it will help more parents decide that it’s not only safe but pleasant for their children to be transported in electric school buses. And that will be a cascade to the rest of public transportation, and cities. And so this itself can be a big business, but it also can have really big impact well beyond for other kinds of fleets, which I’m sure Duncan is eyeing.

    BRIAN KENNY: So, the stakes are huge. Duncan, I think the last thing any school superintendent wants is to be on the news around the start of school because something happens with the school bus fleet. And we see these reports all too often. The case talks about the fact that Highland is a little bit like a duck that’s calm on the surface, but the feet are moving rapidly beneath the water surface. And that speaks a little bit to the complexity of what you’re trying to do here. How do you think about making things as simple as possible for the people who are running the school district, because there’s so many other things that they have to worry about, and this shouldn’t be one of them.

    DUNCAN MCINTYRE: Despite all the benefits of electrification, the process and the path is complex, and the implementation upfront in getting an electric fleet up and running smoothly is complex. And then the ongoing services needed to support the fleet to keep it running smoothly is also complex, and it’s new. And so our approach, to answer your question, is to really bring the complete solution. We’re not bringing a part of it and telling the city they have to bring these three or four other things. The cities very often do have a strong workforce. They’ve got mechanics, and they’ve got drivers. And we typically like to partner with cities to provide workforce development and bring their staff up to speed to continue doing their jobs. But we try to bring all of the technology, all of the equipment, all of the construction that’s needed to build out the depot, make it an electrified depot, build it in a way that’s hardened so it can run for 40 or 50 years as a depot and then do all the implementation needed.

    If you’ve got one piece that’s out of sync, you may have a fleet that’s not running smoothly. And so as a result, since the market is early and still developing, we’ve had to vertically integrate at Highland, we’ve built a team for just about everything, and without that we would lose product control and not be able to deliver that sort of high-touch certainty to the cities and schools that we partner with. And I think over time we’ll find that the market will mature, and there could be more that’s done locally, but we’ve found that bringing it all together and really making it performance-based is the key to success in this stage of the market.

    BRIAN KENNY: Yeah, Rosabeth, let me ask you to comment on that because I’m wondering, and you’ve looked at a lot of different industries, you’ve looked at a lot of big problems at scale. Is this a huge differentiator do you think, for Highland to be able to vertically integrate and provide kind of a one-stop solution?

    ROSABETH MOSS KANTER: I mean, the ability to bundle a lot of services, and then the school district, the buyers, the customer doesn’t have to worry about dealing with lots of different subcontractors. That’s one huge advantage. Another is not displacing the current workforce. I mean, Duncan said work with the drivers, the mechanics that the district already has. Think about that. There’s a little blue-collar rebellion in America going on in light of digital and AI, but we need those mechanics and drivers. I don’t think parents would be happy with a driverless school bus. Maybe we’ll get to that someday, but I think it’s really in the distant future. This is a way to understand how to use existing resources in the school district as well as bring all the other services that model where you bundle. So, there are competitors looking at this, but they’re not necessarily looking at providing the whole services package. That is a differentiator. That’s always been a winning formula for businesses, help your customers succeed by bringing them innovative solutions.

    BRIAN KENNY: Duncan, I’d love to hear a little bit more about the challenges or opportunities with upskilling the existing workforce. The case does mention that some of the drivers that had to get behind the wheel on these buses were resistant. And I don’t know what it’s like for mechanics to work on a diesel engine versus an electric engine, but maybe you can talk a little bit about some of the challenges that you face there.

    DUNCAN MCINTYRE: I think it’s natural for folks to be hesitant if they’ve been in an industry that hasn’t changed much for 25, 30, 40 years, and this is exactly that moment in time. There’s drivers and mechanics who’ve come up through a traditional diesel engine, driving a bus that’s felt roughly the same for a long time. And so it’s natural that they’re hesitant. But once people experience it on their own, and they feel it, they tend to be really excited. The drivers find this ride to be smooth, quiet, and Zen-like, and there’s better braking and better torque.

    BRIAN KENNY: I never thought I’d hear those words in association with a school bus.

    DUNCAN MCINTYRE: I know. It’s really incredibly smooth and quiet. And so even the most steadfast naysayers have come around, and said, I’m never giving this bus back. I love it. So, that’s one piece.

    The second piece is, we often find that schools and cities want to work with us for different reasons. And one of the reasons is because they can’t hire enough diesel mechanics. There aren’t as many people who want to go into that trade anymore. And if you’re short-staffed at the local level, it doesn’t really matter how many drivers you have if you don’t have buses that are operable. And so when you take mechanics who may want to retire early, they’re tired of being covered in grease and oil at the end of the day, they’re tired of just the working conditions, and you show them how to diagnose a problem and how to fix something on an electric vehicle, there’s just very little to fix. There’s very few moving parts, and it’s the early days of the technology being rolled out, but the equipment is really darn good.

    And the net result is we’ve found it incredibly effective to run training and retraining and sort of an ongoing cadence of training in every community that we serve, sometimes monthly. And that makes a huge difference. It allows the workforce to stay in place. It creates a recruiting tool to recruit new drivers in some cases. And we’ve had many, many older drivers say that they’ll stay in the seat for more years because of this product. So, we just see it as essential and as an essential way to partner with communities.

    ROSABETH MOSS KANTER: I hadn’t thought about this as another benefit besides they’re quiet, and you have clean air—you save on laundry!

    DUNCAN MCINTYRE: You save on laundry! You do. We have a driver who came home, and said his wife met him at the door and gave him a kiss for the first time in five years because he didn’t smell like diesel fuel anymore.

    BRIAN KENNY: Imagine that.

    DUNCAN MCINTYRE: I mean, that brought a smile to my face.

    ROSABETH MOSS KANTER: That’s a wonderful story. And in fact, it’s all of these side benefits in children’s health, in the drivers being able to recruit and retain. And then the fact, Duncan, you also mentioned that you do the training, or you lead training, that’s another service that’s very important for the school districts. The school districts, like universities too, get burdened with administration and with having to do all these other things. What they really want to do is teach the children. So, this saves them from a lot of other areas they would have to manage. So, I’m even more sold than I was when I wrote the case.

    BRIAN KENNY: Duncan have you, I’m curious, have you surveyed the children about their experiences on the buses?

    DUNCAN MCINTYRE: We have. And the children universally just think it’s really exciting. One child years ago called it the magic bus, and that’s a name that stuck. They think it’s really interesting, and kids like to sort of get down on their backs, look underneath the vehicle, get inspired by the STEM aspects of how to think about a battery and an electric motor and the difference between that and a combustion engine.

    We’ve definitely been inspired by kids to author a whole bunch of curriculum that’s starting to roll out. This is not the business we’re in, but we’ve done it, and provided it for free to communities that want to think about this as a curriculum part of engagement in the curriculum of, in some cases, middle schools, and in some cases high schools. So, I think the feedback from students has been tremendous. And the last thing I would say is the community engagement is powerful in showing the versatility of these vehicles. These vehicles can actually, they’ve got big batteries, they can go back up a building when the grid’s out. And so we have a snow cone machine, and we send it around, and a school bus will come to a park in the summer and plug the snow cone machine in, and the snow cone machine will run off of the school bus because it’s got this energy-dense battery, and we give out free snow cones to every kid who wants to show up. And it’s been really fun and a neat way to really just get the word out.

    BRIAN KENNY: Yeah, that’s the way to a kid’s heart right there.

    DUNCAN MCINTYRE: That’s right. Snow cones on a hot summer day.

    BRIAN KENNY: Love that.

    Rosabeth, the case talks a lot about the importance of building partnerships, and you and I have had many conversations on this show over the years about how difficult it is to build those partnerships both now in this side we’re talking about with public agencies, with private enterprises. Can you talk a little bit about some of the leadership challenges that Duncan has probably faced—and Duncan, you’re free to jump in on this as well—in building, and maintaining these kinds of partnerships?

    ROSABETH MOSS KANTER: I mean, if you can deliver on your promises, like, that was the issue we talked about at the beginning. You don’t necessarily control how quickly the manufacturers can build buses. You don’t control all the politics, but this has a huge advantage because you don’t have to sell it as a climate solution. It had that, to many people, is a side benefit; to the kids, I’m sure it means a lot, especially the older kids. You sell it on efficiency, you sell it on the immediate benefits, and that’s what you have to do.

    In terms of your partners, I mean, what impresses me about Highland and the culture that you’ve built, Duncan, is that it’s very team oriented. And when a partner has an issue, you’re there immediately. I mean, I don’t want to give away the answer to what you did with Montgomery County, but you were on that airplane, high-emissions airplane, I must say, but high-emissions airplane right there and in their office to talk to them. Partnering is a very hands-on thing. It’s not a matter of signing a contract. It’s a matter of being there when they need you. It’s a matter of being on the ground and knowing their needs. And the customer here is every bit as much a partner as the suppliers, and the utilities. I mean some of these things, once people experience them, are unstoppable, but nurturing partners by being present, by being on the road, by traveling, by listening to them and their needs, by having dedicated teams that are experts in their field, that’s how you do it successfully.

    DUNCAN MCINTYRE: I agree. If I could just build on that, the partnership question, I think, is key. The manufacturers are key partners. We don’t manufacture the buses. We purchase them, we implement them, we get them running, we service them, we finance them, we kind of do everything else, but we don’t manufacture. The manufacturing companies have been leaning into this industry, they’ve been developing good product, but what they need is assurances. If they’re going to invest a hundred million dollars in building a new manufacturing line, they need to know they have an order book behind it. They need to know that the customers will be there, and they need to know that as they get to scale, they can streamline their supply chains and drop the price and make it a durable long-term product that survives without incentives. We are a key partner of the manufacturers in that part of their journey. In many cases, giving them visibility into our order book, giving them visibility into the data that we’re pulling off the vehicles operating every single day, helping them weekly improve the product and think about where we need to stock spare parts, where we need to change diagnostics. So, it’s a deeply integrated technical partnership, but also a partnership that allows us to invest in each other and help each other out as the going gets tough, which it does from time to time.

    And so when Montgomery County was faced with buses showing up late, and that was a difficult time for everyone, for the manufacturer, for the school, and for Highland, the supply chains coming out of COVID made it very difficult for lots of small manufacturers that supply key components to these vehicles. We had to roll up our sleeves and really get into the weeds. And the solution to a problem like that is by going deep into, What is the result we need? We want the electric buses running as soon as possible, but we may need a stopgap for three, four months in the interim. And so, there’s lots of strategies that can be solved quickly and efficiently if you have tight partnerships.

    ROSABETH MOSS KANTER: And the time to build those tight relationships is not when you have a crisis. It’s from the beginning so that when you have a crisis, you already know everybody. You can jump right in, and there will be a crisis. This is my “Kanter’s Law” that everything can look like a failure in the middle. And you hit those middles, and you have to be ready to move fast, because if you give up, it’s gone. It is a failure. If you keep going, if you persist, persevere, find a solution, then you can move it on to success. And here, success means not only that particular contract, because this is a new industry; success means the demonstration to everybody else, because if you give up, they’re going to give up, and the industry starts going downhill. This is an industry still vulnerable. You need people who actively support what you do and see the vision and are willing to go there with you. And so, you have a long-term vision. But it’s not the technology by itself; it’s the people and the relationships that you activate when you need to that make a company like this succeed.

    BRIAN KENNY: Excellent point. And I’ve heard “Kanter’s Law” mentioned a couple of times on this show in the past, so I’m glad that we still bring that up. Duncan, a question for you. Rosabeth talks about the fact that everything can look like a failure in the middle, and you’ve got to press on. Was there any point at which you thought, Oh, man, this is not going to work. I’m in over my head. I got to throw the towel in on this thing?

    DUNCAN MCINTYRE: Not a single time. I don’t mean to sound overly confident, but I’m an eternal optimist. Our mission at Highland has always been to make electrified transportation accessible and affordable to all communities. And so that’s serving Red Lake Nation in Northern Minnesota and serving Montgomery County and serving Compton in California. And it’s urban, it’s rural, it’s affluent, it’s historically very underserved. It’s everything in between. And when you do that enough times, you can see the durability of your service offering, and you can see the value and the benefits you bring to the communities that you serve.

    And then you also get to see the internal piece of the team that we’re building at Highland and the community and the family that we’ve built here. We’ve got 200 employees and growing. We’re serving closing in on a hundred cities by the end of this year. The “Kanter Law,” I like that, I might start using that, is that things will go bad in places. They will. And when you’re running complex transportation infrastructure in an urban environment, you’re going to have an issue every day. Forget about monthly, you’re going to have an issue every day. And so, if you build the teams and the technology backbones to streamline the process of fixing it every time something goes wrong, it’s very calming in the sense that you’re giving them the best experience you can give them. And you’re never going to have 100% uptime in a fleet. But if you can be in the mid to high nineties, that is a lot better than a diesel fleet. It’s a lot better.

    BRIAN KENNY: Pretty good, yeah.

    DUNCAN MCINTYRE: Correct. And so, I’m excited about the business, and I’ve never believed that the towel might have to be thrown in, I’m happy to say.

    BRIAN KENNY: Yeah, this has been a great conversation. We’re getting close to the end of our time. So, I’ve got one question left for each of you, and I’m going to give Rosabeth the last word on this. So, I’ll start with you Duncan. If you sort of imagine 10 years from now, what do you think success will look like for electrification, for Highland specifically? Is there sort of a vision that you have in mind where you’re like, Yeah, we hit our stride. We’re where we wanted to be?

    DUNCAN MCINTYRE: Success for electrification is a broad macro theme, and I believe 10 years from now, the vast majority of on-road transportation will be electric. It’s an upgrade in terms of technology. And I think the vast majority of transportation will be electric. If you unpack that a little bit, there’s always going to be people who want their personal vehicle to be based on a combustion engine platform. There are enthusiasts who I think will be tough to sway, but the vast majority of commuters, travelers are going to end up in an electric platform. When you get into medium and heavy duty, most of these vehicles have a job. They’re picking up trash, they’re moving students, they’re moving people around cities. Those are all incredibly naturally suited for electrification. And 10 years from now, 80, 90% of those fleets I think will be electric.

    The second part of your question is Highland. Our vision is to make this affordable and reliable for communities. And we’re investing to set up shop and prove to those communities that we can serve them long run. It takes a long time to develop those relationships and prove to communities that we’re going to be there for the long run. But that’s the way we’re investing. I think we’re building a really special, unique brand that is all around electrified transportation as a partner with cities. And that’s my vision for the company: I believe, we’ll be a platform business that continues to do what we’re doing today, supporting communities with energy, resiliency, and transportation, and all the workforce development needed to sort of bring those communities into a modern upgrade.

    BRIAN KENNY: So, what I’m hearing is it may not just be school buses in the future; we might be looking at other transportation as well.

    DUNCAN MCINTYRE: We’ll put electric garbage trucks on the road trucks this year. We’ll put a whole host of vans and other vehicles that serve schools and cities. And we’re finding that when we’re up and running in a city, they’re really eager to have our services extend beyond school buses. And so, we’re doing that actively today.

    BRIAN KENNY: That’s a perfect segue into my question for you, Rosabeth, which is, can you maybe talk about some of the leadership lessons that we can learn from what Duncan’s been able to achieve here? And is this really a case about the role of business and society and the kinds of things that business can do both to do well for themselves but also do well for their community?

    ROSABETH MOSS KANTER: This is a great example of how you can accomplish many goals with one solution. And if you’re aware of the larger context, and you have a big vision, then you can accomplish all of those goals for children’s health, for vehicle efficiency, for transportation efficiency, for reducing emissions.

    It’s also a great example of how we sell climate solutions. You don’t have to say “climate.” Again, those who like that will be ecstatic, but those who don’t, there are so many other benefits you bring. And so, you don’t just bring ideology. What business brings is they bring concrete solutions that benefit people. And then there are the micro leadership lessons. Like, you really understand the context your customer is in. You build close relationships with partners. You understand scaling. I mean, Highland scaled from something close to home that was pretty easy because they were very receptive to one of the biggest in the country. And then all this diversity you have to demonstrate over and over again. And then you build great teams with a culture that makes people want to work there and see the vision and care about the mission. And then you never give up. Kanter’s Law, you just never give up, and you celebrate success. So, I also love the culture of celebration that Highland has because each win buoys people’s spirits, and I hope that this particular case will make people see what’s possible. It’s happening, and it’s working.

    BRIAN KENNY: Duncan, the case mentions that there’s a gong every time you win a deal. Somebody hits the gong. I should have had you bring the gong on so we could all hear, but it’s busy, apparently.

    DUNCAN MCINTYRE: It’s a busy gong. That’s exactly right.

    BRIAN KENNY: That’s great. Rosabeth?

    ROSABETH MOSS KANTER: Well, between those snow cones and the gong, I mean, that’s another thing I want to say. I’m concluding that if we don’t make solutions to big problems fun, if we don’t make it enjoyable for people, they will never be part of it.

    DUNCAN MCINTYRE: Well said. Thank you.

    BRIAN KENNY: That’s a great way to end our conversation. Thank you for joining me on Cold Call.

    ROSABETH MOSS KANTER: Thank you.

    BRIAN KENNY: If you enjoy Cold Call, you might like our other podcasts: Climate Rising, Coaching Real Leaders, IdeaCast, Managing the Future of Work, Skydeck, and Think Big, Buy Small. Find them wherever you get your podcasts.

    If you have any suggestions or just want to say hello, we want to hear from you. Email us at coldcall@hbs.edu. Thanks again for joining us. I’m your host Brian Kenny, and you’ve been listening to Cold Call, an official podcast of Harvard Business School and part of the HBR Podcast Network.

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  • Platelets found to mop up DNA fragments and improve early cancer detection

    Platelets found to mop up DNA fragments and improve early cancer detection

    Platelets are probably best known for their role in blood clotting, making scabs and related, if less salubrious, contributions to heart attacks and strokes. But these tiny, saucer-shaped blood cells have other physiological duties as well, including surveillance for viral or bacterial infections, the recruitment of immune cells to the site of a suspected incursion and even the direct destruction of pathogens. Now, thanks to the findings of a Ludwig Cancer Research study, we can add to this rich portfolio an additional and critically important function.

    Researchers led by Ludwig Oxford’s Bethan Psaila and postdoc Lauren Murphy report in the current issue of Science that platelets may also help suppress systemic inflammation. Better yet, the way they do so can be readily harnessed to significantly improve the early and minimally invasive detection of cancer and the sensitivity of prenatal screening.

    While platelets do not have their own nuclei, we discovered that they act like sponges, mopping up the fragments of DNA that are released by dead and dying cells. Our bodies employ multiple mechanisms to clear these bits of DNA from the bloodstream, as they can provoke inflammatory and autoimmune disorders if they accumulate. Our findings suggest platelets play an important role in limiting the abundance of DNA fragments in plasma. Fascinatingly, we also discovered that they then release these pieces of DNA when they are activated, suggesting that platelets can deploy their DNA cargo in a manner that prevents nonspecific inflammation yet elicits targeted inflammatory responses where they’re needed, such as, say, at a site of injury.”


    Bethan Psaila, Ludwig Oxford

    Cell-free (cf) DNA can also include traces of circulating tumor cell-derived DNA (ctDNA). An increasingly sophisticated suite of technologies now exists to isolate and analyze ctDNA for the noninvasive detection of cancers and monitoring of responses to therapy. But ctDNA levels are very low, especially in the earliest stages of disease, when cancers are best detected. Its rarity reduces the sensitivity of cancer screening by such “liquid biopsies”.

    As it happens, the cfDNA collected for these diagnostics is currently isolated from blood plasma after all the blood cells, including platelets, have been discarded. The findings of this study suggest that a substantial proportion of cfDNA, including that derived from tumor cells, is contained within platelets, and this important source of information is therefore being missed.

    “We’ve demonstrated that platelets take up DNA fragments that bear the mutational signatures of cancer cells,” said Murphy. “This is true not only in patients with advanced cancer but, remarkably, also in people who have pre-cancerous polyps in their colon, suggesting that platelets may offer an additional and so far untapped reservoir of cfDNA that could significantly improve the sensitivity of liquid biopsies.”

    The finding that circulating platelets bear the genetic signatures of cancer has significant implications for cancer prevention.

    What prompted the researchers to look for DNA in cells that lack a nucleus?

    Platelets have a notable morphological quirk: they’re shot through, like sponges, with a network of membrane-lined channels called the open canalicular system. These channels allow them to release certain biomolecules essential to clotting and tissue repair upon activation and to pick up others, like viral RNA and DNA, as they circulate. Given the latter capability, Psaila hypothesized several years ago at a multi-institutional, cross-disciplinary brainstorming session organized by the philanthropy Cancer Research UK that platelets might also be picking up genomic cfDNA.

    In partnership with senior author Chris Gregory at the University of Edinburgh, Psaila prepared a pitch, winning a small award that allowed her to hire a research assistant, Murphy, to validate this hypothesis. A year later, the researchers had exciting data that helped Murphy secure a position in a PhD program and a major early detection project grant from Cancer Research UK.

    They and their colleagues, including Ludwig Oxford’s Benjamin Schuster-Böckler, whose lab conducted computational analysis for this study, showed that platelets indeed mop up human cfDNA in lab cultures and clinical samples. To prove that they weren’t just seeing residual DNA from megakaryocytes-nucleated cells from which platelets are derived-the researchers examined DNA from the platelets of pregnant women known to be carrying males. They report that they could predict the sex of the baby in every blood sample they analyzed by detecting fragments of the Y chromosome in the platelets, which could only have come from fetal cfDNA they’d mopped up in their travels.

    “Given their abundance, ease of isolation and tissue-wide perfusion, platelets are ideally positioned to serve as biosensors for genetic perturbations across tissues,” said Psaila.

    Future work in the lab will seek to clarify the role of platelets in the physiological management of cfDNA and the fate and consequences of DNA fragments released upon platelet activation.

    This study was funded by Ludwig Cancer Research, Cancer Research UK, the UK Medical Research Council, Rosetrees Trust, Kidani Memorial Trust and Yosemite.

    Bethan Psaila is an associate member of the Oxford Branch of the Ludwig Institute for Cancer Research and an associate professor in hematology at the University of Oxford.

    Source:

    Journal reference:

    Murphy, L., et al. (2025). Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA. Science. doi.org/10.1126/science.adp3971

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  • Marsquakes reveal exactly how the Red Planet was formed

    Marsquakes reveal exactly how the Red Planet was formed

    Scientists have been curious for years about what is hidden beneath the surface of Mars. With its freezing temperatures, red dust, and dry valleys, the surface of the planet has received most of the attention. But something big is buried deep inside Mars’ mantle.

    Thanks to NASA’s Insight lander, we’re finally getting a clearer look below the surface. And what’s there is surprising: leftover chunks from ancient cosmic crashes are buried deep in the planet’s mantle.


    These rocky fragments aren’t small. Some are as wide as 2.5 miles (4 kilometers). They’re scattered across Mars’ interior like forgotten debris from the solar system’s wild early days.

    Mars got slammed – hard

    Giant space rocks – possibly even protoplanets – crashed into Mars some 4.5 billion years ago. They impacted hard enough to melt enormous chunks of the planet’s crust and mantle, and form vast oceans of molten rock.

    When those impacts occurred, they shattered the surface. They blasted rocky debris, including parts of the impactors, deep into the interior of the Red Planet.

    Unlike Earth, which constantly reshuffles its crust through plate tectonics, Mars’ crust is made of a single plate that has stayed mostly stable.

    That’s why those ancient impact scars haven’t been erased. The fragments are still down there, frozen in place like time capsules.

    “We’ve never seen the inside of a planet in such fine detail and clarity before,” said Constantinos Charalambous of Imperial College London, the paper’s lead author.

    “What we’re seeing is a mantle studded with ancient fragments. Their survival to this day tells us Mars’ mantle has evolved sluggishly over billions of years. On Earth, features like these may well have been largely erased.”

    Scientists believe giant impacts — like the one depicted in this artist’s concept — occurred on Mars 4.5 billion years ago, injecting debris from the impact deep into the planet’s mantle. NASA’s InSight lander detected this debris before the mission’s end in 2022. Credit: NASA/JPL-Caltech
    Scientists believe giant impacts – like the one depicted in this artist’s concept – occurred on Mars 4.5 billion years ago, injecting debris from the impact deep into the planet’s mantle. NASA’s InSight lander detected this debris before the mission’s end in 2022. Click image to enlarge. Credit: NASA/JPL-Caltech

    InSight sees into Mars’ mantle

    All of this comes from a mission called InSight, short for Interior Exploration using Seismic Investigations, Geodesy and Heat Transport. It was run by NASA’s Jet Propulsion Laboratory in Southern California and the lander arrived on Mars in 2018.

    InSight was the first lander to place a seismometer on Mars’ surface. That device was incredibly sensitive and recorded 1,319 marsquakes before the mission ended in 2022.

    Quakes send out waves that travel through the planet. As those waves move through different materials, they change speed and direction.

    Scientists can study how those waves behave to figure out what’s inside the planet, kind of like how doctors use ultrasound to see inside the human body.

    “We knew Mars was a time capsule bearing records of its early formation, but we didn’t anticipate just how clearly we’d be able to see with InSight,” said Tom Pike of Imperial College London, coauthor of the paper.

    What causes marsquakes?

    Marsquakes still happen, usually for two reasons. Some are caused when rocks crack under pressure and heat. Others are caused by meteoroids slamming into the surface.

    A study published earlier this year in Geophysical Research Letters showed that meteoroid impacts can create high-frequency seismic waves.

    These waves travel deep into the mantle, which is a thick layer of rock beneath the crust. The mantle can be nearly 960 miles (1,545 kilometers) thick, and reach temperatures as high as 2,732 °F (1,500 °C).

    Eight of the marsquakes recorded by InSight had strong, high-frequency signals that got noticeably scrambled and delayed.

    “When we first saw this in our quake data, we thought the slowdowns were happening in the Martian crust,” Pike said.

    “But then we noticed that the farther seismic waves travel through the mantle, the more these high-frequency signals were being delayed.”

    Buried lumps in Mars’ mantle

    Computer simulations helped scientists figure it out. Those delays only happened when the quake waves passed through small regions of the mantle that had a different composition from everything around them. These were the buried impact fragments.

    Some were massive. Others were smaller. All were mixed into the mantle, which Charalambous compared to “shattered glass – a few large shards with many smaller fragments.”

    That fits with what we already know: In the early solar system, planets like Mars got hit often and hard.

    Charalambous said the fact that these features are still visible “tells us Mars hasn’t undergone the vigorous churning that would have smoothed out these lumps.”

    A cutaway view of Mars in this artist’s concept (not to scale) reveals debris from ancient impacts scattered through the planet’s mantle. On the surface at left, a meteoroid impact sends seismic signals through the interior; at right is NASA’s InSight lander. Credit: NASA/JPL-Caltech
    A cutaway view of Mars in this artist’s concept (not to scale) reveals debris from ancient impacts scattered through the planet’s mantle. On the surface at left, a meteoroid impact sends seismic signals through the interior; at right is NASA’s InSight lander. Click image to enlarge. Credit: NASA/JPL-Caltech

    What other planets might be hiding

    This discovery doesn’t just help us understand Mars. It also gives clues about other rocky planets – especially ones that don’t have tectonic activity, like Venus and Mercury.

    If Mars is holding onto traces of ancient impacts deep in its mantle, maybe those planets are, too.

    Mars has always been a quiet planet on the surface. But now we know that, deep inside, it’s holding the scars of an ancient and violent past – and it hasn’t let them go.

    The study was published in the journal Science.

    Image credit: NASA/JPL-Caltech

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