Andrea Thompson: Ever since I was a kid, I wanted a dog. But it wasn’t until I was an adult–newly laid off and missing a beloved cat that had passed more than a year earlier–that my husband and I adopted a 1-year-old mutt named Jack.
[CLIP] Thompson: Hi bud!
Thompson: Jack is a classic shade of brown, but a cartoonish mixture of a pitbull’s head and muscly chest and some unknown breed’s short little legs (our best guess is corgi). Sometimes when he sneezes, his head loudly–and hilariously–knocks against the floor. In the six years we’ve had him, Jack has come with his share of challenges. He is an incorrigible stealer of tissues and loses his mind when the doorbell rings.
[Barking]
Thompson: But he is an expert cuddler and loves every single person he has ever met. He is silly and playful. Having Jack has helped us meet so many more of our neighbors, get much more regular exercise walking rain or shine, and helped us teach our toddler about respecting the space and bodies of other beings. But it’s also meant that I’ve wanted to learn more about Jack and the relationship we have with our dogs.
This is Science, Quickly. I’m Andrea Thompson, Scientific American’s news editor for earth and environment – and sometimes fun animal science. Today, we’re speaking with University of Maryland computer scientist and famed internet “dog mom” of a pack of golden retrievers Jen Golbeck about her new book, The Purest Bond: Understanding the Human-Canine Connection, written with science writer Stacey Colino. It delves into the science of how we humans relate to our puppy pals and the many ways they improve our lives.
Thompson: Hi Jen, thanks for speaking with us.
Jen Golbeck: So glad to be here!
Thompson: One of my favorite moments in the book is when you describe how you cope with tough days and stress by laying on the floor and being enveloped “in a cloud of golden retrievers” licking and lying on top of you. It sounds like heaven. Jumping off from there, since your book is all about the bond people dogs, can you talk a little about some of the bonds you’ve had with your own pups throughout your life and what those have meant to you?
Golbeck: So we open the book with middle school. I had a really hard time in middle school. I mean, I was bullied. Everything in life sucked. And my parents bought me a golden retriever puppy whose name was Major. And he was everything I needed at that point, you know, non-judgmental. I didn’t feel awkward around him. And I loved dogs before that. But he, I think, was the first one who kind of opened my eyes to like the real power that that relationship can have. And so fast forward a bunch of time. Right now we have five dogs. We rescue special needs golden retrievers, seniors, hospice cases, like really complicated medical ones. And we get so much out of it, I can just lay on the floor and they all just like, come and envelop me. And I’m sure we’ll get into this with the science. It just makes you more relaxed and mindful. And in the moment.
Thompson: I did want to get to the science because I think that’s a lot of what’s really interesting in the book is that you get into all of these studies and really delve into the science of how we relate to our dogs and the impact they can have on us and vice versa. I don’t think people always know the nitty gritty of that, and I wondered if you could particularly get into some of the physiological impacts that dogs have on us and talk about the science there.
Golbeck: Yeah, if you look at any part of your life, whether it’s your physical health, your mental, your psychological, your social health, your dogs are going to make all of that better. So if we look, let’s just say at [the] physical health side, which is actually like how I got into the science of this. There is a great study that I saw maybe 15 years ago that talks about if you have a heart attack, for example, and you own a dog, you will live longer, then if you don’t have a dog and you could be like, well, yeah, if your dog, you’re like, walk more.So of course that would be why. But even if you controlled for the amount of walking, people who have dogs still live longer.
Thompson: Hmm.
Golbeck: And so this was a real question, right? Why? If it isn’t the physical activity, why is it that you live longer? And in fact, if you look across all of these different studies of the way that our physical health is improved by having dogs, one of the themes that emerges is something that we actually already knew from psychology, which is if you have a really robust system of social support, all of your health markers tend to be better like that. Social support is actually really critical for your physical health, not just your psychological health. And it turns out dogs are able to serve as those social support systems in our lives as well. So if we look at, say, older adults who, you know, maybe they’ve lost their spouse and their social circles are just smaller, dealing with loneliness. If they have dogs, they see these really dramatic increases in benefits from the dogs where people who have lots of people around them, really strong social systems, those benefits are still there, but they’re smaller. So it’s really clear that the dogs serve as social supports for us and give us that benefit on top of the fact that they do in fact get us out and walking more. They get us out spending time outside, which we know is really good for us. So there’s all these ways they kind of boost all of this stuff that we know is good for us and be like, Hey, you’ve got to come do this thing. Like we’re going to have a good time. And also it’s going to make you better.
Thompson: We’ve talked a lot about some of the specific areas of the science of dogs and humans and their bond. But of the dozens of studies that you guys mention in the book and you know, all of the research you guys did, were there any sort of favorite bits that stood out to you or anything that really surprised you?
Golbeck: Yeah. So one one favorite really stood out to me and I will say that when I was in middle school, I had a science teacher who told us that dogs didn’t really love us back and that like if they liked us, it’s because we were salty and they just wanted the salt then.
Thompson: Huh!
Golbeck: And I remember being so mad, but I also was 12, right? So I had like no capacity to argue back with the science teacher. But now I do. Now I have written a book to avenge that memory of probably sixth grade or whatever. The science is so clear that dogs love us back. Like I think anybody who has a dog knows that’s true. But my favorite result that we came across when we were doing the book is on that point. So we know from psychology about this thing called attachment bonds and the attachment bonds that we form with our parents, especially our moms, will go on to influence all of our relationships for the rest of our lives. They get set really early in our first couple of years. So if you’ve got a parent who is, you know, responsive and gentle and kind, you’re going to have secure attachment. If your needs are neglected, you might get a kind of anxious attachment. You know, you can sometimes change it, but it’s really important. So there’s a ton of research on attachment bonds. And one of the ways we’ve studied that is that they will put babies in fMRI machines, which are the things that show the part of your brain that light up when you’re thinking about different stuff. And then they’ll let them see their moms and a certain part of their brain lights up. That doesn’t light up for friends, you know, people who are they’re used to seeing or acquaintances. So we know that part of the brain is responsible for the attachment bond. That’s where it manifests neurologically. So researchers have done this study with dogs. They train dogs to lay really still in an MRI, which is kind of amazing by itself. And then they would have the dogs, humans come up so they could see and smell the person. And the same part of the dog’s brain lit up when they saw their human as happened in babies, when they saw their mother. So what we know is like on a neurological level, dogs have that same kind of love response when they see us as babies have when they see their moms. And that’s that. The only study that shows we have this real like biological evidence that our dogs love us back. We can measure it in hormone levels, like when we pet and interact with our dog, we all get that surge of oxytocin, this really good cuddle love hormone, but the dogs get it, too. So yeah, that was my favorite evidence that we found. And I just love how it’s this really classic science of love and connection that shows up perfectly with dogs.
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Thompson: So you got this a little bit in your answer, but are there any other misconceptions that maybe people have about dogs or how we relate to our dogs that any of the research you cite in your book got into or that you particularly want to dispel?
Golbeck: Yeah. One thing that I think is really important is a lot of people still have this idea of the alpha dog that there’s like this hierarchy. And people will ask me this all the time and I’m like, I have five golden retrievers, and they’re like, Which one is the Alpha? If I’m feeling kind, I will say I am.
Thompson: Right.
Golbeck: And the side effect of that environment was that they ended up establishing this hierarchy to survive these kind of torturous situations. Dogs are very social creatures. They live in families. So if you think of a family, you know, so you’ve got maybe some parents, you’ve got some kids, like is there an alpha there? I mean, there’s maybe somebody who’s a little more in charge and they’ve got a different personalities, but you’re all kind of coexisting together. And that’s really what dogs want to do. So if you try to adopt this kind of aggressive, like I am the alpha, you will do what I say, whatever, pin them down, do all of that stuff. Sure. I mean, dogs are smart and they’ll respond to that, but it’s not their natural way of doing it. They want to have a, you know, respectful, gentle, caring relationship. You know, you got to keep your dog in line sometimes, right? Sometimes we kill our dogs. No, you have to yell at them. It’s not like, oh, don’t ever say anything bad to them, but you don’t need to be this really dominating force. And I think a lot of people have that Alpha idea left over. And the science is really clear that that’s not the way that it works. Yeah, I think that’s great to get across to people.
Thompson: So to kind of wrap, I wanted to ask, what do you want people who maybe already have a dog or thinking about getting a dog to really take away from the book?
Golbeck: We talked about making a PowerPoint to go with the book for people who are trying to convince their family members to get a dog and just be like, Here is all the ways, right? Like presentation time. So if you are thinking about getting the dog, then you need evidence. That’s all this book is, is like evidence that the dogs have been good and like pretty much any aspect you care about. But you know, I think probably our main audiences, people who have dogs already on one hand, I don’t think there’s anything in there that’s going to be earth shattering for them. I think what it’s really going to be is recognizing a lot of your own experience. And then what you’re going to find is here is all this really rigorous science that backs up your own experience. One of the takeaways that I’ve heard a lot of people say is that I just felt so validated because sometimes people treat us like we’re little crazy or loving dogs as much as we do right? And this is going to give you all the scientific evidence that, like, you’re not making it up. All of this is real. It’s really profound. It has a great impact on you and you’re going to feel validated and you hopefully find out some new things about just how deep that relationship goes. I could have used that PowerPoint when I was a kid trying to convince my parents together. Maybe I’ll still make it. I’ll take some time for kids.
Thompson: Science quickly is produced by Jeff DelViscio and Tulika Bose. Our show was edited by Ella Feder and Alexa Lim. Our theme music was composed by Dominic Smith. Don’t forget to subscribe to science quickly wherever you get your podcasts. For science quickly, I’m Andrea Thompson.
New research on asexuality shows why it’s so important for doctors and therapists to distinguish between episodes of low libido and a consistent lack of sexual attraction
Credit: Marcos Chin
In graduate school people often asked Megan Carroll whether she was gay. Her sociology dissertation was on inequalities within communities of gay fathers, so her research participants were curious about how she identified. “I would say, ‘Oh, I’m maybe mostly straight? I don’t really know. It’s complicated.’” It was, at the time, the closest she could get to the truth. She’d had crushes on both boys and girls in high school and had been in a relationship with a man; being around her romantic interests sent her heart fluttering in her chest. But nothing like that happened when she considered having sex with any of them—she simply wasn’t interested. Her friends assured her she just needed to meet the right person, someone who would light her fire.
When that hadn’t happened by the time she was 18, Carroll thought she might simply have a low libido and went looking for an explanation. Thinking her birth control might be to blame, she spoke with a nurse, who suggested that perhaps her boyfriend was “just a bad lover.” Then Carroll wondered whether it was the pills she was taking to treat her depression. Over the next 12 years she visited multiple therapists, psychiatrists and physicians and tried different antidepressants—including a less commonly prescribed drug that gave her tachycardia, or a faster heart rate. Eventually she settled on one that had shown no measurable effect on sex drive in clinical trials.
Throughout these years of experimentation, Carroll’s libido—the physiological desire for sexual stimulation and release—did fluctuate. But what remained constant was that her libido was rarely, if ever, directed at another person, even her crushes.
In 2016 Carroll stumbled on a Facebook post about asexuality. She’d heard the term, typically defined as experiencing little to no sexual attraction, but had never felt that it applied to her. Then Carroll read a comment that mentioned demisexuality, a specific experience of feeling sexual attraction only after developing an emotional bond with someone. The idea that asexuality was a spectrum opened an entire world that had never been discussed in her gender and sexuality courses—one in which sexual desire was not necessary for a fulfilling life.
Because this idea subverts a cultural assumption about what it means to be human, it is often difficult for asexual people to recognize, let alone embrace, their identity. “Your very existence is, in some way, in opposition” to the societal norm, says CJ Chasin, an asexual gender and sexuality scholar at the University of Windsor in Canada. Even after realizing she probably was asexual, Carroll still visited doctors to experiment with her medications before finally accepting that she just is the way she is.
Over the past two decades psychological studies have shown that asexuality should be classified not as a disorder but as a stable sexual orientation akin to homosexuality or heterosexuality. Both cultural awareness and clinical medicine have been slow to catch on. It’s only recently that academic researchers have begun to look at asexuality not as an indicator of health problems but as a legitimate, underexplored way of being human.
In biology, the word “asexual” typically gets used in reference to species that reproduce without sex, such as bacteria and aphids. But in some species that do require mating to have offspring, such as sheep and rodents, scientists have observed individuals that don’t appear driven to engage in the act.
This behavior is more analogous to human asexuality, a concept rarely mentioned in medical literature until recently. In a pamphlet published in 1896, pioneering German sexologist Magnus Hirschfeld described people without sexual desire, a state he called “anesthesia sexualis.” In 1907 Reverend Carl Schlegel, an early gay rights activist, advocated for the “same laws” for “the homosexuals, heterosexuals, bisexuals [and] asexuals.” When sexologist Alfred Kinsey devised his scale of sexual orientation in the 1940s, he created a “Category X” for the respondents who unexpectedly reported no sociosexual contacts or reactions—exceptions from his model whom he estimated made up 1.5 percent of all males between the ages of 16 and 55 in the U.S. Asexuality was largely absent from scientific research over the subsequent decades, although it was occasionally referenced by activists and scholars in the gay liberation movement.
It wasn’t until the World Wide Web emerged that asexual people around the globe began finding one another on Internet forums. They started building a shared language in the early 2000s, mapping the landscape of asexuality through a grassroots development of concepts and labels. Calling themselves “aces,” they tended to split sexual and romantic attraction into spectrums of their own; asexual people can experience varying levels of each. Aces can be sex-repulsed, sex-neutral or sex-favorable; they may have sex frequently or never.* There are aces who have high libidos and aces with none to speak of. Some aces masturbate, and others don’t. Different as they are, members of the ace community are unified by their relative lack of sexual, and sometimes romantic, attraction to others.
At the time, however, being asexual could be considered indicative of a psychiatric disorder, according to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM). If someone reported being distressed by their low sexual desire, a doctor could diagnose them with hypoactive sexual desire disorder (HSDD). A person could also qualify for the diagnosis if their partner was upset by their low sexual desire—even if they themselves were fine with it. In other words, the person in a couple “who didn’t like sex enough had the disorder,” explains David Jay, founder of the Asexual Visibility and Education Network (AVEN), an online forum that became a starting point for much of the ace community.
Credit: Marcos Chin
Levels of sexual desire can fluctuate throughout life for many reasons that may or may not be a cause for medical concern, including changes to hormone levels or mental health. If someone is experiencing significant distress about a dip in desire, they may benefit from diagnosis and treatment. But asexual people tend to experience their lack of sexual attraction to others as a relatively stable orientation rather than a disorder requiring intervention. So when work began on an updated version of the DSM in the late 2000s, Jay and others at AVEN wanted to make this clear to the scientists drafting it. “We wanted researchers to, at the very least, understand how we think about ourselves before they interpret data about us,” Jay says. The AVEN team conducted a review of the literature and interviewed seven researchers, most of them psychologists.
AVEN put its findings in a report and sent it to the committee in charge of reevaluating the HSDD diagnostic criteria for the DSM‘s fifth version. One committee member was Lori Brotto, a psychologist at the University of British Columbia who was conducting some of the earliest studies of asexuality. Brotto found that AVEN’s report aligned well with what she was already learning from her research, which compared the behavior, experiences and physiological responses of self-identifying asexual people with those of nonasexual people who had received an HSDD diagnosis. She consistently found differences in responses among the asexual group that suggested asexuality shouldn’t be categorized as a sexual dysfunction.
In 2013 the DSM-5 was published with a revamped section on sexual dysfunction that split HSDD into male and female disorders with new names. Each one contained a line specifying that someone who identifies as asexual should not be given the diagnosis. This change meant that asexuality was no longer a disorder in the eyes of the American Psychiatric Association, and it opened up new ideas for researchers investigating sexual desire.
The study of asexuality developed throughout the mid-2010s and is now growing rapidly, says Jessica Hille, a gender and sexuality researcher at Indiana University’s Kinsey Institute. In a review published in November 2022, Hille found 28 studies on asexuality published between January 2020 and July 2022, “whereas 10 years ago I don’t know that you would have found 28 papers in the [entire] field,” she says.
Today “asexuality is widely accepted as a sexual orientation in the literature,” Hille says, but cultural awareness remains in its infancy, especially compared with other orientations under the LGBTQIA+ umbrella. Saying you don’t experience sexual attraction is still like saying you don’t eat, Hille explains, and “if you don’t eat, there’s something wrong with you, and you’re hurting yourself.” Asexual people sometimes get this message not just from family and acquaintances but from their health-care providers.
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Shelby Wren, a health equity researcher at the University of Minnesota, published a study in 2020 in which 30 to 50 percent of respondents who had disclosed their asexuality in a medical setting said a therapist or doctor had attributed their asexuality to a health condition. The proposed diagnoses included anxiety, depression and, in one case, a personality disorder. “You don’t know what’s going to happen when you disclose your sexual orientation,” Wren says. “And for a lot of people, that stops them from talking about things that could be relevant to their health care.”
For Rowan, an actor and writer based in Scotland, who asked to be identified by first name only, this very experience began with a routine appointment with their gynecologist. When the nurse asked whether they were sexually active, they said no—they had a boyfriend but hadn’t had penetrative sex. “I don’t want to,” Rowan recalls explaining to the nurse. “I don’t feel anything. I don’t feel ready enough.” Rowan, who was in their early 20s at the time, felt ashamed, “like there was part of me that wasn’t right, and I wanted it to be fixed.” The doctor referred Rowan to a psychosexual therapist. In their first therapy appointment, Rowan suggested that they might not be sexually attracted to anyone. They don’t recall the therapist mentioning that again over the course of four appointments; instead the therapist suggested a physical exam of Rowan’s genitals.
During the internal exam, Rowan felt “nothing” and removed from their body. “That was really confusing for me at the time, that a medical exam is just as cold and devoid of any feeling” as was physical intimacy with their boyfriend. Rowan recalls the therapist reporting that nothing was physically wrong with them and then spending the next few sessions trying to identify Rowan’s mental blockage. These encounters had lasting effects on Rowan, including dissuading them from seeking therapy to treat their depression.
Rowan is not alone. In a report on asexual discrimination published in October 2023 by Stonewall, a U.K.-based LGBTQIA+ rights organization, many interviewees reported that low awareness of asexuality had negatively impacted their health care at some point. One participant’s therapist told her to set goals to get over her “fear of sex” and to take a medication to increase her libido. Another participant’s therapist assumed that her asexuality stemmed from childhood trauma and would change with time, which led the participant to force herself to do things she was not comfortable with. And another participant’s doctor assumed her asexuality came from her antidepressants. (While antidepressants have been shown to impact one’s physiological desire for sexual release, or libido, there is no evidence that they lower one’s sexual attraction to others, which is the component of desire that is most relevant to asexuality, Carroll explains. Some asexual people have never taken these medications, including sources quoted in this article.)
Other stories in the report show what can happen when asexuality becomes the focus of doctor’s visits for completely unrelated issues, interfering with treatment and even causing harm. This was an “overwhelming pattern” in the report, says lead author and asexual activist Yasmin Benoit. One participant who was suffering from pelvic pain, for example, described how her general practitioner would not give her a referral to a gynecologist until she first saw a psychosexual therapist. This prerequisite resulted in a seven-month delay in treatment and, according to the participant, “extensive muscular damage.”
Refraining from disclosing one’s asexuality to a mental health provider is often a “very rational decision,” Chasin says. “It’s always much worse to be actively rejected and misunderstood.” For instance, asexual people are sometimes subjected to conversion therapy, a practice aimed at changing someone’s sexuality or gender identity. It is banned for minors in 22 U.S. states because of its well-documented and extensive harms, including increased rates of suicide. A 2018 U.K. government survey of LGBTQIA+ people found that asexual respondents were the most likely to be offered conversion therapy and as likely as gay and lesbian people to receive it. A recent survey by the Trevor Project found that 4 percent of asexual youths in the U.S. were subjected to conversion therapy, on par with bisexual respondents.
On the legislative level, bans on conversion therapy should explicitly reference asexuality, Benoit says. So, too, should professional associations of health-care practitioners, says Samantha Guz, a social work researcher at the University of Chicago. “Asexual people are made to be so invisible in our society that I don’t think just having a broad call against conversion therapy is specific enough,” Guz says.
Even well-meaning doctors might unwittingly harm their patients. To a clinician, a patient who is worried that they should feel more sexual desire—and who does not know they are simply asexual—might initially look similar to patients who want sexual intimacy and could benefit from treatments aimed at increasing or restoring desire. Treatments for certain types of sexual dysfunction do help some people whose level of sexual desire leaves them distressed and unsatisfied, Brotto says. For some people, though, this distress may be coming not from an intrinsic desire to want sex but from external pressures such as partners or society as a whole. “I have worked with folks where it’s taken us many, many months for the person to really understand how well asexuality fits with their identity,” as opposed to having an issue that is rooted in a health problem or a situational condition, Brotto says. Most doctors, though, don’t know that such a distinction exists or is necessary, she adds.
Since coming to embrace their asexuality, Rowan has become more comfortable with expressing love and receiving it from friends and partners without the weighted expectations of sex. With their most recent therapist, they finally had a positive experience talking about asexuality in therapy. “She would ask me specific questions about [my asexuality], but she didn’t make assumptions about what it meant,” Rowan says.
In early 2022 the American Association of Sexuality Educators, Counselors and Therapists published a position statement on how to care for asexual patients. It says asexuality is not a disorder or a response to trauma and that asexual individuals often face difficulty in finding affirming health care. (Unlike the DSM, the World Health Organization’s International Classification of Diseases still hasn’t specified that asexuality isn’t a disorder.) The association opposes “any and all” attempts to change or pathologize someone’s asexual orientation and labels such attempts as conversion therapy.
Jared Boot-Haury, a clinical psychologist and certified sex therapist, who drafted the statement, hopes that larger organizations such as the American Medical Association will put forward similar statements and, ultimately, clear and empirically supported guidelines for clinicians.
Meanwhile many studies of asexuality are moving beyond confirming it exists, instead exploring how ace people find intimacy in their relationships and personal fulfillment outside of the cultural scripts for building a life around a sexual or romantic partner. The asexual community has had to reimagine love and relationships to fit its needs; this wisdom could help everyone, asexual or not, Jay says. He cites the U.S. surgeon general’s recent report of an “epidemic” of loneliness, which showed how social connection has significantly decreased over the past 20 years.
“Because the ace community was denied the infrastructure of intimacy and had to invent our own, we have become this site of innovation that a lot of people, especially nonqueer people, suddenly are interested in,” Jay says. He is raising a child in a three-parent family, which was the subject of a 2020 Atlantic article. Jay now counsels people, asexual or otherwise, on how to build intentional relationships outside of cultural norms.
Carroll, now a sociologist at California State University, San Bernardino, also investigates resources for ace people that might apply more broadly. Some of her latest work examines the difficulty that asexual and aromantic people often face in accessing middle-class housing systems, which are built for nuclear family structures that might not be attainable or desirable for many asexual people, she explains.
Having found a home in the ace community both personally and professionally, Carroll now understands the distress that drove her to doctors’ offices quite differently. She must have known “deep down inside” that her disinterest in sex wasn’t a problem; it’s “the rest of the world that’s a problem,” she says. Today her students seem so “receptive to asexuality, wanting to learn about what I know.”
It’s not just young people who are coming around. When Carroll lectures about asexuality, she often tells a story about her mother, Laura Vogel, a licensed professional counselor who specializes in recovery from sexual trauma. Vogel knew traumatic experiences could decrease someone’s desire for sex, but for a long time she didn’t know that asexuality could be something entirely separate from that. When Carroll came out as asexual to her mother in 2017, Vogel began reading up on the subject and realized how her lack of awareness might have affected her clients. “That was a learning period for me,” Vogel told me recently. Since then, if a client expresses little to no desire to have sex, she sends them home with resources about asexuality to see whether it resonates.
“If a therapist had done what my mom now does … it’s hard to describe what that would have meant for me personally,” Carroll says. “That awareness can save asexual people years and years of uncertainty.”
Mucosal vaccines that prevent SARS-CoV-2 infection might provide benefits beyond existing intramuscularly administered vaccines: through enhanced individual-level protection against disease, and population-level reduction of viral carriage and transmission. Secreted neutralising antibodies are most likely to be the crucial effectors for such vaccines generating a mucosal response.
However, it is unclear to what extent intramuscular administration of SARS-CoV-2 vaccines enhances neutralising antibody titres in the mucosal compartment, nor the breadth of variants that are neutralised.
In response, we describe an adapted version of our high-throughput live virus microneutralisation assay for mucosal samples to establish the effect of fourth dose intramuscular mRNA vaccination on neutralising antibodies against six SARS-CoV-2 variants (Omicron BA.1, BA.2, BA.5, BQ.1.1, XBB.1.5, and XBB.1.16) in paired serum and mucosal samples from 149 participants (appendix p 4)
Mucosal samples were self-collected via nasopharyngeal swabs into viral transport media.
We found that intramuscular administration of a bivalent (ancestral + BA.1) mRNA vaccine enhanced mucosal neutralising activity (appendix pp 2,5), even when stratified by anti-nucleocapsid (anti-N) IgG negative and positive serostatus (previously uninfected or infected, respectively; appendix p 2). This boost appears restricted to variants closely related to the administered SARS-CoV-2 spike mRNA, with statistically significant enhancement for BA.1, irrespective of previous infection status (p=0·02 and p=0·032 in anti-N IgG negative and positive groups, respectively) and without statistically significantly improving neutralising capacity against more recently circulating (since summer 2023) and antigenically-distant variants in either anti-N IgG- (BQ.1.1 p=0·091; XBB.1.5 p=0·058; and XBB.1.16 p=0·67) or IgG+ groups (BQ.1.1 p=0·32; XBB.1.5 p=0·22; and XBB.1.16 p=0·25). Individuals with an equivalent number of exposures to the SARS-CoV-2 spike protein (through infection or vaccination) had similar quantities of mucosal neutralising antibodies (four exposures: [anti-N IgG- after dose four] vs [anti-N IgG+ before dose four]; BA.1 p=0·18; BA.2 p=0·32; BA.5 p=0·55; BQ.1.1 p=0·85; XBB.1.5 p=0·93; and XBB.1.16 p=0·18), reminiscent of serological findings
in which the number of spike exposures was the crucial determinant of neutralising titres.
To establish which antibody isotype might contribute to the boosting of mucosal neutralisation capacity, we measured the concentrations of total IgA and IgG in viral transport medium samples (appendix p 2). We found that IgA contributed much more to the mucosal immunoglobulin compartment than IgG (median fold-difference [IQR]; pre 20·5 [9·8–53·3]; post 21·6 [12·5–81·2]), and that neither isotype was boosted after vaccination (appendix p 4, IgA p=0·66; IgG p=0·061). However, we did detect a post-vaccine increase in the concentration of immunoglobulins that bound ancestral receptor-binding domain (RBD), present in individuals with and without previous infection (appendix p 4, anti-N IgG- p=9·4 × 10–7; anti-N IgG+ p=0·0064), by use of anti-N IgG serostatus to stratify previous infections. At a population level, anti-ancestral RBD antibody concentrations were positively correlated with variant-specific mucosal neutralisation (appendix p 4). These ancestral RBD binding per variant neutralisation relationships weaken with more antigenically distinct variants, and in those without previous infection.
Next, we established if there were relationships between serum and mucosal neutralisation (appendix p 7). We found positive correlations between serum and mucosal samples before dose four for BA.1, BA.2, BA.5, and BQ.1·1 (p=0·00025, p=0·00021, p=0·0025, and p=0·0015, respectively) but not the more recent variants XBB.1.5 (p=0·13) or XBB.1.16 (p=0·23). After dose four, there were no statistically significant correlations between serum and mucosal neutralisation, suggesting these compartments are differentially boosted. Within the pre-dose four comparisons, stratified by the presence of anti-N IgG, the correlations were predominantly driven by the individuals with previous infections (appendix p 7). Together, these observations suggest a weaker relationship between serum and mucosal neutralising immunity in uninfected individuals than in individuals with previous infections.
In summary, we have described a high-throughput method for live virus microneutralisation by use of nasopharyngeal sampling into viral transport medium and report several findings with broad applications. Nasopharyngeal self-swabbing into viral transport medium has the advantages of being an easy and economical method of sampling the upper respiratory compartment, avoiding proprietary sampling strips, and allowing repurposing of swabs used for viral testing and isolation. Importantly, parenteral vaccination boosts total mucosal neutralising capacity. Since this boost occurs in individuals both with and without previous mucosal challenge from infection, our data argue against a closed system of mucosal immunity only triggered by a mucosal challenge, such as infection.
Similarly, we identified a positive correlation between serum and mucosal neutralisation that was most apparent in individuals with previous infections, thus showing that infection propagates antibodies in both serum and mucosal compartments, and arguing against large mucosal-only locally produced antibody after infection.
Furthermore, similar quantities of mucosal neutralisation after equivalent numbers of exposures to SARS-CoV-2 spike proteins—via infection or vaccination—suggest that further boosts with intramuscular vaccines can enhance and potentially broaden mucosal neutralising capacity, as we have seen in the serum compartment. Identifying the sources for these mucosal neutralising antibodies will be the next steps (appendix p 8).
Ongoing large cohort studies will offer the opportunity to further explore these concepts and provide insights relevant to the adjudication of the best monovalent or multivalent formulations for vaccines targeting mucosal immunity. The viral transport medium sampling approach described here enables large-scale sample collection and testing for mucosal neutralisation required for vaccine evaluation,
and will allow further exploration of cross-compartment neutralisation—for both present and future generation vaccines—including those directly generating a mucosal response.
The year 2023 marked the 25th anniversary of the first detected outbreak of Nipah virus disease. Despite Nipah virus being a priority pathogen in the WHO Research and Development blueprint, the disease it causes still carries high mortality, unchanged since the first reported outbreaks. Although candidate vaccines for Nipah virus disease exist, developing new therapeutics has been underinvested. Nipah virus disease illustrates the typical market failure of medicine development for a high-consequence pathogen. The unpredictability of outbreaks and low number of infections affecting populations in low-income countries does not make an attractive business case for developing treatments for Nipah virus disease—a situation compounded by methodological challenges in clinical trial design. Nipah virus therapeutics development is not motivated by commercial interest. Therefore, we propose a regionally led, patient-centred, and public health-centred, end-to-end framework that articulates a public health vision and a roadmap for research, development, manufacturing, and access towards the goal of improving patient outcomes. This framework includes co-creating a regulatory-compliant, clinically meaningful, and context-specific clinical development plan and establishing quality standards in clinical care and research capabilities at sites where the disease occurs. The success of this approach will be measured by the availability and accessibility of improved Nipah virus treatments in affected communities and reduced mortality.
The increase in mpox (formerly known as monkeypox) cases in west Africa in 2017 should have served as a warning sign for potential outbreaks elsewhere. However, it was not until the multicountry outbreak in 2022, when WHO declared a public health emergency of international concern, that the disease received substantial global attention.
This mpox outbreak highlighted two issues in global health that must be addressed: high-consequence infectious diseases receive attention only when they affect high-income countries; and even when interventions are available, they might not reach those who need them most,
We must avoid repeating the same pattern with Nipah virus disease. Recurrent outbreaks in economically disadvantaged rural communities in south and southeast Asia have resulted in few attempts to understand and mitigate the disease. We should not wait until an extensive outbreak affects high-income countries before acting towards developing better treatment options and deploying them when and where they are needed.
Nipah virus is a highly lethal zoonotic paramyxovirus, which can infect humans through contact with infected bats, pigs, or humans or by consuming contaminated raw date palm sap.
The virus causes a rapidly progressive illness that affects the respiratory system and CNS, causing respiratory distress and encephalitis, with a very high case-fatality ratio. Since its discovery in 1998 and 1999 in Malaysia and Singapore, respectively, Nipah virus has caused sporadic outbreaks in Bangladesh, India, and the Philippines. Concerns exist about future outbreaks in other regions where Pteropus fruit bats, the zoonotic reservoir of Nipah virus, are found (table 1). The wide geographical distribution of these bats across Africa, south Asia, and Oceania, combined with the virus’ capacity for person-to-person transmission and evidence of ongoing viral evolution, underscores the potential for larger epidemics.
In 2018, WHO listed Nipah virus as a priority pathogen for urgent research and development and produced a roadmap to address the research needs for Nipah virus, including developing diagnostics, therapeutics, and vaccines.
Encouragingly, the Coalition for Epidemic Preparedness Innovations, primarily funded by public and philanthropic organisations, with some contributions from the private sector, has invested in the development of multiple vaccine candidates for Nipah virus. Notable progress has been made, with at least two candidates having reached in-human (phase 1) clinical trials.
In contrast, investment and progress in therapeutics development is less advanced; there are no approved therapies available for Nipah virus disease.
Clinical outcomes in patients with Nipah virus disease
Nipah virus mortality varies widely, from 9% in Singapore (the only high-income country reporting Nipah virus cases), to 100% in some transmission clusters,
The reasons for the differences in mortality rates between countries, which require further investigation, are presumably multifaceted and might include variations in the infecting Nipah virus strains (Nipah virus Malaysia vs Nipah virus Bangladesh),
patient characteristics, and access to adequate supportive care. In 2023, Bangladesh had the largest Nipah virus outbreak since 2015, with a case-fatality ratio of 71% with ten (71%) deaths out of 14 reported cases.
The continued high mortality is possibly a result of several factors, including delays in diagnosis, absence of specific therapies, and poorly effective supportive care.
The absence of laboratory infrastructure and diagnostic capabilities in rural areas where Nipah virus outbreaks occur creates challenges in early diagnosis, thereby impeding timely treatment.
Additionally, the non-specific initial signs and symptoms of Nipah virus infection, combined with the absence of point-of-care rapid diagnostic tests, often lead to delays in diagnosis in endemic areas, where many patients present with encephalitis of various causes. Distinguishing Nipah virus infection, representing only about 3% of all encephalitis cases in Bangladesh, from other causes of encephalitis is, therefore, challenging.
Treatment involves administration of oxygen, fluids, and nutritional support, and resuscitation as needed, alongside symptomatic treatment, including the use of antipyretics, anticonvulsants, medication for raised intracranial pressure, hypoglycaemia, and shock. Empirical treatment is typically initiated with antibiotics (intravenous ceftriaxone), antivirals (intravenous aciclovir), and steroids.
Patients with worsening conditions, such as deteriorating levels of consciousness, uncontrolled seizures, haemodynamic instability, and multiorgan failure are assessed for transfer to an intensive care unit or tertiary centre.
Improving patient outcomes in ongoing Nipah virus outbreaks remains a major challenge because there is no standardised supportive care available to patients in endemic areas, including timely access to intensive care units. Advancing knowledge to guide clinical care and improve outcomes for isolated Nipah virus infections and small clusters will be good preparation for a potential larger epidemic in the future.
Why is there so little progress in improving patient outcomes?
There are several key barriers to identifying and evaluating therapeutic interventions for Nipah virus disease.
Epidemiological challenges
Nipah virus disease is characterised by low prevalence even in endemic areas, with sporadic cases and unpredictable outbreaks in terms of location, size, and timing.
These characteristics present enormous methodological and operational challenges for clinical trials. Bangladesh, where the epidemiology of Nipah virus is well understood, and which has had the highest number of reported outbreaks, is a suitable site for potential Nipah virus therapeutic trials.
However, even in Bangladesh, Nipah virus infections remain infrequent and geographically dispersed, with an average of 14 confirmed cases reported each year.
The current epidemiological conditions make doing traditional phase 3 efficacy trials impossible.
Operational challenges
Nipah virus disease outbreaks occur in areas with little research infrastructure and clinical research capacity, leading to poor understanding of the clinical characteristics and outcomes of the disease and hindering the implementation of effective clinical trials. In addition, the shortage of laboratory and clinical infrastructure in rural communities in Bangladesh and India creates challenges for timely diagnosis and enrolment into research studies.
Moreover, the absence of biosafety level 4 facilities in Bangladesh to manage the high-level biocontainment requirements for handling Nipah virus, impedes locally led research on disease pathogenesis and the in-vitro and in-vivo evaluation of therapeutics.
In Bangladesh, where Nipah virus is endemic, surveillance of Nipah virus disease relies on a central laboratory located in the capital city, Dhaka. As a result, confirming a diagnosis can take several days or weeks.
Therefore, the development of rapid, ideally point-of-care, diagnostic tests and improved laboratory infrastructure and diagnostic capabilities is key for the accurate diagnosis and timely treatment of patients and prevention of disease spread.
Market and policy challenges
Apart from one inconclusive open-label trial with ribavirin during the Malaysian outbreak and a phase 1 study with the monoclonal antibody m102.4 done in healthy volunteers in Australia, no other human clinical trials have been done for any potential Nipah virus therapeutic candidates.
Little progress in therapeutic development reflects both a market failure and a global health policy failure. The small number of Nipah virus infections in countries unable to provide the substantial financial resources required to invest in the research and development process or to pay for stockpiling therapeutics, means that there is no financial incentive for profit-driven private sector investments. Equally, there have been few public investments made both at the local level and globally to support the discovery and development of new therapeutics and attract private sector actors into the types of public–private partnerships that have pushed drugs through the research and development pipeline in other disease areas, ideally creating affordable products and a sustainable local market.
There are potential therapeutic candidates for henipaviruses, including Nipah virus, currently progressing through the research and development pipeline, including at least eight small molecules and four monoclonal antibodies, which are mainly in the preclinical stage (table 2).
Only the monoclonal antibody m102.4 has phase 1 data available, and both m102.4 and ribavirin have been used on a compassionate basis during outbreaks.
To effectively evaluate potential interventions for improving patient outcomes in light of the aforementioned challenges, a coordinated, public health-focused approach must be adopted that maximises the chance of identifying and progressing the best therapeutic options in a timely way, that emphasises fairness, transparency, and equitable access to interventions for Nipah virus-affected communities.
We propose a model, similar to the West Africa Lassa fever Consortium, to generate essential elements of a pathway to develop and make available new treatments to people in need.
This model includes: laying out a clinical development plan that is regulatory-compliant, clinically meaningful, and context-specific; strengthening research sites’ capacity to meet regulatory quality standards (good clinical practices and good clinical laboratory practices); and ensuring good participatory practice for trials.
Moreover, the model recognises the need for involving key stakeholders both in Nipah virus-endemic countries and internationally, and establishing an end-to-end partnership and financing structure, in which all actors commit to the collective end goal of equitable access to effective treatments. The key aspects of this plan are summarised in the following sections.
Enhanced clinical epidemiology
A key clinical difference between Nipah virus outbreaks is that despite a consistently high proportion of patients presenting with encephalitis (about 97%), in Malaysia, fewer people had concomitant respiratory symptoms (14–29%),
The variation in pulmonary involvement is possibly caused by differences in Nipah virus strains and the route of infection. Experimental evidence indicates that the Nipah virus-B strain replicates more efficiently in human tracheal and bronchial epithelium than the Nipah virus-M stain.
Whether early ribavirin treatment during the Malaysian outbreak might have had a role in controlling virus replication in the lung, thus accounting for lower mortality, is unclear.
To gain a comprehensive understanding of the clinical characteristics and natural history of Nipah virus disease, including both encephalitis and pulmonary presentations, prospective observational clinical research is essential. This research can form the foundation for developing standardised clinical trial methodologies.
Such enhanced clinical epidemiology studies should also document current clinical care practices to identify gaps and inform the development of context-specific standard-of-care guidelines. During the Malaysian outbreak in 1998–99, ten (91%) of 11 patients cared for in a Singapore hospital survived,
suggesting that improving elements of supportive care can greatly improve patient outcomes.
Defining use cases and target product profile (TPP) for Nipah virus therapeutics
Developing safe and effective therapeutic agents to treat acute Nipah virus disease and acceptance of these agents by clinicians and patients is crucial for improving survival rates and reducing Nipah virus-associated morbidity and long-term disability. However, to design and select therapeutics that meet these objectives, we need to define use cases and a clear criterion for down-selection and prioritisation of candidate products for clinical trials.
Defining use cases of potential therapeutic options (figure) is essential to support the development of the TPP that serves as a guide for drug developers and other actors in the clinical development pathway, indicating the necessary and suitable characteristics for future therapeutic candidates after consultation with key stakeholders and end users.
The methodology for developing a TPP for Nipah virus disease should adhere to WHO principles, encompassing a major public-health need, considering end users’ perspectives, promoting access and equity, and fostering consensus among stakeholders for ethical research and drug development.
The TPP development process should also incorporate an end-to-end perspective connecting product development and regulatory, policy, and financing considerations.
This process should involve relevant stakeholders from national and international regulatory agencies, ethics boards, ministries of health, and clinicians experienced in treating Nipah virus disease. The needs and preferences of end users, clinicians, and survivors should also be incorporated into the TPP development process to define ideal treatment characteristics.
Rapid diagnostic capability, including point-of-care testing, is needed for early case detection and optimal deployment strategies for diagnostics in different geographical areas. Local laboratories must be able to do proficiency testing to monitor the reproducibility and performance of diagnostic field assays. National laboratory strategies for Nipah virus diagnosis and detection in the countries most affected by the virus should also be established.
Clinical trial design
To progress effectively, we need therapeutic candidates to advance through preclinical research, early human safety testing, and manufacturing, so that they can be tested clinically. Clinical trial protocols are also essential to ensure a coordinated and standardised assessment of the candidate drugs’ clinical safety and efficacy.
Pharmacometric trial
Repurposing existing marketed compounds for treating Nipah virus disease is a potential alternative or complement to developing new drugs, as this strategy capitalises on the existing compounds’ established safety profiles and reduces costs and time. Similar approaches were successfully used for COVID-19.
Pharmacometric modelling and simulation can be used to model in-vitro activity of potential repurposed therapeutic candidates targeting Nipah virus disease to evaluate the likelihood of clinically significant antiviral activity in vivo.
With potential preclinical data in animal models for Nipah virus therapeutic candidates (eg, remdesivir and favipiravir), pharmacometric evaluation of Nipah virus clearance rate from serial oral swabs quantitative PCR viral density estimates might offer a cost-effective and time-efficient method to prioritise potential candidates for further evaluation in clinical trials.
Core outcome sets, data variables, and phase 2/3 trial protocol
To establish a basis for the development of clinical trial methods, a core set of data variables and outcome measures should be developed and incorporated into trial protocols.
Consultation and consensus with stakeholders, such as clinicians, statisticians, clinical researchers, patients and public health representatives, regulators, and ethics boards are crucial to obtain their views on the trial design. The goal should be to use tools that are freely and publicly available, and ready ahead of time to be implemented in phase 2/3 therapeutic trials for Nipah virus disease. Although containing a recommendation for a core method, the tools should allow for context-specific adaptation and use by any member of the Nipah virus research community.
Given the challenges of phase 3 Nipah virus-specific trials in the current epidemiological conditions, a patient-centred syndromic approach appears to be pragmatic. By concentrating on encephalitis, the primary and predominant clinical presentation of Nipah virus disease patients (97% in India, 90% in Bangladesh, 88% in Singapore, 64% in the Philippines, and 55% in Malaysia), and doing trials to assess therapeutic approaches for all-cause encephalitis in endemic regions, we could substantially improve the management and clinical outcomes of encephalitis at large (figure). Previous encephalitis treatment trials, although low in number, have not succeeded in improving clinical outcomes. This two-pronged approach integrating Nipah virus-specific interventions into a broader syndromic strategy does not only address encephalitis in a patient-centred manner, but also provides a practical solution for dealing with low Nipah virus caseloads and builds clinical research capabilities that could respond to a change in epidemiology.
Creating a clinical trial platform that evaluates therapeutics to treat all-cause encephalitis, complete with a network of strategically positioned sites that have enhanced capacity, capability, and essential infrastructure required for trials, would be essential to empower local actors to assess clinically the candidate treatments selected. Given the low number of patients and available sites where trials can be done, the trials should adopt a portfolio approach, in which multiple drug candidates can be prioritised and evaluated under a single protocol.
An adaptive design should be used to allow inclusion of new drugs as they become available, either sequentially or simultaneously, and to drop that fail to meet efficacy and safety criteria and are not accepted by the patient community.
Capacity strengthening plan for clinical trials in endemic countries
To ensure effective clinical trials for Nipah virus disease, adequate research, clinical care, and diagnostic capabilities at participating sites are essential. The trial capacity assesment would involve mapping out potential study sites and assessing their capacity, including facilities, equipment, human resources, research infrastructure, and background information on Nipah virus disease case management. Capacity gaps should be identified, and capacity strengthening requirements should be defined to assess individual, organisational, and environmental capacity needs, along with the required investments to upgrade. These assessments should be done using standardised methods.
Investments should be made to boost sustainable research capacity across the Nipah virus research landscape, including training of clinicians and researchers, development of data platforms for observational and multicounty research, outreach, education, and enhancing capacity for data sharing and analysis. Meeting good clinical practice, good laboratory practice, and good participatory practice for trials will be a prerequisite for research centres to participate in these trials.
Community outreach and engagement
Understanding the expectations of the Nipah virus-affected communities and involving their members in the research is essential for successful and impactful research. Furthermore, as research interventions aim to improve the outcomes of people affected by Nipah virus, patients and Nipah virus survivors should be involved in the decision-making processes, the results of which will ultimately affect them and future patients. Examples of this engagement could include community involvement in the TPP development process of new therapeutics, where factors such as acceptable drug administration and side-effects can be advised from a community standpoint.
These engagement initiatives will also lead to a greater chance of acceptance and implementation of any potential therapeutic interventions. However, social and behavioural barriers might also affect the implementation of interventions through preventing patients from accessing health care. Nipah virus-related stigma is one such barrier. Tools are being developed in collaboration with the International Centre for Diarrhoeal Disease Research, Bangladesh to measure the types and extent of stigmatisation associated with Nipah virus disease to reduce this issue.
The International Centre for Diarrhoeal Disease Research in Bangladesh in collaboration with the Institute of Epidemiology Disease Control and Research, the Ministry of Health and Family Welfare, and Government of the People’s Republic of Bangladesh, has developed a Nipah virus survivor support programme. This programme involves following up a cohort of Nipah virus survivors to monitor the long-term consequences of Nipah virus disease. By involving these survivors in research design and gaining insights into their lived experiences, valuable information can be gathered to inform strategies aimed at helping communities access the health care they need while promoting the uptake of potential treatments.
Developing a viable value proposition and ensuring access to potential therapeutics
To effectively respond to the urgent public health needs for Nipah virus therapeutics, a comprehensive approach is required that includes securing funding from multiple sources, advocacy to policy makers and global stakeholders, and the development of a clinical trial platform embedded in the local health system that serves as the central asset around which value is created.
The value proposition should be informed by a robust assessment of the risk of future Nipah virus outbreaks and the economic, societal, and health effects that such outbreaks could generate. A partnership between drug developers and the trial sites platform should be defined upfront to serve public health goals, leveraging different capabilities and financing opportunities towards ultimate availability and access to potential Nipah virus treatment. Having pre-established agreements in place for drug availability and pricing will avoid repeating the inequalities seen in cases, such as Ebola virus disease and COVID-19.
Ebola virus disease, COVID-19, and mpox epidemics have underscored the importance of a coordinated, public health-centred, and end-to-end research and development ecosystem that can deliver appropriate countermeasures to address outbreaks where and when they occur.
This approach will help to ensure equitable access to adequate health care for neglected populations, and to prevent onward wider transmission and spillover.
In addressing the challenges posed by Nipah virus, a coordinated public health approach is essential to prioritise fairness, transparency, and equitable access to interventions for Nipah virus-affected communities. The clinical development plan for Nipah virus therapeutics should be co-developed with the leadership and ownership of the Nipah virus-endemic country. Collaboration among researchers and institutions within affected nations should empower local communities and ensure they are the primary beneficiaries of research outcomes when needed. To address concerns about equitable access to potential interventions in Nipah virus-endemic countries, especially where trials are done, post-trial access and benefit-sharing commitments must be integrated into trial protocols, financing contracts, and collaboration agreements upheld by local authorities and ethics committees. International research institutions and funding bodies must design funding mechanisms with clear conditionalities that prioritise the development of suitable treatment and enable their availability and equitable access.
Health-care systems, food supply chains, and society in general are threatened by the inexorable rise of antimicrobial resistance. This threat is driven by many factors, one of which is inappropriate antimicrobial treatment. The ability of policy makers and leaders in health care, public health, regulatory agencies, and research and development to deliver frameworks for appropriate, sustainable antimicrobial treatment is hampered by a scarcity of tangible outcome-based measures of the damage it causes. In this Personal View, a mathematically grounded, outcome-based measure of antimicrobial treatment appropriateness, called imprecision, is proposed. We outline a framework for policy makers and health-care leaders to use this metric to deliver more effective antimicrobial stewardship interventions to future patient pathways. This will be achieved using learning antimicrobial systems built on public and practitioner engagement; solid implementation science; advances in artificial intelligence; and changes to regulation, research, and development. The outcomes of this framework would be more ecologically and organisationally sustainable patterns of antimicrobial development, regulation, and prescribing. We discuss practical, ethical, and regulatory considerations involved in the delivery of novel antimicrobial drug development, and policy and patient pathways built on artificial intelligence-augmented measures of antimicrobial treatment imprecision.
Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0–100), 5-year progression-free survival was 80·5% (95% CI 72–92), and 5-year overall survival was 77·2% (95% CI 65–89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25–26 Gy in one fraction, or 42–48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.
Mammographic screening for the detection of breast cancer has been the subject of a divisive debate for more than 20 years. Major arguments against screening have been the frequency of false positive scan results and overdiagnosis. However, with breast cancer incidence and mortality due to late diagnosis increasing globally, along with improvements in screening technology, there has been a growing acceptance that screening extends lives. However, questions continue to emerge with respect to screening age, who to screen, and how often to screen, among other issues.
Breast cancer screening in high-income countries includes a large age range and often involves frequent screening. The US Preventive Services Task Force recommends screening for women starting at age 40 years; the Ontario Government in Canada, will permit self-referral for publicly funded mammograms at age 40 years beginning in autumn, 2024; in the UK, all women between the ages of 50 and 70 years are invited for screening every 3 years; and the European Commission’s Initiative on Breast Cancer Guidelines strongly recommends women between the ages of 50 and 69 years have screening every 2 years. However, breast cancer screening rates vary substantially. In the EU, rates are as high as 83% in Denmark and as low as 21% in Bulgaria.
In comparison, breast cancer screening coverage and access in low-income and middle-income countries (LMICs) is alarmingly low. In sub-Saharan Africa, diagnosis of breast cancer is largely based on self or clinical examination, and is often found at an advanced stage of disease, leading to poor treatment outcomes and high mortality. Mammography technology is difficult to adopt and maintain due to availability issues, high costs, and shortage of experienced practitioners. A large proportion of Black women present with aggressive triple-negative breast cancer at a younger age and with high breast tissue density, which makes disease detection by mammography less accurate. Furthermore, poverty, sociocultural and religious beliefs, misconceptions about the disease, stigma, and lack of autonomy make women hesitant to proactively approach the health-care system. Breast cancer awareness campaigns have been somewhat successful at promoting engagement with prevention and screening strategies, but much more remains to be done. In December, 2001, The Lancet Oncology published an Editorial on poor cancer-screening uptake among ethnic minorities; 22 years later, screening awareness, access, and uptake continues to be inadequate.
To achieve the benefit of screening across ethnicities and geographies, it is important to acknowledge that a one-size-fits-all approach will not work. Current screening programmes are predominantly based on an understanding of breast cancer in White women. The genetic and lifestyle modifiers in more diverse populations remain largely unknown. There is an urgent need to design new paradigms of screening that incorporate a greater understanding of the varied risk profiles of diverse populations.
It is time to apply the principles of precision oncology to breast cancer screening strategies. The idea of risk-based screening is not groundbreaking—it is already standard practice to screen women with BRCA gene mutations at an earlier age and more frequently than the general population. Breast cancers vary tremendously in their timing of onset, rate of growth, and probability of metastasis, and tailoring screening on the basis of an individual woman’s risk would be the ultimate goal. The WISDOM Study is an example of a trial that aims to compare a personalised risk-based approach to traditional annual breast cancer screening strategies. It is important to recognise that programmes that are beneficial in high-income countries might be difficult to implement and unrealistic in low-resource settings. Per the WHO Global Breast Cancer Initiative, early detection strategies will vary based on health-system readiness. Until the required infrastructure and quality control measures are established, breast cancer screening in LMICs might require focusing on affordable, easy-to-use, alternative solutions, such as the iBreastExam.
There is no doubt that timely screening saves lives by enabling treatment at earlier stages when it is more effective, better tolerated, and less expensive than in advanced cancers. We have come a long way from the start of the screening controversy, and by adopting a tailored, region-specific, biology driven, dynamic approach to screening, precision screening of high-risk individuals is within our grasp.
An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk.
Methods
In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40–70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol–SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone–SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 – the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing.
Findings
3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106–156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol–SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone–SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol–SHBG ratio, but not in quartile 1 (0·18 [–0·60 to 0·59]).
Interpretation
These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor.
A cancer diagnosis can carry a heavy economic toll on people who are already experiencing financial hardship, and there are systemic inequalities in end-of-life care that are not yet fully understood. Although there is consistent evidence that dying at home is generally considered preferable to dying elsewhere, people from socioeconomically deprived areas are less likely to die at home, the gap in at-home deaths between rich and poor people is widening, and the relatives of the deceased report low levels of satisfaction with the care their loved ones received. However, socioeconomic research can potentially reduce complex life experiences to dry statistics, and researchers run the risk of dehumanising people who have already been marginalised at a time when respecting their dignity is paramount. In light of this, Glasgow University’s End of Life Studies Group commissioned award-winning photographer Margaret Mitchell to document the lives of some of the people who are facing financial hardships alongside terminal illnesses as part of their Economic and Social Research Council-funded research projectDying in the Margins. Over the course of the study, she produced As the Day Closes, a body of work that documents individuals living in financial hardship at the end of their life and provides an insight into what preoccupied them towards the end of their lives.
The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up.
Methods
VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete.
Findings
From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1–5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58–70] vs 56% [50–63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59–1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21–32] vs 40% [34–46], HRstrat 0·61 [95% CI 0·45–0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60–73] vs 57% [50–64], HR 0·71 [95% CI 0·52–0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18–30] vs 38% [32–45], HR 0·55 [0·39–0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]).
Interpretation
Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer.
ARYAN'S BLOG 
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