Tragedy strikes in Mexico as Shane Dorians traveling companion … – BeachGrit

"All action, no lulls."

The wait is finally over. Surf fans have, since the invention of the World Surf League in 2015 circa 1976, have circled these rough dates on the calendar and wait with bated breath each and every year. For it is generally around this time, here, that the global home of surfing releases its tagline which will be used for the season.

The World Surf League, dedicated to changing the world through the inspirational power of surfing by creating authentic events, experiences, and storytelling to inspire a growing, global community to live with purpose, originality, and stoke, has produced some memorable ones in the past.

But who, here, could forget the classic You cant script this which directly highlighted the fact that professional surfing can, in fact, be easily scripted.

Or the gem It takes a tour to make a title that was rolled out right as the brain trust was sorting out how to make a title happen in one finals day.

All very good but 2024s has to be the best.

All action, no lulls.

Now, the aforementioned surf fans know, well, that professional surf watching is around 80% lull, even when the waves are firing. We also know that this past 2023 Championship Tour season reached a whopping 97% lull. It is an accepted part of the game, moments when Joe Turpel dribbles words, Strider Wasilewski ups amp, Pete Mel considers orthopedic shoes. Lulls are essential but Im certain the conversation around flat seas reached all the way to the offices of the twin CEOs, whom took over after Erik Logans belittling, and started the wheels turning.

How to fix?

Like anyone who has ever been taught how to master a job interview in high school, the WSL brass decided to turn weakness into strength, though.

Seriously.

The new slogan is All action, no lulls.

David Lee Scales and I discussed, anyhow, during our weekly chat along with a dive into professional baseball being way, way edgier than surfing.

In the parlance of our time, it was all action, no lulls.

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Tragedy strikes in Mexico as Shane Dorians traveling companion ... - BeachGrit

Cases of HIV cure | aidsmap – aidsmap

This page provides information on people who have been cured of HIV or appear able to control the virus without treatment. These cases have all been reported by scientists in medical journals or at scientific conferences. Sometimes, people are described as having long-term viral control without antiretroviral therapy (ART) or being in remission. This reflects uncertainty about whether HIV levels might eventually rebound.

While these cases are unusual, a major focus of HIV cure research involves finding out how these people manage to control their HIV, and developing therapies to help more people do the same thing.

Several cases of HIV cure or long-term viral control have been reported in people who received stem cell transplants to treat life-threatening leukaemia or lymphoma. Stem cells are cells produced bybone marrow (aspongytissue found in the centre of some bones) that can turn into new blood cells.

In all but one of the cases, people with HIV received stem cells from a person who had natural resistance to HIV infection due to the presence of the double CCR5-delta-32 mutation. People with this rare genetic mutation do not have CCR5 receptors on their immune system cells, so HIV is unable to gain entry to cells.

The first person cured of HIV was Timothy Ray Brown, an American then living in Berlin, who received two stem cell transplants to treat leukaemia in 2006. The donor had double copies of a rare gene mutation known as CCR5-delta-32 that results in missing CCR5 co-receptors on T cells, the gateway most types of HIV use to infect cells. He underwent intensive conditioning chemotherapy and whole-body radiotherapy to kill off his cancerous immune cells, allowing the donor stem cells to rebuild a new HIV-resistant immune system.

Brown stopped ART at the time of his first transplant but his viral load did not rebound. Researchers extensively tested his blood, gut, brain and other tissues, finding no evidence of replication-competent HIV anywhere in his body. In December 2010, Brown, known as the Berlin patient, began speaking to the press and at this point researchers started using the word cure for him. It was revealed that Browns cure for HIV had been far from easy. Despite this, Brown survived for 14 years from the date of his bone marrow transplant without any sign of HIV returning. He moved back to the US and became an ambassador for HIV cure research. He died in September 2020 at the age of 54, of the leukaemia that first prompted his treatment.

Browns case led researchers to look for similar donors in subsequent situations where people with HIV needed stem cell transplants.

A second case was reported in 2019. Adam Castillejo, the London patient, received a stem cell transplant from a donor with natural resistance to infection as part of treatment for Hodgkin lymphoma. He stopped antiretroviral treatment 16 months after the transplant, by which time all his CD4 cells lacked CCR5 receptors. Still controlling the virus without ART a year later, Castillejo went public. The COVID pandemic prevented him and Timothy Ray Brown ever meeting, but they did talk on the phone before Browns death. He has now been off ART for five years with no trace of HIV.

Marc Franke, the Dsseldorf patient, received a stem cell transplant to treat leukaemia from a donor immune to HIV in 2013. More cautious than Castillejo, he did not stop taking ART until November 2018. His remission from HIV was first announced at the same time as Castillejos in 2019, although it attracted little attention at the time. In February 2023, after more than four years of extensive testing, his doctors declared him cured of HIV. Later that year, Franke told POZ magazine that he has met his donor and also keeps in contact with other people cured of HIV.

The New York patient was described in February 2022. She was notable as being the first female case, and as of that date had been 14 months off ART without her HIV returning. She received a haplo-cord blood transplant to treat leukaemia in 2017. This is a different kind of stem cell transplant, used in circumstances where it is difficult to find a close genetic match, using cells from more than one donor. In this case, umbilical cord blood from a donor with the double CCR5-delta-32 mutation were supplemented by cells from a relative without the CCR5-delta-32 mutation. This procedure was necessary because the woman was mixed-race and the mutation that confers immunity to HIV is found almost solely in people of White European ancestry.

Paul Edmonds, the City of Hope patient, is a Californian named after the cancer centre where he was treated. As reported in July 2022, he received a stem cell transplant to treat leukaemia from a donor with a double CCR5-delta-32 mutation. He is the oldest person so far to experience viral control without treatment (63 years), has been living with HIV the longest (31years), and has the lowest CD4 nadir (below 100). He stopped ART two years after his transplant and has shown no trace of HIV in the 17 months since, with his leukaemia also in remission. Edmonds went public to the newspaper USA Today in April 2023.

Most recently, a Swiss man known as the Geneva patient became the first person to experience HIV remission after a stem cell transplant in 2018 containing cells that did not have the double CCR5-delta-32 mutation. Based on the results of some previous transplants, scientists had assumed that HIV remission after a stem cell transplant was possible only after a transplant from a donor with the double CCR5-delta-32 mutation.

The Swiss man had been taking antiretroviral treatment which fully suppressed HIV since 2005. He received the transplant after chemotherapy and radiotherapy to treat leukaemia. Host CD4 cells were completely replaced within a month of the transplant, but he had graft-versus-host disease, which occurs when donor immune cells attack the recipients body. This required treatment with ruxolitinib, a JAK 1/2 inhibitor, which has also been shown to reduce the size of the HIV reservoir. Ultrasensitive viral load testing could not detect HIV after the transplant and the man undertook a planned treatment interruption. No viral rebound had occurred 54 months after transplantation and HIV DNA levels continued to decline off treatment. This intriguing case raises new questions about potential mechanisms that could lead to HIV remission.

Researchers stress that these are unusual cases and attempts to replicate them in other people undergoing cancer treatment have failed in some cases. Stem cell transplants are far too risky for people who do not need them to treat life-threatening cancer, and the intensive and costly procedure is far from feasible for the vast majority of people living with HIV worldwide.

Several cases of HIV control after discontinuing treatment have been reported. These individuals are known as post-treatment controllers.

In many but not all of these cases, the post-treatment controllers had received very early antiretroviral treatment within the first few weeks after infection which sometimes allows the immune system to get ahead of HIVs ability to evade the bodys natural response to it, producing broadly neutralising antibodies and other immune responses that stop more HIV being produced. This results in a much smaller than usual reservoir of cells containing intact proviral DNA. This strategy usually only works if people are treated very early, and it only produces long-term viral control in a fraction, such as a number of patients in France, the US and Germany.

In 2022, the latest report on the French VISCONTI cohort identified six men and four women who started a course of ART within three months of infection, subsequently stopped it, have remained undetectable and have not re-started treatment. Viral loads before treatment were generally high and ART was taken for at least one year. Seven of the ten have now remained undetectable for more than ten years, including one man who stopped treatment 17 years ago.

Acronym for antiretroviral therapy. Antiretroviral therapy usually includes at least two antiretroviral drugs.

Cells from which all blood cells derive. Bone marrow is rich in stem cells.

A substance that acts against retroviruses such as HIV. There are several classes of antiretrovirals, which are defined by what step of viral replication they target: nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; integrase (strand transfer) inhibitors.

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

However, there were an additional nine people in the cohort who had periods of low but detectable viral load during follow-up, and a further three people who needed to re-start ART due to raised viral loads.

Its possible that cases of post-treatment control are not more commonly identified simply because, once having started ART, few people stop. A review of several studies suggests that around one person in nine treated very soon after infection may be able to control HIV for at least a year without treatment, while another suggested the proportion might be less than one in 20.

Children started early on ART are thought to be especially good candidates for post-treatment control as they can be started on ART very soon after infection, and they have fewer effector-memory T-cells, which are the type that become latent and hide HIV.

A South African childs case was first presented in 2017. Born with HIV, he was started on ART when he was two months old and taken off it, as part of a clinical trial of early-treated children, when he was one year old. He was still undetectable off ART in 2022 at the age of 13. He had a very weak immune response to HIV but strong activity in a gene that codes for PD-1, an immune checkpoint cell-surface protein that forces immune cells into latency in other words, to force HIV to hide inside the reservoir cells and not come out.

A study of 281 mother-infant pairs identified five South African boys who had controlled HIV despite non-adherence to postnatal antiretroviral treatment. All infants in the study who had acquired HIV received antiretroviral treatment after delivery and 92% were also exposed to the medication in the womb. Infants had been off antiretroviral treatment for between three and 19 months at the time the study reported its findings. HIV control off treatment was associated with HIV that remained sensitive to type 1 interferon and virus with higher replicative capacity. The study suggests that there may be a gender difference in HIV control in infants, as girls are less likely to have HIV sensitive to type 1 interferon because they produce higher levels of type 1 interferon during gestation.

Another case of HIV control after discontinuing treatment in a child treated soon after birth was reported in 2020. A child in Texas started treatment within two days of birth, had a positive HIV DNA test two weeks after birth and discontinued treatment at the age of 13 months. Three years later the child had undetectable HIV RNA and HIV DNA was detectable at extremely low levels intermittently during the follow-up period.

However, there have been a number of reported cases in which HIV DNA was not detectable on any tests, but HIV subsequently rebounded. In 2013, details of a Mississippi baby who received antiretroviral treatment from very soon after birth were reported. Treatment stopped after 18 months as the mother and baby stopped attending the clinic. HIV DNA was undetectable five months later when the mother and baby returned to the clinic and HIV remained undetectable for 27 months before viral load rebound occurred.

One remarkable case of post-treatment control is an Argentinian woman described as the Buenos Aires patient. She had not received treatment in early infection and there was nothing particularly advantageous in her medical history such as a consistently low viral load. On the contrary, when diagnosed in 1996, she had a low CD4 count (160) and at least one AIDS-related illness (toxoplasmosis). Her viral load, initially 2200, rose to 36,000 a year later due to adherence difficulties but after switching her ART regimen she never had a detectable viral load again despite stopping ART in 2007 due to side effects.

When her case was reported in 2021, she had been off ART with an undetectable viral load for at least 12 years. Investigations in 2015 and 2017 could not find any replication-competent HIV DNA in 2.5 billion white blood cells and an upper limit of one unit of intact viral DNA in 390 million CD4 cells. Though her CD4 cells retained immune responses to HIV, her CD8 cells had very weak responses. Unusually, even for HIV controllers, she is now HIV negative, having lost her antibodies to the virus.

This woman does have HLA B*57, a genetic variant associated with lower viral loads and slow progression, but it does not seem to have stopped her developing a severe HIV infection in the first place. Exactly how she has managed to control her HIV so profoundly remains a mystery but her seroreversion disappearance of antibodies and her sluggish CD8 response do seem to be extreme examples of processes seen in some other post-treatment controllers.

A Barcelona woman has controlled HIV for more than 15 years without treatment. Diagnosed with HIV during acute infection, she received four different immune-modulating drugs in addition to her normal antiretroviral treatment as part ofa clinical trial. However, she was the only person out of 20 participants in the trial to maintain long-term viral control off ART, so it is difficult to know whether to ascribe her control to the extra treatment or not.

Like the Buenos Aires patient, she had had typical or even severe initial HIV infection. Her CD4 T-cells were receptive to HIV and her viral DNA turned out to produce replication-competent virus. But the CD8 T-cells of her cellular immune system and the natural-killer (NK) cells of her innate immune system both proved to have particularly strong activity against HIV. Even if her control was achieved only with extra therapy, the immune signatures of these controllers are interesting because they point the way towards how viral control might be induced in other people.

The reasons for viral control off treatment are still not fully understood. Learning how to reproduce this state in a much larger proportion of people, and in those who didnt start treatment soon after infection, is a major goal of cure research.

A small proportion of people living with HIV (perhaps 0.5%) are described as elite controllers. They are able to maintain consistently undetectable viral loads despite never taking antiretroviral therapy. Much rarer still are exceptional elite controllers individuals whose own immune system appears to have cleared all intact viral material from their bodies without any antiretroviral treatment.

Loreen Willenberg is a Californian woman who was diagnosed with HIV in 1992 when she was 37. From the start she maintained a high CD4 count and undetectable viral load since diagnosis (except for one viral blip). She volunteered for studies of long-term non-progressors (people who maintain intact immune systems without treatment) and in 2011 learned that scientists could find no replication-competent HIV in her immune cells. Loreen went public about her story in 2019 and was featured in The New York Times in 2020.

It appears that Willenbergs immune response to HIV is characterised by CD8 cells that have a strong and specific response to the parts of HIV that are most conserved. This means that they are the parts that change least, because to do so would impair viral fitness. They are therefore less likely to mutate away from the attention of the immune system.

In elite controllers this highly selective immune attack has led to the only replication-competent DNA they have being located in so-called gene deserts parts of the host DNA that lack the necessary conformation to allow viral genes to activate. In Willenbergs case, and in a few others, this process has gone further. Although some of her immune cells do contain junk HIV DNA proof that she once did have an active HIV infection no replication-competent DNA can be found.

The scientists who investigated Loreens response to HIV and some other researchers, notably in Spain, have found a few other patients who appear to have achieved self cures. No more than nine of these exceptional elite controllers have yet been documented.

One such is the Esperanza patient. This woman is named after her home town in Argentina. Diagnosed at the age of 21 in 2013, she took one six-month course of ART during pregnancy in 2020 to safeguard her baby but has never otherwise been on ART and has never had a detectable viral load test in nine years. As with Loreen Willenberg, researchers could find no replication-competent HIV DNA in 1.2 billion white blood cells, and also in 500 million placental cells sampled when she gave birth. In the case of this patient, doctors know that the likely source partner had a high HIV viral load, so her apparent self-cure is not due to viral factors.

There is also the case of an Australian man who appears to have cleared his own infection. This case was published in 2019 but attracted little attention, partly because the subject had an unusual combination of factors (a defective virus, one of his two CCR5 co-receptor genes missing and a response to HIV characteristic of slow progressors) that most people with HIV would not share. However, these factors did appear to have given his body more time than usual to mount a strong CD8 response, and a very specific CD4 response, to HIV. This is the kind of immune response researchers would like to replicate in other people.

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Cases of HIV cure | aidsmap - aidsmap

JAK Inhibitors, Mutations, and Transplantation in Myelofibrosis … – Cancer Network

John O. Mascarenhas, MD, led a panel discussion on myelofibrosis management including the use of JAK inhibitors and transplantation.

At an Around The Practice program hosted by CancerNetwork, a panel of experts discussed advances in the testing and treatment of patients with myelofibrosis. The panel was led by John O. Mascarenhas, MD, a professor of medicine at the Icahn School of Medicine and director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai in New York, New York.

The panelists included Gaby Hobbs, MD, the clinical director of the Leukemia Service at Massachusetts General Hospital in Boston; Kristen Marie Pettit, MD, a clinical associate professor of medicine at the University of Michigan in Ann Arbor; and Andrew Kuykendall, MD, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

Mascarenhas: How do patients present with myelofibrosis?

Kuykendall: The interesting thing with myelofibrosis is that they dont have to present in 1 set way. You have patients with classic myeloproliferative neoplasms [MPNs] who present with a lot of constitutional symptoms, such as fevers, chills, night sweats, bone pain, weight loss, or abdominal pain related to splenomegaly or organomegaly. You could also have patients who just present with abnormal lab counts that were done at their primary care office with unexplained anemia or maybe some immature blood cells floating around. That might clue physicians in to do a more extensive workup and try to figure out exactly whats going on.

Mascarenhas: There were some abstracts at recent meetings, [such as] the 2023 American Society of Clinical Oncology Annual Meeting, [that] elucidated or identified clinical features and symptom burden. What is the association between thrombocytopenia and symptoms?

Pettit: Not surprisingly, both anemia and thrombocytopenia have been shown to be associated with different aspects of myelofibrosis. Both have been shown to be associated with worse overall survival [OS] for patients with a higher risk of leukemic transformation. Thrombocytopenia is also associated with worse symptom burden, which is not surprising, given what we see clinically in our patients on a [daily] basis.

Hobbs: One of the questions I get all the time from patients is: If my blood counts look better, why dont I necessarily feel better? or If my counts are controlled, why are my symptoms still present? One of the things that we know, both in clinical practice and from some of the abstracts that were highlighted, is that blood counts dont always tell the whole story. Its interesting to think about patients who arent transfusion dependent but still have tremendous fatigue. Theres a lot that we need to understand [regarding which] cytokines are driving those symptoms and how we make those better. Do we need to target the anemia so theyre not short of breath and have those classic symptoms of anemia resolved, or is there something else contributing to those symptoms? We dont have great measures other than the MPN Symptom Assessment Form, which is a way of making it less subjective. The burden of symptoms is sometimes out of proportion to whats going on from a CDC perspective.

Mascarenhas: What happens to patients with myelofibrosis? Are they just getting polymerase chain reaction [PCR] tests for a driver mutation? Are they getting next-generation sequencing [NGS]? How often do you do it? When you see your patients with myelofibrosis, whats your approach in terms of getting their genetic data?

Pettit: These diseases are very heterogeneous in the clinic as far as how patients present. They are also very heterogeneous as far as the outcomes and what happens to patients over time. One thing thats less heterogeneous is the driver feature of the disease, which is the overactivation of JAK/STAT signaling. We see that occurs most commonly through mutations in JAK2, CALR, or MPL. We always check for those 3 mutations at baseline. Whats also important, prognostically, are additional somatic mutations that can be present on top of those JAK/STAT activating mutations.

My personal practice in the clinic is to test for these things at the time of diagnosis for all my patients with myelofibrosis. Depending on whats been done already, we sometimes already know the JAK2, CALR, or MPL status when patients come to us. If we dont know those already, I sometimes do single-gene PCR tests for those because they can be done in [approximately] a 3-day turnaround time, which can help diagnostically. Sometimes it is important to get those done quickly. At the same time, I always send a NGS panel as well. We use an internal panel that weve developed and continue to refine over time that has all the high-risk mutations of interest here, including TP53, ASXL1, SSF2, IDH1/2, and EZH2. That turnaround time tends to be a little longer, though. Its very important, prognostically, to know at baseline, but it does take a little bit of time to get back. I routinely do that for all my patients with a new diagnosis of myelofibrosis.

As far as serial monitoring over time, though, thats an interesting question and something that has yet to be determined as to how often we should be testing over time. I always repeat NGS if I see a change in the disease behavior. If a patient goes from having more proliferative myelofibrosis with a high white blood cell count, large spleen, and high inflammatory symptom burden before developing some more cytopenic disease behavior with lower blood counts and more fatigue, then Im always repeating NGS. I [also] do it if there are any signs of disease progression toward acute leukemia at that point.

Mascarenhas: What are some concrete examples of where mutational profiling might have a direct impact on therapeutic decision-making?

Hobbs: When I first meet a patient in the clinic, and I may not have all their information, there can be a lot of risk stratification without the mutations using the Dynamic International Prognostic Scoring System Plus Score, for example. Having those molecular markers is important when you first meet a patient to risk stratify them. It centers that discussion on what to expect for the patient, and it helps in terms of making the decision of whether this patient should undergo a transplant sooner rather than later. Its always difficult in practice when you have a patient who may look like theyre lower riskmaybe their blood counts are OKbut then you do the NGS and find a lot of these high-risk mutations like ASXL1, TP53, or others. You may not necessarily act on that immediately, but at least it heightens your awareness about that patient, and you may follow that person more closely and refer them for a transplant. For prognostication and referral to transplant, having that additional information is key.

Mascarenhas: Does the presence of driver mutations help you in deciding the use of a JAK inhibitor?

Hobbs: My decision to initiate JAK inhibitor treatment is based primarily on whether that person either has systemic symptoms or symptoms from their spleens. What driver mutation they have doesnt influence the decision to use a JAK inhibitor. The additional mutations also dont factor into that. It does factor into how I phrase the conversation to patients, where I may say, Im going to start you on a JAK inhibitor to help with your spleen and symptoms, but based on these mutations, the end goal is still to get you to transplant.

Mascarenhas: When you put someone on a JAK inhibitor, do you do any serial monitoring of that driver mutation? Is there any value in doing that?

Hobbs: Patients have started asking more and more for repeat testing of their driver mutations. I do not do that routinely for myelofibrosis. If theres a change in the behavior of the disease, the patients going to transplant. If I think theyre developing leukemia, theres some value to repeating that testing. Honestly, I find it hard to interpret different levels of those mutations, and it leads to a lot of anxiety. Ive had patients who looked like theyre doing wonderfully on a therapy only to check the variant allele fractions again to see that they went up. Its hard to act on those changes because we still dont know how to interpret them, and our treatments arent made to target those mutations specifically. Even though we may see that JAK inhibitors may lead to a decrease in variant allele fractions in JAK2, we still dont know what to do with that information.

Mascarenhas: Moving away from molecular markers, are there any other biomarkers that might be helpful?

Kuykendall: There is lactate dehydrogenase [LDH], this generic marker that could be looked at as a measure of a hypoxic state or cell turnover to some degree. Its interesting within myelofibrosis and within MPN because LDH can sometimes help differentiate between things like essential thrombocythemia and myelofibrosis. When you get more hypercellular marrows, you get more cellular turnover and start to get elevated LDH levels. Across the board, LDH by itself doesnt help too much. However, there are times when you see a baseline LDH thats very high, which makes you think there is a lot more going on with this disease at the mere level than you otherwise thought. You may see a change in LDH levels in a specific patient, whod been running at an LDH that is 2 or 3 times the upper limit of normal and goes to 6 or 7 times the upper limit of normal. It may make you think that maybe the disease is either changing or theres something else going on. We saw this a lot during the era of COVID-19, where LDH levels would go up transiently soon after vaccination before tapering back down toward a more normal level. When the numbers changed, you had to realize that maybe there was some other influence that was going on. LDH can be helpful to clue you into some change either in the disease or some exogenous factor thats causing it, although it certainly must be taken into context.

Mascarenhas: What about a biomarker like bone marrow fibrosis? Is there any value in repeating that bone marrow after a certain interval on a JAK inhibitor? If that fibrosis grade goes down, does that have any actual clinical impact?

Kuykendall: There are a lot of problems with bone marrow fibrosis. When we look at large studies, we can retrospectively see that there is some prognostic significance to fibrosis. In large populations, the more fibrosis you have, the worse the overall prognosis would be. On an individual patient level, its very difficult to understand the value. If someone goes from having moderate to mild fibrosis, is that a change in their underlying disease, or is that just a sampling change or something that isnt truly related? Stephen T. Oh, MD, PhD, from Washington University School of Medicine in St Louis in Missouri, presented data on fibrosis changes in response to JAK inhibitors, suggesting that they dont correlate with outcomes.1 On the flip side, we see fibrosis go away when patients get stem cell transplants, and thats certainly something that reflects the disease being gone in those patients. It may come down to the type of treatments or the way were getting improvements in fibrosis. When you look at the paper presented by Oh, highlighting how youre getting fibrosis changes over the course of 6 months, it might not be a relevant timeline to look at fibrosis changes. Maybe JAK inhibitors are not what were expecting to see as true disease-modifying agents. But maybe if we got more disease-modifying agents and we looked over time frames of 1 to 3 years, we could see a clinical relevance to a change in fibrosis over that period.

Mascarenhas: Is there anything that should be highlighted about the population?

Pettit: Treating the triple-negative [disease] is tricky overall. When I see a patient with triple-negative myelofibrosis, my first step is to always make sure Im clear on the diagnosis and its not something else thats causing fibrosis in the marrow. Not everything that causes marrow fibrosis is myelofibrosis. For example, there is myelodysplastic syndrome with fibrosis, chronic myeloid leukemia with fibrosis, and autoimmune myelofibrosis. Those things are important to rule out and can sometimes be easier said than done. Based on the bone marrow morphology and the presence of other cytogenetic or molecular mutations, if were confident about the diagnosis of triple-negative myelofibrosis, those patients tend to have a bit of a rougher course. They tend to be a little more difficult to treat and have a bit more aggressive disease. That is one finding in triple-negative myelofibrosis that does make me think more about the possibility of transplant earlier rather than later for patients, even though triple-negative status isnt necessarily worked into most of our prognostic scoring systems.

Mascarenhas: Similarly, with the driver mutations and the use of JAK inhibitors, is there any reason why you would not use a JAK inhibitor in a patient with triple-negative disease?

Pettit: No, theres no reason why you would avoid a JAK inhibitor. I made my decision to use a JAK inhibitor based on the presence of symptoms and symptomatic splenomegaly, not the driver mutation status. However, there are some factors that can correlate with response or lack of response to JAK inhibitors. For example, some of the RAS pathway mutations have been associated with resistance to JAK inhibitors. It doesnt necessarily play into my decision of whether to use the agent, but it does slightly change my monitoring and counseling of the patient before we get started with the agent.

Mascarenhas: Lets say you have a patient with 12% blasts in the peripheral blood or in the bone marrow. Do you and your transplant colleagues want to reduce the situ of those patients before transplant, or do you get them right into their transplant?

Hobbs: On paper, I would say the transplant doctors often do want to see some situ reduction. It also relates to whats going on with the patient and what else is going on other than the 12% blasts. Weve all seen patients [who] come in one day with 12% blasts, then 2% blasts on the next day. They fluctuate wildly. Its a matter of seeing whats going on in the bone marrow and what other mutations that person has. Does that person also have splenomegaly, things that correlate with worse outcomes after transplant? For the most part, at least 1 or 2 cycles of some form of cytoreductive therapywhether that be adding a hypomethylating agent by itself or adding some venetoclax [Venclexta]might be something that we would consider for that type of patient prior to going to transplant.

Mascarenhas: Do the transplanters want a certain spleen volume or spleen length before they take the patient to transplant?

Pettit: Its a controversial topic, and I am always going back and forth about this one. We have good data highlighting that the earlier we do transplants, the lower the grade of disease there will be, the smaller the spleen will be, and the better patients do overall.2 Does that mean we should be shooting for the smallest spleen possible before transplant? Does that improve things, or does the risk of splenectomy outweigh the potential benefit? I dont know the answer to that yet. I believe there is a trial going on trying to answer that question. Hopefully we will have some more guidance there.

Right now, were just going based on retrospective and observational data. Our approach that our center has come up with is to do everything medically that we can to shrink the spleen before transplant. I often do that even at the expense of blood counts for some patients, too. In that situation, I will accept a bit more anemia and thrombocytopenia if its with the goal of getting someone to transplant with as small of a spleen and as good of disease control as possible. But for patients with very massive spleens, we end up occasionally doing splenectomies before transplant. Its not a common thing to do. Our soft cutoff has been a spleen size of [approximately 20 cm] by imaging. That is a very soft cutoff. Weve made exceptions on either side of the spectrum there, but I hope we have more hard data to go off of soon.

Mascarenhas: What are some relevant myelofibrosis National Comprehensive Cancer Network [NCCN] updates that others should be aware of?

Kuykendall: There havent been substantial updates to the NCCN guidelines. Theres been tweaks of some things as we get new approvals, but in myelofibrosis, were still stratifying patients as higher or lower risk, and were treating patients who are lower risk with symptoms as we would for patients who are high-risk. Its important to note that these risk scores identify patients [who] should be considered for transplant; thats the purpose of the risk scores. Its not something that should factor much into our current treatments. Some trials enroll patients with higher-risk disease, but the treatments are very much aimed at symptoms and enlarged spleens. Its not so much driver mutation or risk as much as symptoms that drive what were trying to accomplish.

Within the NCCN guidelines, were favoring JAK inhibitors for patients with higher-risk or symptomatic lower-risk disease. For the most part, we differentiate by platelet count. For those with greater than 50,000 platelets, we consider ruxolitinib [Jakafi] or fedratinib [Inrebic], which are approved there. For those with fewer than 50,000 platelets, we favor pacritinib [Vonjo], which has an accelerated approval in this markedly thrombocytopenic patient population.3 One caveat thats overlooked a lot in the NCCN guidelines is it makes it seem like any patient who is high-risk should receive ruxolitinib or fedratinib, but that excludes those who are high-risk where anemia is their driving issue. If their main issue is anemia and they dont have too much in the way of constitutional symptoms or symptomatic splenomegaly, then they are probably not a great candidate for a JAK inhibitor as an up-front treatment. That sometimes gets lost in the guidelines, but there is a drop-down as far as where to go when youre considering directing your therapy at myelofibrosis-associated anemia as the prominent issue.

When you look past the first-line setting in the NCCN guidelines, anything is open. At that point in time, platelet thresholds dont matter as much, and pacritinib can be considered as an option in the second-line setting. It has this accelerated approval for fewer than 50,000 platelets, but there has yet to be a completed trial that was focused on fewer than 50,000 platelets as the inclusion criteria. Its been studied in any platelet count of fewer than 100,000, and then theres an ongoing study looking at those with fewer than 50,000 platelets, but we know its an effective agent regardless of platelet count. Those with fewer than 50,000-platelet count is where the specific agent could be utilized. In the second-line setting, it can be used there as well, just like fedratinib. If you started with fedratinib or pacritinib, dose-modified ruxolitinib could be also a consideration in the second-line setting.

Mascarenhas: Why is pacritinib different?

Kuykendall: Pacritinib is somewhat more of a JAK2 selective inhibitor, which differentiates it from ruxolitinib. Fedratinib is also somewhat selective toward JAK2. Pacritinib has this additional inhibition of IRAK1 and maybe ACVR1. The early trials with pacritinib were interesting in the fact that it didnt seem to cause the same degree of myelosuppression that was seen with ruxolitinib and fedratinib. Some of this had been attributed to IRAK1, an NF-B pathway target that may be involved in some other symptoms, some cytopenias, and a different inflammatory pathway. More recently, building off the knowledge that momelotinib is an ACVR1 inhibitor, it was seen that pacritinib may be a more robust ACVR1 inhibitor. This is something that is a relevant target in the treatment of anemia and cytopenias. Perhaps this is why we can safely leverage pacritinib into this more cytopenic myelofibrosis population and target splenomegaly symptoms with full doses of this JAK inhibitor in a patient population that is more difficult to provide fedratinib or ruxolitinib to.

Mascarenhas: Do you ease patients into pacritinib, or do you use the full dose?

Pettit: Its tough, and how we do this is evolving. Personally, it depends on a case-by-case basis. If the patient is on ruxolitinib at 20 mg twice a day, I would consider a taper or maybe a steroid overlap because of the risk of the JAK inhibitor rebound as youre switching from one agent to the other. If they are on a small dose of a JAK inhibitor, I would just switch them right over from ruxolitinib to pacritinib.

Mascarenhas: What would you do at the full dose?

Pettit: One of the benefits of pacritinib is being able to start the full dose of 200 mg twice a day regardless of the platelet count, hopefully maximizing that JAK2 inhibition that youre getting into somebody because you dont have the JAK1 inhibition thats going to lower their platelet count more.

Mascarenhas: How closely do you follow someone when youre transitioning them from ruxolitinib to pacritinib?

Pettit: I follow them closely for several reasons: symptom burden, worsening of spleen size, any toxicities from the drug, and cytopenias.4 I typically monitor complete blood counts [CBCs] depending on the situation. If their platelet count is getting low, Id probably check their platelet count and CBC maybe once a week or every other week and follow up with them clinically within 1 to 2 weeks of starting the drug. One of the things to keep in mind with pacritinib is that the toxicity profile is a little different than it is with ruxolitinib. There are some things in patients with myelofibrosis that we need to think about proactively with some of the newer agents [such as] fedratinib or pacritinib. The main thing is gastrointestinal [GI] toxicity. Diarrhea is very common early on. Nausea and vomiting can [also] happen early on. Those are things I generally tell patients to expect. Its better to be proactive and be prepared for it rather than to be surprised by it, because its harder to get on top of it once its already developed.

I make sure in advance that patients have loperamide [Imodium] on hand at home. I [also] often make sure they have an antiemetic, or are at least very easily able to get an antiemetic from our clinic if they need it once they start the agent. The good news is that these GI toxicities with pacritinib do tend to get better over time, not worse, [and] they dont tend to be long-lived. They tend to be things that occur within the first couple weeks then improve over time. If were proactive about it, there are things we can get through without too much difficulty in the first couple of weeks.

Mascarenhas: With low platelet counts, what is your comfort level in terms of dosing ruxolitinib to manage thrombocytopenia?

Kuykendall: It depends on what other options you have. Before pacritinib was available, we tried to slowly bring patients along on ruxolitinib to keep them on a JAK inhibitor. A lot of it depends on what youre aiming for with the treatment. If patients are benefiting from a substantial dose of ruxolitinib, they can keep their spleen volume and symptoms in check, and their platelets are running at 50,000 or maybe 40,000 consistently, Im not necessarily switching them to pacritinib. They are very different patients than the ones whose platelets are a lot more volatile; those are patients who could switch to pacritinib.

Mascarenhas: Why is it possible to sequence JAK inhibitors? Is there any evidence that suggests there may even be molecular predictors?

Hobbs: To some degree, yes, we can sequence JAK inhibitors, and it is surprising. Weve learned that the JAK inhibitors can hit the kinases a little differently. In that regard, it makes sense that you could sequence and block the JAK/STAT signaling pathway that you werent able to block with the prior JAK inhibitor. It also makes sense when youre thinking about switching from a JAK1 or JAK2 inhibitor to one of the newer JAK inhibitors, [such as] pacritinib, that target IRAK1 [and] ACVR1, which may yield a new response where you lost a response previously. Understanding each JAK inhibitors mechanism of action can help you understand why you can salvage some of those patients or have a response in the second- or third-line setting. If the treatment goal is to improve splenomegaly and to not get to transplant, its nice to know we can do that. However, if the goal is to get to transplant, knowing that you can successfully sequence one patient from one JAK inhibitor to another shouldnt make you lose track of your objective. If a patient is losing their response to a JAK inhibitor, their spleen is growing back, their symptoms are coming back, or their platelet counts are looking much worse, thats not a time to switch from one drug to the other but a time to get that person to transplant if that hadnt been part of the conversation.

Mascarenhas: Is there anything you want to share from this discussion that you think is important to remember?

Pettit: We need to raise the bar for response in myelofibrosis. Now that we have all these available agents with many more coming, our antiquated 35% spleen volume reduction goal and even 50% symptom score reduction goal are low bars for us to be shooting for. Now that weve scratched the surface of the disease, we should be trying to get deeper into the disease in quality-of-life improvements, OS improvements, prevention of progression, and treating the underlying disease.

Hobbs: I agree completely. Its time to raise the bar on our end points, and thats going to require more targeted agents and having the regulatory agencies revisit what a meaningful end point is. We all did a nice review of what therapies are currently available. The way that we think about when to use JAK inhibitors is important. Another point we all made was that an early transplant referral is important, even though those discussions can often take many visits until you finally determine whether that patient will go to transplant and when theyll go to transplant. Outcomes for patients with myelofibrosis have improved significantly with transplant, with reduced intensity conditioning, and with the use of ruxolitinib and other JAK inhibitors before and perhaps after transplantation. Remembering that patients can make it through transplant is important. While all these other therapies are being developed and we get better end points, we do have a therapy that does work and is curative. Helping to increase the use of that therapy is an important goal.

Kuykendall:We have all these options that make us think we have something for everyone now. However, we should be considering clinical trials in every aspect of this disease. Whether its in the frontline or second-line setting, or we see low, high, or normal platelet counts, were still getting clinical improvements. When the best we can do is make [patients] feel a little better and make them live a little longer, then we need to leverage that and try to do better in all aspects of the disease. What I hope doesnt happen with the approval of a third and a fourth JAK inhibitor is that were seeing patients in the academic setting after theyve received 4 JAK inhibitors. We have the option of getting [patients] on good, novel, meaningful trials in the frontline setting, where we can build on the success weve had with JAK inhibition and then see [whether] we can do a little more as well.

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JAK Inhibitors, Mutations, and Transplantation in Myelofibrosis ... - Cancer Network

Stanford plans to put a 3D-printed human heart in a pig by 2028 – Freethink

This article is an installment of Future Explored, a weekly guide to world-changing technology. You can get stories like this one straight to your inbox every Thursday morning bysubscribing here.

Countless medical issues could be solved if there were simply an Amazon.com for new body parts. Heart failure? Order a new organ in your size for a transplant. Got into a car accident and broke your leg? Great news free shipping on tibias.

Unfortunately, warehouses filled with replacement human bones, organs, and tissues dont exist but 3D bioprinting could lead to something even better.

Like traditional 3D printers, these machines use computer files to create 3D objects with potentially complex structures, but instead of extruding plastic or metal, they work with bioinks containing living cells.

Because tweaking a design is as simple as making a change to a file, we could eventually see 3D bioprinters used to create personalized replacement organs, tissues, and bones, on demand with our own cells used in the inks to prevent our bodies from rejecting the new parts.

This isnt some far off future, either. 3D bioprinting is already creating miniature organs, patches for heart defects, and more. Here are a few of the latest examples of how the technology is being used to revolutionize healthcare, from our heads to our hearts.

Damage to the brain, whether from a stroke, a fall, or a disease, can be life threatening, and even if a person survives, the injury can leave them without the ability to think, move, and communicate the way they could before.

Trials have shown that implanting stem cells at the site of brain damage can improve some patients motor function, but no one has been able to get stem cells to fully reverse damage, returning the brain to its original state.

Oxford University researchers believe getting stem cells to better mimic the natural architecture of the brain will bring us closer to that goal and that 3D bioprinting can do it.

The 3D-bioprinted stem cells successfully integrated into the mouse tissue, both structurally and functionally.

In a new study, published in Nature Communications on October 4, they created something that mimics the complex architecture of the human cerebral cortex, which has six layers two deep layers and four upper layers each with its own type of neuron.

They first took human induced pluripotent stem cells (HiPSCs) adult cells that are reprogrammed back into stem cells and coaxed them into developing into two special types of neural stem cells. One was a precursor to upper layer neurons and the other to the deep layer neurons.

Next, they created two bioinks from the neurons and printed them into a two-layer structure. When they implanted this printed tissue into slices of mouse brains, it successfully integrated into the mouse tissue, both structurally and functionally.

Researchers have yet to figure out the precise recipe to coax stem cells into developing into precursors of all six distinct types of neurons in the cerebral cortex, but the Oxford team believes its 3D bioprinting technique will be able to generate six-layered cortex tissues once that hurdle is overcome.

[O]ur 3D printing project demonstrates substantial progress in controlling the fates and arrangements of human iPSCs to form the basic functional units of the cerebral cortex, said senior author Zoltn Molnr.

More than 6,000 people die in the US every year because they needed an organ transplant and a donor organ wasnt available in time, but researchers at Stanford are hopeful that 3D bioprinting will be able to close that gap between supply and demand.

On September 28, they were awarded a $26.3 million contract by the National Institutes of Healths Advanced Research Projects Agency for Health (ARPA-H) to bioprint a human heart and transplant it into a pig within the next five years.

Its truly a moonshot effort, but the raw ingredients for bioprinting a complete and complex human organ are now in place for this big push, said Mark Skylar-Scott, the projects principal investigator.

Your own heart, made out of your own cells; that is the dream.

Like the brain, the heart contains a great variety of cell types that have to be arranged in a precise design to work, so the Stanford teams plan is to use stem cells to produce tons of these different types of cells in containers called bioreactors, which provide the ideal environment for living cells to thrive.

Using those cells as their bioink, the team will then 3D print their replica of the human heart Skylar-Scott expects that the bioreactors will produce enough of the cells to print one heart every two weeks.

We will use these vast numbers of cells to practice, practice, practice and learn all the design rules of the heart and optimize viability and function at the whole-heart scale for eventual implantation into a pig, he said.

The ultimate goal is to use a persons own stem cells as the basis for the bioink used to print their replacement heart. This would potentially eliminate the need for immunosuppression to prevent organ rejection, which leaves patients at higher risk of infection.

Your own heart, made out of your own cells; that is the dream, said Skylar-Scott.

If your skin is severely damaged by a burn, disease, or injury, your doctor might perform a skin graft, where healthy skin from a different part of the body is removed and placed over the injured area.

Skin consists of three layers, and during a graft, doctors only remove the top one-and-a-half to two layers, depending on the severity of the injury. The bottommost third layer the hypodermis is never transplanted.

Not only do these procedures require patients to damage a part of their body that was healthy, the transplanted skin usually has a scarred appearance.

These results show that the creation of full thickness human bioengineered skin is possible.

On October 4, researchers from Wake Forest University published a study detailing how they used 3D bioprinting to create full-thickness skin with all three layers something no one had done before.

The bioinks used for the study contained a mix of hydrogels and all six of the primary cell types found in human skin, which the researchers grew in bioreactors. Using those inks, they printed the three-layered structure of real skin in petri dishes.

When the bioprinted skin was transplanted on top of wounds in mice and pigs, the injuries healed faster and showed less signs of scarring than wounds that werent treated.

Future studies will be needed to see how the bioprinted skin compares to traditional skin grafts, but even if its only as good as those, it could still free people from having to injure a healthy part of their body in order to obtain the skin needed to repair damage.

Comprehensive skin healing is a significant clinical challenge, affecting millions of individuals worldwide, with limited options, said primary author Anthony Atala. These results show that the creation of full thickness human bioengineered skin is possible, and promotes quicker healing and more naturally appearing outcomes.

These are just three major advances in 3D bioprinting ranging from the bodys largest organ (the skin) to its most vital (the brain and heart) and the fact that they all happened in just the past few weeks should tell you how quickly the field is advancing.

In addition to these projects, other researchers are using 3D bioprinting to create new bone, cartilage, and blood vessels. Still others are developing 3D bioprinters that could print directly inside a persons body to minimize the risks of implantation surgery.

While most of this research is still in the preclinical stage of development, some bioprinting-based treatments are already being trialed in people, and if this progress continues, it might not be long before doctors can 3D print whatever new body parts we might need.

Wed love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at[emailprotected].

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Stanford plans to put a 3D-printed human heart in a pig by 2028 - Freethink

A Mother’s Letter to Staff – CHEO

Who comes to mind when you think of love? You might think of your parents, your partner, your children, your grandparents, or your pets. For Dawn Pickering, she recently discovered a different kind of love one for the medical team that saves your childs life.

(Photo: Ollie, CHEO's therapeutic clowns and his dad, Mario).

In the summer of 2019, Ollies family discovered a bump on his neck. That November, after four months of not being able to find out the cause behind the bump, the ENT Clinic at CHEO diagnosed the seven year old with anaplastic large cell lymphoma ALK+ (anaplastic lymphoma kinase positive). He would spend the next six months at CHEO for cancer and relapse treatments. During this time, the cancer would render Ollie blind, forcing him to re-learn everything hes ever known. The journey that Ollie and his family were about to go on would be the most testing, agonizing time of their lives.

In March 2020, he and his family went to The Hospital for SickKids in Toronto for stem cell treatment. Because this was the start of the pandemic, planes were grounded and no travel was allowed so they couldnt use one of the three perfect matches on the international stem cell registry. So who stepped in to become Ollies half match stem cell donor? None other than his big sister, Abby.

On March 31, her cells were harvested, but a week before he was supposed to start total body radiation in preparation for transplant, Ollie relapsed a second time in his brain.

The family would spend the next five weeks in Toronto trying a cancer inhibitor drug that ultimately wouldnt work. They were told that there were few options left.

(Photo:Abby gets her stem cells harvested at SickKids).

No one can imagine the stress of going through cancer treatment and a stem cell transplant during the first few months of a pandemic. But much to everyones delight, the transplant went smoothly.

After three years of countless blood tests, scans, consults, frequent hospital visits, multiple relapses and undergoing all of his childhood vaccines again after transplants wiped his immunities outOllie is a survivor. He only has to come once a year to see his oncology team at CHEO, a thought that makes Dawn emotional. You feel incredible gratitude and a special kind of love for the individuals who saved your sons life.

(Photo:Abby, Mario, and Dawn surround Ollie in his wheelchair at Sick Kids on discharge day).

He and his Canadian National Institute for the Blind (CNIB) Buddy Dog Hope were also featured in AMI-TVs Blind Trust: A Guide Dogs Journey back in August. He has so much to be proud of.

He will speak at the upcoming International Society of Pediatric Oncology (SIOP) Congressin Ottawa this month on patient-centred care. We cant wait to see you there, Ollie! He's also been asked to speak at the CNIB's Day on Parliament next month.

(Photo: Ollie and Dawn pose in front of the Canadian Cancer Society backdrop on their Day on the Hill).

Here is part of Dawns message for all of them:

With love and gratitude always,

The Acosta-Pickering Family: Dawn, Mario, Abby and Ollie

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A Mother's Letter to Staff - CHEO

The 7 Biggest K-Beauty Trends of 2023 – Allure

Devices that provide an alternative to microneedling, in particular, are ever-popular, and much like the real thing, they can make passageways in the skin and increase skin-care product absorption, says Dr. Chang. It is supposed to help with improving skin glow, texture, and pores.

Ultrasound or microcurrent devices are increasing in popularity, too. Some iterations use a combination of ultrasound and red light to enhance collagen stimulation and fight skin laxity, Dr Chang explains. Dr. Park highlights devices that use something called High-Intensity Focused Ultrasound (HIFU). It is used to address signs of aging such as wrinkles, fine lines, and sagging skin," she says, adding, that there is a great deal of variability in using this technology at home. It is very popular in Korea, but I would recommend using it with caution.

Another popular device format you might have seen in American retailers: LED masks. As Allure previously reported, LED light therapy can stimulate collagen, improve the appearance of acne, reduce redness, stimulate blood circulation, and more, depending on what type or color of light is used. Though LED light therapy offered in-office is generally more effective, LED masks can still provide results from home and it's why theyre becoming ubiquitous in Korea. The trend aligns with the growing demand for accessible, innovative, and self-empowering beauty tools in the ever-evolving world of Korean beauty, Cho says.

As far as Koreas most popular in-office procedures go, skin-boosting treatments, encompassing a plethora of topicals and injectables, reign supreme. They can address concerns including skin dryness, dullness, hydration, texture, and tone, Dr. Park explains. They are further categorized as those that contain hyaluronic acid only versus those that contain other collagen-boosting ingredients such as polydeoxyribonucleotide [or PDRN, a type of DNA extracted from salmon roe].

Injectable skin boosters include the hyaluronic acid treatment Skinvive by Allergan, (which, by the way, is the only injectable skin booster approved for use in the US as well as Korea, according to Dr. Park). Other traditional fillers with low density are used off-label as a hyaluronic skin booster, she explains. Some injectable skin boosters like Rejuran and Juvelook are not approved in the US market. Dr. Park adds that the NCTF skin booster, nicknamed the Chanel injection, for reasons unknown, is extremely popular in Korean doctors' offices. It is a cocktail of 56 skin nutrients to improve hydration and brightness, she says.

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The 7 Biggest K-Beauty Trends of 2023 - Allure

A New Law of Physics Could Support the Idea We’re Living In a … – Slashdot

A physicist from the University of Portsmouth has explored whether a new law of physics could support the theory that we're living in a computer simulation. Phys.Org reports: Dr. Melvin Vopson has previously published research suggesting that information has mass and that all elementary particles -- the smallest known building blocks of the universe -- store information about themselves, similar to the way humans have DNA. In 2022, he discovered a new law of physics that could predict genetic mutations in organisms, including viruses, and help judge their potential consequences. It is based on the second law of thermodynamics, which establishes that entropy -- a measure of disorder in an isolated system -- can only increase or stay the same. Dr. Vopson had expected that the entropy in information systems would also increase over time, but on examining the evolution of these systems he realized it remains constant or decreases. That's when he established the second law of information dynamics, or infodynamics, which could significantly impact genetics research and evolution theory.

A new paper, published in AIP Advances, examines the scientific implications of the new law on a number of other physical systems and environments, including biological, atomic physics, and cosmology. Key findings include:

- Biological systems: The second law of infodynamics challenges the conventional understanding of genetic mutations, suggesting that they follow a pattern governed by information entropy. This discovery has profound implications for fields such as genetic research, evolutionary biology, genetic therapies, pharmacology, virology, and pandemic monitoring. - Atomic physics: The paper explains the behavior of electrons in multi-electron atoms, providing insights into phenomena like Hund's rule; which states that the term with maximum multiplicity lies lowest in energy. Electrons arrange themselves in a way that minimizes their information entropy, shedding light on atomic physics and stability of chemicals. - Cosmology: The second law of infodynamics is shown to be a cosmological necessity, with thermodynamic considerations applied to an adiabatically expanding universe supporting its validity. "The paper also provides an explanation for the prevalence of symmetry in the universe," added Dr. Vopson. "Symmetry principles play an important role with respect to the laws of nature, but until now there has been little explanation as to why that could be. My findings demonstrate that high symmetry corresponds to the lowest information entropy state, potentially explaining nature's inclination towards it."

"This approach, where excess information is removed, resembles the process of a computer deleting or compressing waste code to save storage space and optimize power consumption. And as a result supports the idea that we're living in a simulation."

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A New Law of Physics Could Support the Idea We're Living In a ... - Slashdot

Kelly Slater gifts incurably ill surf filmmaker Greg Browning and … – BeachGrit

The "momentum of professional surfing" looking less and less real.

It has, by any measure, been a rough year for our World Surf League. Small waves cursed the tour from the very beginning, its CEO Erik Logan got up to some monkey business in Brazil leading to his unceremonious firing and, to cap it all off, its once-proud Santa Monica headquarters placed on the market, forcing the global home of surfing to share space with injured animals.

Eight, or such, years ago there were only wide open vistas for the WSL. Future so bright. It had a billionaire funding and a bullish chief, Paul Speaker, who vowed to soon outgrown the powerful National Football League.

Alas, bummer upon bummer upon bummer until today where we have the NFLs Miami Dolphins straight robbing the WSL, officially being dubbed The Greatest Show on Surf.

There is speed for days with Tyreek Hill, DeVon Achane, Raheem Mostert being fed the skin by Hawaiis Tuanigamanuolepola Tagovailoa, and the team is pressing every advantage.

The Dolphins were honored with the tag after amassing 2568 total yards of offense in the first five games of the season, surpassing the 2000 St. Louis Rams teams 2527 yards.

Those Rams were The Greatest Show on Turf.

The Greatest Show on Surf much cooler.

But there is certainly scrambling in the new WSL headquarters today. Chief of Sport Jessi Miley-Dyer scrambling around, trying to call various newspapermen in order to share viewership numbers from the most recent Finals Day at Lower Trestles.

Smashing into veterinarians along the way.

Weeping the momentum of professional surfing is REAL!

Is it though?

More as the story develops.

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Kelly Slater gifts incurably ill surf filmmaker Greg Browning and ... - BeachGrit

Long-Dormant Viruses Are Now Waking Up After 50,000 Years as … – Slashdot

This week Bloomberg explored so-called "zombie viruses" that is, long-dormant microbes which they call "yet another risk that climate change poses to public health" as ground that's been frozen for "milleniums" suddenly starts thawing for example, in the Arctic, which they write is warming "faster than any other area on earth." With the planet already 1.2C warmer than pre-industrial times, scientists are predicting the Arctic could be ice-free in summers by 2030s. Concerns that the hotter climate will release trapped greenhouse gases like methane into the atmosphere as the region's permafrost melts have been well-documented, but dormant pathogens are a lesser explored danger. Last year, virologist Jean-Michel Claverie's team published research showing they'd extracted multiple ancient viruses from the Siberian permafrost, all of which remained infectious...

Ways in which this could present a threat are still emerging. A heat wave in Siberia in the summer of 2016 activated anthrax spores, leading to dozens of infections, killing a child and thousands of reindeer. In July this year, a separate team of scientists published findings showing that even multicellular organisms could survive permafrost conditions in an inactive metabolic state, called cryptobiosis. They successfully reanimated a 46,000-year-old roundworm from the Siberian permafrost, just by re-hydrating it...

Claverie first showed "live" viruses could be extracted from the Siberian permafrost and successfully revived in 2014. For safety reasons his research focused only on viruses capable of infecting amoebas, which are far enough removed from the human species to avoid any risk of inadvertent contamination. But he felt the scale of the public health threat the findings indicated had been under-appreciated or mistakenly considered a rarity. So, in 2019, his team proceeded to isolate 13 new viruses, including one frozen under a lake more than 48,500 years ago, from seven different ancient Siberian permafrost samples evidence to their ubiquity. Publishing the findings in a 2022 study, he emphasized that a viral infection from an unknown, ancient pathogen in humans, animals or plants could have potentially "disastrous" effects.

"50,000 years back in time takes us to when Neanderthal disappeared from the region," he says. "If Neanderthals died of an unknown viral disease and this virus resurfaces, it could be a danger to us."

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Long-Dormant Viruses Are Now Waking Up After 50,000 Years as ... - Slashdot

World-First Trial of Gene Therapy To Cure Form of Deafness Begins – Slashdot

An anonymous reader quotes a report from the Financial Times: A world-first trial of a gene therapy to cure a form of deafness has begun, potentially heralding a revolution in the treatment of hearing loss. Up to 18 children from the UK, Spain and the US are being recruited to the study, which aims to transform treatment of auditory neuropathy, a condition caused by the disruption of nerve impulses traveling from the inner ear to the brain. Participants will be monitored for five years to gauge whether their hearing improves, with initial results expected to be published next February.

Auditory neuropathy can be due to a variation in a single gene -- known as the OTOF gene -- which produces a protein called otoferlin. This protein typically allows the inner hair cells in the ear to communicate with the hearing nerve. Mutations in the OTOF gene can be identified by genetic testing. However, [Professor Manohar Bance, an ear surgeon at Cambridge University Hospitals NHS Foundation Trust who is leading the trial in the UK] said it was a condition often missed when newborn babies were screened for potential hearing problems. "This is one of the few conditions where everything works except the transmission between the hair cells and the nerve. So everything else looks fine when you test it, but they can't hear anything. So these poor kids' [difficulties] end up being missed," Bance added.

The new gene therapy aims to deliver a working copy of the faulty OTOF gene using a modified, non-pathogenic virus. It will be delivered via an injection into the cochlea under general anaesthetic. Bance estimates that about 20,000 people across the US and five European countries -- the UK, Germany, France, Spain and Italy -- have auditory neuropathy due to OTOF mutations, underlining the potential significance of a successful treatment.[...] "If it works, it's 'one and done'" but the cost to health systems "is something that worries me," he added, noting that gene therapies could be priced in "the million dollar range" per patient. However, he hoped that "economies of scale" as the technology developed further would ultimately allow them to be provided more cheaply.

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World-First Trial of Gene Therapy To Cure Form of Deafness Begins - Slashdot