A small clinical trial involving 12 patients with Parkinson's disease has reported no safety concerns with a newly developed human stem-cell-based therapy.

The therapy called TED A9 was delivered as a cell transplant injected directly into the brain of the participants as part of a Phase 1/2a clinical trial, which is principally concerned with assessing safety and dosing requirements.

The drug's developer, S.Biomedics, in Seoul, South Korea, claimed in a press release: 'According to Professor Jin-Woo Chang, [the principal investigator of the transplant conducted at Severance Hospital, Seoul,] none of the 12 Parkinson's disease participants had any side effects, complications, or unusual adverse reactions following the transplantation of TED-A9'.

The trial participants were aged between 50 and 75 years old, had been diagnosed with Parkinson's disease for more than five years, and had already motor complications such as freezing of gait or dyskinesia.

To ensure and monitor the safety of the treatment, an initial three patients were injected with a low dose (3.15 million cells) and monitored for three months, before another three patients were treated at high dose (6.3 million cells) and also monitored for three months.

No side effects, complications, or unusual adverse reactions were seen in either group during the three-month assessment period. Therefore, the clinical trial continued by adding three further patients to each of the low-dose and high-dose groups. Again, no safety concerns were seen.

Parkinson's symptoms are caused by the progressive loss of neurons that produce dopamine, a major chemical messenger in the brain. The TED-A9 therapy contains dopaminergic progenitor (precursor) cells, which had themselves been derived in the lab from embryonic stem cells.

The drug developers at S.Biomedics hope that the dopaminergic precursor cells in TED-A9 will treat Parkinson's disease by replacing the mature dopamine-producing nerve cells that are lost in patients.

Professor Dong-Wook Kim, a neurosurgeon and the principal developer of TED-A9, said: 'We have developed a fundamental therapeutic mechanism that directly replaces dopaminergic neurons lost in patients with Parkinson's disease. TED-A9 could represent a fundamental treatment that surpasses current therapies, which only temporarily alleviate the symptoms of Parkinson's disease,'.

The trial is expected to continue until February 2026, allowing safety of the therapy to be monitored for a total of five years. As part of the study, exploratory efficacy will also be examined for two years using clinical measures of motor symptoms and a patient questionnaire of daily life quality.

More Information is available at ClinicalTrials.gov.

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Human stem-cell-based therapy for Parkinson's disease proven safe PET - BioNews

Researchers at Osaka Metropolitan University have innovatively reprogrammed canine stem cells from urine to create induced pluripotent stem cells (iPSCs) without feeder cells. This breakthrough in non-invasive, pain-free stem cell generation paves the way for new advancements in veterinary regenerative medicine and genetic disease research, offering hope for treating previously incurable diseases in dogs. Credit: Shingo Hatoya, Osaka Metropolitan University

Dog owners may need to learn to appreciate their best friends urine. Researchers at Osaka Metropolitan University have developed a new method thats efficient, non-invasive, and painless for reprogramming stem cells from dogs urine. This breakthrough paves the way for advancements in veterinary regenerative treatments for our four-legged companions.

Induced pluripotent stem cells (iPSCs) have been widely employed in studies on human generative medicine. With the growing importance of advanced medical care for dogs and cats, there is an expectation that new therapies utilizing iPSCs will be developed for these companion animals, just as they have been for humans.

Unfortunately, canine somatic cells exhibit lower reprogramming efficiency compared to those of humans, limiting the types of canine cells available for generating iPSCs. IPSC induction often involves using feeder cells from a different species. However, considering the associated risks, minimizing xenogeneic components is often advisable, signifying the need to improve the efficiency of reprogramming various types of canine cells in dogs without using feeder cells.

A research team led by Professor Shingo Hatoya and Dr. Masaya Tsukamoto from the Graduate School of Veterinary Science at Osaka Metropolitan University has identified six reprogramming genes that can boost canine iPSC generation by about 120 times compared to conventional methods using fibroblasts. The iPSCs were created from urine-derived cells using a non-invasive, straightforward, and painless method.

Additionally, the researchers succeeded in generating canine iPSCs without feeder cells, a feat that had been impossible until now. The team aims to disseminate their findings in the global research community, contributing to advances in regenerative medicine and genetic disease research in veterinary medicine.

As a veterinarian, I have examined and treated many animals, explained Professor Hatoya. However, there are still many diseases that either cannot be cured or have not been fully understood. In the future, I am committed to continuing my research on differentiating canine iPSCs into various types of cells and applying them to treat sick dogs, hopefully bringing joy to many animals and their owners.

Reference: Generation of canine induced pluripotent stem cells under feeder-free conditions using Sendai virus vector encoding six canine reprogramming factors by Masaya Tsukamoto, Kazuto Kimura, Takumi Yoshida, Miyuu Tanaka, Mitsuru Kuwamura, Taro Ayabe, Genki Ishihara, Kei Watanabe, Mika Okada, Minoru Iijima, Mahito Nakanishi, Hidenori Akutsu, Kikuya Sugiura and Shingo Hatoya, 21 December 2023, Stem Cell Reports. DOI: 10.1016/j.stemcr.2023.11.010

The study was funded by the Japan Society for the Promotion of Science, the Japan Science and Technology Agency, Anicom Specialty Medical Institute, Inc, and Osaka Metropolitan University.

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The Future of Dog Health: Scientists Develop Unprecedented Painless Method To Reprogram Canine Stem Cells - SciTechDaily

Dog owners might find a new reason to value their pets urine, thanks to groundbreaking research from Osaka Metropolitan University involving canine stem cell therapy.

A team of scientists has developed an innovative method to reprogram stem cells from canine urine, marking a significant step forward in veterinary regenerative treatments. This non-invasive and pain-free technique could revolutionize how we approach our furry friends healthcare.

In the realm of human medicine, iPSCs have been a cornerstone in regenerative studies. Recognizing the growing need for advanced medical treatments for pets, researchers anticipate similar breakthroughs for dogs and cats using iPSCs. However, a challenge has been the lower reprogramming efficiency in canine cells compared to human cells, limiting the potential applications in veterinary medicine.

Traditionally, iPSC induction often requires feeder cells from different species, which poses certain risks. The Osaka Metropolitan University research team, led by Professor Shingo Hatoya and Dr. Masaya Tsukamoto, tackled this issue head-on.

They identified six reprogramming genes that enhance canine iPSC generation by approximately 120 times using urine-derived cells compared to conventional fibroblast methods. This achievement is notable not only for its efficiency but also for eliminating the need for feeder cells.

The creation of iPSCs from urine is a significant milestone, offering a straightforward and humane method for cell collection. This advancement opens doors to new therapies in regenerative medicine and genetic disease research in veterinary science. The research team is eager to share their findings globally, hoping to enrich the field of veterinary medicine significantly.

Professor Hatoya, reflecting on his career and the limitations in treating various animal diseases, expressed his commitment to this research.

As a veterinarian, I have examined and treated many animals. However, there are still many diseases that either cannot be cured or have not been fully understood. In the future, I am committed to continue my research on differentiating canine iPSCs into various types of cells and applying them to treat sick dogs, hopefully bringing joy to many animals and their owners, Hatoya concluded.

This groundbreaking research not only exemplifies scientific innovation but also highlights the deep bond between humans and their canine companions, offering hope for more effective treatments in veterinary medicine.

As discussed above, stem cell therapy represents a significant leap in medical science, offering potential treatments for various diseases and injuries.

Stem cells are unique cells capable of transforming into various cell types in the body. They play a crucial role in the bodys healing process. There are two primary types of stem cells:

Stem cell therapy involves using stem cells to repair or replace damaged tissues or cells in the body. This process typically includes:

Stem cell therapy has a wide range of applications, including:

Stem cell therapy, particularly involving embryonic stem cells, faces ethical debates and regulatory hurdles. Concerns revolve around the moral implications of using embryonic cells and the need for stringent regulations to oversee stem cell research and therapy.

Advancements in stem cell research continue to unveil new potential therapies. Areas like iPSCs (induced pluripotent stem cells) are showing promise, as they can be generated directly from adult cells, circumventing ethical concerns associated with embryonic stem cells. The future of stem cell therapy holds promise for personalized medicine, where treatments are tailored to individual genetic profiles.

In summary, stem cell therapy is an exciting field of medicine with the potential to revolutionize treatment for various diseases and injuries. While it offers significant benefits, challenges and ethical concerns must be addressed to fully realize its potential. As research progresses, stem cell therapy may become a cornerstone in the treatment of many currently incurable diseases, heralding a new era in medical science.

The full study was published in the journal Stem Cell Reports.

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Jackie Brown

Pet expert Jackie Brown has spent 20 years following her passion for animals as a writer and editor in the pet publishing industry. She is contributing writer for National Geographics Complete Guide to Pet Health, Behavior, and Happiness: The Veterinarian's Approach to At-Home Animal Care (April 2019) and author of the book Its Raining Cats and Dogs: Making Sense of Animal Phrases (Lumina Press, 2006). Jackie is a regular contributor to pet and veterinary industry media and is the former editor of numerous pet magazines, including Dog World, Natural Dog, Puppies 101, Kittens 101 and the Popular Cats Series. Prior to starting her career in publishing, Jackie spent eight years working in veterinary hospitals where she assisted veterinarians as they treated dogs, cats, rabbits, pocket pets, reptiles, birds and one memorable lion cub. She lives in Southern California with her husband, two sons and miniature poodle Jger. Reach her at jackiebrownwriter.wordpress.com.

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Stem Cell Study Aims to Heal Your Dog's Allergies - Dogster.com

Performances by Jay Allen and Kylie Morgan, Melinda Doolittle, Charles Esten, Paul Freeman, Paul Greene, Ginna Claire Mason, MaRynn Taylor, Noah Thompson, Alicia Witt, and more covering hits from the early 2000s

Event raises awareness and funds for the Alzheimer's Association research grant program

*Photos available*

NASHVILLE, Tenn., Nov. 13, 2023 /PRNewswire/ -- Hallmark stars Ashley Williams and Nikki DeLoach hosted the sixth annual Dance Party to End ALZ on Sunday, November 12 at Nashville's Wildhorse Saloon, which raised more than $300,000 for the Alzheimer's Association research grant program. The event founded by Kimberly Williams-Paisley was emceed by Apple Music radio host Kelleigh Bannen.

Williams and DeLoach opened the evening with a surprise performance of "Party In the U.S.A." The dynamic duo welcomed guests and shared why co-hosting the event meant so much to them after both losing a parent to dementia. Williams' mom, Linda, passed away with Alzheimer's in 2016, and DeLoach's dad, David, passed away with Pick's disease, a rare form of dementia, in 2021.

Dressed in 2000s fashion, performers took to the stage covering throwback hits from the era. Accompanied by Wildhorse Saloon's house band Three Lane, performances included:

"We are beyond grateful to the Nashville community, performers, generous sponsors and attendees near and far who joined us at the sixth annual Dance Party to End ALZ," said co-hosts Ashley Williams and Nikki DeLoach. "Everyone coming together for this cause means the world to us and our families. Together, we raised awareness and funds to support the Alzheimer's Association's research grant program, which is helping us get one step closer to ending Alzheimer's and all other dementia."

Event committee included:

Generous sponsors included:

Celebrities in attendance included:

Funds raised through the Dance Party to End ALZ will directly support the Alzheimer's Association's research grant program. To date, Dance Party to End ALZ has raised more than $2.1M to fund diverse and exciting Alzheimer's research from studying the impacts of genetics and sleep on the brain, to developing a smartwatch-based intervention for dementia risk reduction.

For more information and to donate, visit alz.org/DanceParty.

About the Alzheimer's AssociationThe Alzheimer's Association leads the way to end Alzheimer's and all other dementia by accelerating global research, driving risk reduction and early detection, and maximizing quality care and support. Our vision is a world without Alzheimer's and all other dementia. For more information, visit alz.org or call the 24/7 Helpline at 800.272.3900.

SOURCE Alzheimer's Association

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Ashley Williams and Nikki DeLoach Host Sixth Annual 'Dance Party ... - PR Newswire

You walk into your practice and one of your favorite clients calls in a panic: Gertrude has been vomiting all night! You can see her at 4 PM. Three oclock rolls around, and Gertrudes owner calls to cancel. She has stopped vomiting and is doing better.

Two days later, Gertrude is not doing well. Shes lethargic and weak. Your heart drops as you reach to pet her and notice her mucus membranes are jaundiced. You set to work running bloodwork and starting intravenous (IV) fluids. Her laboratory test results come back with screamingly high liver enzymes. You recommend transferring to a 24-hour care facility to give Gertrude the best chance.

What happened? Gertrude unfortunately got into Amanita mushrooms and has since gone into fulminant liver failure. Lets look at identifying these toxins and what we can do to prevent illness from them in the future.

Amanita mushrooms. (ikostudio / stock.adobe.com)

With more than 10,000 species of mushrooms estimated in North America and approximately 100 being toxic, identifying each mushroom isnt realistic.1 Treating each mushroom ingestion as a worst-case scenario may be the best course of action to save your patients life. Toxic mushrooms can cause hepatotoxicity, gastrointestinal disease, SLUDGE (saliva, lacrimation, urination, defecation, gastrointestinal signs, and emesis) signs, neurotoxicity, and even nephrotoxicity. In general, mushroom toxicities can have a quick onset or prolonged onset. Although not foolproof, those that have an onset of less than 3 hours typically are self-limiting, while those that have an onset of greater than 6 hours after ingestion tend to be the more life-threatening ones. With no true antidote, decontamination and supportive care are required.2

When working as an emergency veterinarian, I was taught that unless youre a mycologist, treat a patient for the worst-case scenario, as follows:

Knowing where mushrooms are often found is a great way to start. Although toxic mushrooms can be found throughout the United States, we can use what we know about their ecology to help clients identify the higher risks. Mushrooms generally like moist environments with decaying matter and woody debris. Many can be found in spring to fall, but it depends on the climate; some are happy to be out in the winter if the temperature is suitable, like in the Pacific Northwest.3

We know where to look; how do we tell whos who? Some will be obvious; for instance, the Amanita muscaria is depicted throughout art as a little red toadstool with white spots. And if your client admits to having psychedelic mushrooms, then maybe your job is a little easier. But for the rest of them? The death cap (Amanita phalloides) and angel of death (Amanita ocreata) both look like white mushrooms. If a client calls about a mushroom exposure, have them bag the fungi in a paper bag wrapped in a moist paper towel (tell them to wash their hands), in case you or a mycologist can identify them, but prepare them for treatment for the worst-case scenario. There is a list of volunteer mycologists on the North American Mycological Associations website.4 You can also try animal poison control, though they may not have a mycologist available.

What can we do to prevent pets from being exposed in the first place? Educate our clients!

First, we want to prevent exposure in our pets environment by eliminating the source. Educate your clients to check their yard for mushrooms weekly and remove them, stem and all. I pair it with instructions to clean up dog waste and ensure that its bagged and thrown in the trash to prevent spreading spores. Wash your hands. And please dont put it in compost.

For hiking, encourage clients to keep pets on a regular leash (not a retractable one) and stick to the middle of the trail so they can watch for any tempting mushrooms. Clients should keep their dogs within sight when off leash. If they live in a high-risk area and their dog likes to eat things, an off leash park may not be a good place for them unless they have a perfect leave it/drop it and recall. They could also walk the park to look for potential hazards before letting their dog loose.

If your client has a dog who likes to eat everything on walks, talk to them about muzzle training. Muzzles are a great tool not only for preventing bites but also for preventing dietary indiscretion. Ensure its a basket muzzle so the dog can pant, drink, and take treats. I prefer the JAFCO muzzle for this purpose, as they can still pant, drink, and take treats through a centrally placed hole in the front. Check out the Muzzle Up! Project for more information on utilizing muzzles and training dogs to wear them.5

To protect pets from recreational mushrooms, encourage clients to keep their pets in a separate room to avoid any chance of them getting into substances like psilocybin mushrooms. Educate your clients that if their pet is exposed to these, they should contact their veterinarian. Remind them we are not the authorities and want to help their pet.

Finally, let clients know what to do if their pet ingests a mushroom:

Utilize your social media and newsletters to send out mushroom education and reminders of what clients should do each season mushrooms sprout in your area to save time in the exam room. Keep mushrooms on your differential list and train your team to ask questions about mushroom exposure for sick patients. And remember, toxic mushrooms can look innocent, so unless you are a mycologist, it may be best to assume the worst.

A pocket of prevention is a recurring column brought to you by the American College of Veterinary Preventive Medicine (ACVPM). The ACVPM is an American Veterinary Medical Association-recognized veterinary specialty organization offering board certification in preventive medicine with the option of a specialty in epidemiology. Becoming a diplomate of the ACVPM means joining some of the most distinguished veterinary professionals in preventive medicine and public health at national and international levels. For more information, go to acvpm.org.

References

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Preventing mushroom toxicosis in our companion animals - DVM 360

Red blood cells: vipman4 - stock.adobe.com

Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) alone or combined with targeted agents (R-CHOP-X) demonstrated efficacy and safety in patients with newly diagnosed, intermediate-risk, or high-risk diffuse large B-cell lymphoma (DLBCL), according to findings published in Cancer Cell.1

In the randomized, phase 2 GUIDANCE-01 trial (NCT04025593), patients were randomized 1:1 to receive R-CHOP-X or R-CHOP.2 A higher response rate was observed with R-CHOP-X vs R-CHOP arm, meeting the primary end point of the study, (88% vs 66%; P =.003), with an overall response rate (ORR) of 92% (95% CI, 85-99) in the R-CHOP-X arm vs 73% (95% CI, 62-85) in the R-CHOP arm (P =.005).1

With R-CHOP-X vs R-CHOP, 2-year progression-free survival (PFS) rates were 88% vs 63% (P <.001). For overall survival (OS), 2-year OS rates were 94% compared with 77% (P =.001). Additionally, the safety profile of R-CHOP-X was manageable, and no new clinically significant or unexpected toxicities were observed.

Our findings demonstrate efficacy and safety of R-CHOP-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in patients with newly diagnosed DLBCL, wrote the study authors led by Mu-Chen Zhang, MD, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.1

A total of 134 patients were screened and treated between July, 2019 and December, 2020, and 128 ended up being randomly assigned 1:1 to receive R-CHOP-X (n = 64) or R-CHOP (n = 64). The primary end point of the study was complete response (CR) rate.2 Secondary end points were PFS, OS, ORR, and number of patients with adverse events (AEs).

Between arms, baseline clinical and pathological characteristics were similar.1 The median age of those enrolled was 64 years (range, 25-74), most patients presented with relatively high-risk disease (77%), and 80% of patients had an elevated serum LDH level. Additionally, 52% of patients had 2 or more extranodal involvement sites, and 65% had international prognostic index 3-5. A total of 36% of patients presented with MYC/BCL2 double expression and 1 presented with MYC/BCL6 rearrangement lymphoma. No patients had MYC/BCL2 rearrangement.

To characterize patients, simplified 20-gene algorithm was established to include MCD-like (20% of patients), BN2-like (18%), N1-like (4%), EZB-like (2%), TP53 mutations (16%), and not otherwise specified (39%).

At the end of treatment, the CR rate was 88% (95% CI, 79-96) with R-CHOP-X vs 66% (95% CI, 54-78) with R-CHOP arm. For genetic subtypes, CR rates were 85% (95% CI, 62-100) for MCD-like, 91% (95% CI, 71-100) for BN2-like, 100% for N1-like, 100% for EZB-like, 82% (95% CI, 55-100) for TP53mut, and 88% (95% CI, 74-100) for NOS in the R-CHOP-X arm. In the R-CHOP arm, these rates were 54% (95% CI, 23-85), 67% (95% CI, 35-98), 50%, 100%, 60% (95% CI, 23-97), and 80% (95% CI, 63-97), respectively.

With a median follow-up of 36 months, the median PFS and OS were not reached. With R-CHOP-X, 3 patients had a partial response (PR), 2 of whom received radiotherapy of the residual lesion revealed by final positron emission tomography-computed tomography evaluation. The other underwent a splenectomy and was pathologically confirmed with DLBCL. Three patients had stable disease (SD). Two of these patients received chimeric antigen receptor (CAR) T-cell therapy and achieved CR, and the other died from disease progression. Further, 2 patients had progressive disease (PD) and were salvaged with second-line chemotherapy. These patients died from disease progression.

In the R-CHOP arm, 5 patients had a PR with 3 receiving radiotherapy and 2 given second-line treatment. Four of the 7 patients with SD received second-line treatment followed by autologous hematopoietic stem cell transplantation and achieved CR, and the other 3 died from disease progression, including 1 patient who was treated with CAR T-cell therapy. Additionally, 10 patients had PD. Three of the patients with PD were given CAR T-cell therapy and died from disease progression, and the other 7 received second-line therapy. Six of the 7 patients died from disease progression.

Looking at safety, grade 3-4 neutropenia was the most common AE observed in both treatment arms (81% with R-CHOP-X v 75% with R-CHOP). In the R-CHOP-X vs R-CHOP arms, grade 3-4 thrombocytopenia was seen in 31% vs 11% of patients, grade 3 anemia in 25% vs 20%, and febrile neutropenia that was a maximum of grade 3 in 20% vs 11%.

No grade 4 anemia was reported. While there were increased rates of cytopenia and thrombocytopenia with R-CHOP-X, this did not lead to an increase in grade 3 pulmonary infection (6% v 5%) or gastrointestinal bleeding complications (2% v 3%) compared with R-CHOP. Moreover, any grade infections were seen in 22% vs 20%, respectively, and no treatment-related mortality was seen.

The study authors concluded, genetic subtype-guided targeted agents combined with R-CHOP are effective, safe, and clinically feasible in newly diagnosed DLBCL. With the encouraging results of the POLARIX trial [NCT03274492], this genetic subtype-guided treatment of targeted agents combined with Pola-R-CHP [polatuzumab vedotin-piiq (Polivy), rituximab, cyclophosphamide, doxorubicin, and prednisone] may further improve the clinical outcomes for [patients with] intermediate-risk or high-risk DLBCL.1

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Phase 2 GUIDANCE Trial of R-CHOP-X Meets Primary End Point in ... - Targeted Oncology

Morris Animal Foundation is inviting animal lovers to provide donations to its year-end fundraising campaign that is committed to advancing veterinary scientific exploration. Through this initiative, the organization aims to support longer, healthier lives for animals everywhere.

"The best gift we can give is the one that keeps our best friends by our side for years to come," expressedRyan Welch, Morris Animal Foundation Interim President & CEO, in an organizational release.1 "We're asking for the support of animal lovers to make that possible. Gifts to the Foundation this holiday season will directly power studies leading to new diagnostics, preventives, treatments, and even cures for the life-threatening diseases and painful conditions affecting animals everywhere. The need now is greater than ever."

The donations will support over 160 ongoing animal health studies. Some highlights include:

Those interested can also support the Morris Animal Foundations efforts by ordering holiday cards. These cards are eligible for the Board of Trustees matching gift to help animals around the world while offering loved ones a cherished note.

The campaign launched today and will run throughDecember 31, 2023.

References

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Baseline characteristics and topography of LVAD infections

Baseline characteristics of the study population are shown in Table 1. The median interval between LVAD implantation and initial 18F-FDG-PET/CT was 700 (IQR: 3431589) days.

DLIs were detected in 92/118 (78%) patients by 18F-FDG-PET/CT. Irrespective of DLI, an exclusive infection of the internal LVAD-components was found in 10/118 (8%). It is noteworthy that with 65/118 (55%), only half of the entire cohort presented with clinically apparent DLI. As an important finding, DLI could be identified by PET/CT in 30/53 (57%) patients who had a clinically inapparent driveline entry sites. Besides increased metabolic activity at the driveline entry site or the subcutaneous driveline pathway, in 43/118 (36%) infection of the outflow graft and in 38/118 (32%) the pump pocket was found (Fig.2B). At the time of PET/CT, 75/118 (64%) patients had a positive microbiological smear at the driveline entry site. The pathogens most frequently detected were Staphylococcus aureus in 19/75 (25%), Staphylococcus epidermidis and Pseudomonas aeruginosa in 13/75 (17%) each, aerobic gram-positive bacilli in 8/75 (11%), enterobacteria in 7/75 (9%), Corynebacterium amycolatum, Escherichia coli and Serratia marcescens in 5/75 (5%) each. Bloodstream infections were detected in 13/118 (11%) patients, 3 of whom had VAD-related bloodstream infections. Compared to patients with negative blood culture results, those with positive results showed increased levels of CRP (p<0.001) and WBC (p=0.02). At the time of PET/CT, 83/118 (70%) patients were already covered by antibiotic therapy due to a LVAD-specific infection or an unknown infection focus with an indication for empiric antibiotic therapy. No patient was in the intensive care unit at the time of infection diagnosis. A comparison of PET/CT parameters between the patients with and without driveline infection in PET/CT is shown in Table 2. CRP levels correlated with metabolic tissue activity close to internal components such as the pump pocket (r=0.27, p=0.003) and the outflow graft (r=0.19, p=0.047), but less with the subcutaneous driveline (r=0.17, p=0.073) and not with the driveline entry site (r=-0.08, p=0.40). Also, CRP levels correlated with imaging-derived systemic inflammatory activity (spleen signal (r=0.22, p=0.022), bone marrow signal (r=0.22, p=0.021), and mediastinal lymph node signal (r=0.27, p<0.001)). Of note, only 21/89 (24%) patients with DLI on PET/CT showed CRP levels below the upper reference limit (5mg/L), but 82/88 (93%) patients had a normal WBC (<10,5109/L). Fever (>38C) was found in 1/82 (1%) of the patients at the time of the PET/CT-diagnosed infection. Pulmonary infiltrates as a competing focus of infection and cause of an increase in inflammation parameters were detected in 9/118 (8%) patients in PET/CT. This group showed a significantly higher CRP (10.4mg/L (4.626) vs. 32.1mg/L (18.3 99.2), p=0.004).

(A) Schematic illustration of the LVAD system, subdivided in 4 components: (1) driveline entry site, (2) subcutaneous driveline pathway, (3) pump pocket, (4) outflow graft; (B) Infection topography; (C) Infection of subcutaneous driveline pathway; (D) Infection of subcutaneous driveline pathway and thoracic components.

WBC count did not correlate with any imaging-derived inflammatory parameters.

Sternal co-infection was associated with pump pocket infection (p<0.001, OR=7.25, 95% CI 2.6120.11), outflow graft infection (p=0.005, OR=3.8, 95% CI 1.4410.01), number of infected LVAD components (p=0.002) and PET/CT signal of mediastinal lymph nodes (p=0.031).

Correlation analysis of PET signal with device components, activity of aortic vessel walls and lymphoid and hematopoietic organs is shown in Fig.3. Metabolic activity at the driveline entry site correlated with a) the aortic vessel signal (r=0.32, p<0.001) and b) both lymphoid organs, namely spleen signal (r=0.20, p=0.030), and bone marrow signal (r=0.20, p=0.030), highlighting systemic interactions. Metabolic activity of the aortic vessel walls itself correlated with spleen signal (r=0.46, p<0.001) and bone marrow signal (r=0.32, p<0.001).

Heatmap: Spearman correlation of the parameters of the first PET/CT, n=118, in four patients CRP and CBC were missing; blue: r=-1, red: r=1; CRP C-reactive protein, WBC white blood cell count, SUV standardized uptake value, thVSL thoracic vessels, SPL spleen, BM bone marrow, MLNs mediastinal lymph nodes, scDL subcutaneous driveline pathway, DLES driveline entry site, OG outflow graft, PP pump pocket.

Multivariable analysis including metabolic activity at the driveline entry site, aortic vessel wall activity, spleen signal and bone marrow signal revealed an independent association between aortic vessel wall activity and metabolic activity at the driveline entry site (=0.04, 95% CI 0.010.06, p=0.001) and spleen signal (=0.43, 95% CI 0.180.68, p<0.001).

A longitudinal sub-analysis of repeated PET/CTs was performed to investigate potential changes in metabolic activity in the vessel wall, revealing stability over time (ANOVA, p=0.27).

Within the observation period, 22/118 (19%) patients suffered a CVE, of which 15/22 (68%) had an ischemic stroke and 8/22 (36%) a haemorrhagic stroke. No patient suffered a transient ischemic attack (TIA) during the follow up period. One patient suffered both, an ischemic and haemorrhagic stroke. Seven patients had 2 or more CVE and 11/22 (50%) died within a median of 263days after the CVE (Table 3).

Characteristics of patients with ischemic stroke (n=15) compared with those without ischemic stroke (n=96) after excluding patients with haemorrhagic stroke (n=7) are shown in Table 4. The group with ischemic stroke after PET/CT demonstrated significantly higher metabolic activity at the driveline entry site (p=0.04), whereas the activity of other device components or CRP and WBC did not differ. In multivariable analysis adjusting for type of anticoagulant (VKA, heparin, others) and device exchange, higher metabolic activity at the driveline entry sitewas not significantly associated with ischemic stroke(OR=1.16, 95% CI 11.33, p=0.05). The type of anticoagulation (OR of heparin or others vs. VKA=3.22, 95% CI 1.317.88, p=0.01) proved to be an independent predictor for ischemic stroke. The type of anticoagulation in LVAD patients is often modified in the course of an inpatient stay and can therefore serve as an indicator for hospitalization with severe comorbidity, e.g., bleeding complications. Consequently, not only anticoagulation itself is a relevant competing cause of stroke, but also an indication of other contributing risk factors. The severity of infection as measured by fever (p=0.505), number of infected LVAD components on PET/CT (p=0.232) and laboratory parameters showed no association with the occurrence of CVEs. At the time of stroke, 14/22 (64%) patients were hospitalized due to following concomitant conditions: acute pump stop (n=1), driveline infection (n=6), gastrointestinal hemorrhage (n=1), heart transplant (n=2), device thrombosis (n=3) with indication for device exchange and domestic fall (n=1). In this context, VKA was paused in some patients, and anticoagulation was switched to heparin (n=6) or Argatroban (n=2). At the time of ischemic stroke, 8/15 (53%) patients were anticoagulated with vitamin K antagonists, four of whom were within, one was below and three were above the intended target International Normalized Ratio (INR) range. 7/15 (47%) patients were on heparin therapy under activated Partial Thromboplastin Time (aPTT) control, of which three were below and one was above the target aPTT range. At the time of haemorrhagic stroke, 6/7 (86%) patients were receiving anticoagulation with vitamin K antagonists, with one patient within and five patients above the intended target INR range. 1/7 (14%) patient was receiving heparin therapy and was within the target aPTT range. Ischemic stroke occurred more frequently in patients with Heparin/Argatroban compared to those who remained on VKA (p<0.001). In a log-rank test the incidence of ischemic stroke differed between patients with SUVmax of the driveline entry site above the median compared with those under the median (Fig.4; 2(1)=5.21, p=0.023). The hazard of ischemic stroke, adjusted for type of anticoagulation, hyperlipidemia and diabetes mellitus, was about 10 times higher in the group with an increased uptake of the driveline entry site (HR=10.21, 95% CI 1.6463.52, p=0.013). Receiver operating characteristics (ROC) analysis demonstrated the diagnostic ability of the activity of the driveline entry site to predict ischemic stroke after initial PET/CT (Fig. 1 in supplement; AUC=0.67, p=0.04).

Kaplan Meier analysis on ischemic stroke-free survival; differences in the incidence of ischemic stroke between patients with SUVmax of the driveline entry site above versus below the median. The analysis revealed a significantly differing hazard for ischemic stroke (2(1)=5.21, p=0.023; HR=10.21, 95% CI 1.6463.52, p=0.013).

A log-rank test was used to determine the incidence of CVE for the comparison of SUVmax of the subcutaneous driveline pathway above versus below the median. The incidence of stroke differed significantly between the two groups (Fig. 2 in supplement; 2(1)=6.76, p=0.009). The hazard of suffering a CVE was 3.5 times greater in the group with an increased uptake of the subcutaneous driveline pathway (HR=3.53, 95% CI 1.289.72, p=0.015).

During the observation period, 47/118 (40%) patients died within 1715 (1050) days after implantation. Causes of death were sepsis (50%), right heart failure (17%), hemorrhage (6%), pump thrombosis (6%) and brain herniation after intracerebral hemorrhage (4%) or middle cerebral artery infarction (2%). Cause of death was unknown for 9%.

Deceased patients showed more often hyperlipidemia (p=0.008), increased CRP values (p=0.001) and history of device exchange (p=0.016).

In addition, metabolic activity of the subcutaneous driveline pathway (p=0.005) and thoracic lymph node signal were significantly higher in deceased patients (p=0.017). Binary logistic regression analysis including metabolic activity of the subcutaneous driveline pathway, hyperlipidemia, mediastinal lymph node signal and device exchange revealed increased mortality in patients with hyperlipidemia (OR=1.90, 95% CI 1.292.79, p=0.001) and higher metabolic activity of the subcutaneous driveline pathway (OR=1.13, 95% CI 1.021.24, p=0.016). No association was found between mortality and severity of infection as measured by fever (p=0.232), number of infected LVAD components in PET/CT (p=0.268) and laboratory parameters.

A log-rank test revealed a significant difference in survival of patients with metabolic activity of the subcutaneous driveline pathway above the median compared with those below the median (Fig.5; 2(1)=9.18, p=0.002). Patients with increased subcutaneous driveline metabolic activity showed a 13% increase in the risk of mortality in Cox regression analysis after adjustment for age, diabetes mellitus and hyperlipidaemia (HR=1.13, 95% CI 1.051.21, p<0.001).

Kaplan Meier survival analysis: Mortality; differences in survival between patients with SUVmax of the subcutaneous driveline pathway above versus below the median. The analysis revealed a significantly differing distribution of survival (2(1)=9.18, p=0.002; HR=1.13, 95%CI 1.051.21, p<0.001).

We performed a ROC analysis for prediction of mortality (Fig. 2, 3 in supplement). The analysis showed that both, CRP in the morning of the first PET/CT (Fig.3; AUC=0.68, p=0.001) and metabolic activity of subcutaneous driveline (Fig. 4 in supplement; AUC=0.65, p=0.005), can help to predict mortality.

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ShipRocked, the horror-themed rock music cruise vacation, will be back for its 14th edition next February 4 to 10, 2024, onboard the Carnival Magic. The cruise is already completely sold out, with staterooms snapped up in just three days a new record. But don't worry, there's a waitlist you can join if you're still hoping to get on board this floating rock festival.

Joining the already impressive roster are some fantastic musicians for ShipRocked's fan-favorite all-star band, The Stowaways. Prepare to rock out with Michael Starr (Steel Panther), Hayley Cramer (Pop Evil), Bumblefoot, Roy Mayorga (Ministry / Stone Sour), Keith Wallen (Breaking Benjamin), Elias Soriano (Nonpoint), Emily Armstrong (Dead Sara), and many more. Kid Kapichi has also joined the ShipRocked lineup, promising a diverse array of rock performances.

Michael Starr of Steel Panther expressed his excitement, saying, "Hell yes! Im really excited to be invited to ShipRocked to jam with The Stowaways next year. Looking forward to hanging with everyone and having a kick-ass cruise together."

And it's not just about the music. ShipRocked goes the extra mile by offering onboard tattoo services, and in 2024, the talented Dawn Webb, along with tattoo artists Samantha Taylor and Colin Orion, will be there to make sure you leave with a piece of art on your skin.

The 2024 ShipRocked cruise sets sail from Miami, Florida, making stops at three new ports for ShipRockers: Bimini, The Bahamas; Ocho Rios, Jamaica; and Grand Cayman.

The ShipRocked community is also deeply committed to charitable efforts, with the annual ShipRocked Cancer Sucks! onboard charity auction raising an incredible $125,000 for cancer research during the 2023 cruise. It's proof that this community knows how to rock for a good cause.

The full music lineup for ShipRocked 2024 is as follows:

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Sold Out SHIPROCKED 2024 Reveals Line-Up Additions - Metal Injection