Tag Archives: Novel

AUSTRALIAN AUTHOR LAUNCHES DEBUT NOVEL ‘SKULDUGGERY’ IN INDIA

'Skulduggery' released in India

Paul Rushworth-Brown’s novel ‘Skulduggery’ released in India

“You are kept in suspense ’til the final pages with this historical romance, mystery, whodunit. ”

SYDNEY, NSW, AUSTRALIA, July 17, 2021 /EINPresswire.com/ — Australian historical fiction author Paul Rushworth-Brown will debut his novel “Skulduggery” which will be available in India July 15, 2021 as part of Shawline Publishing’s historical fiction line. He has appeared on America Tonight with Kate Delaney, the BBC with Sanchez Payne and 2RDJ-FM with Neil Lithgow in Australia.

The novel has already earned acclaim, with one reviewer describing it as “masterful and thoroughly enjoyable. A fascinating and wonderful example of historical fiction and the old-time romance and whodunit really added to the story. Thoroughly researched, it is written in such a way that puts you in the time and place.”

Set on the “Bleak Pennine moors of Yorkshire, England, a beautiful, harsh place, close to the sky, rugged and rough, no boundaries ‘cept the horizon which in some places went on forever. Green pastures and wayward hills, the colours of ochre, brown and pink in the spring. Green squares divided the land on one side of the lane and on the other. Sheep with thick wool and dark snout dotted the hills and dales. One room, cruck house cottages, scattered, smoke billowing out of some and not others. Dry stone walls dividing and falling, a patchwork of green, green and greener. Long grasses whispered while swaying in the chilled wind waiting for the summer months.”

The novel, set on the moors of West Yorkshire, follows wee Thomas and his family shortly after losing his father to consumption. Times were tough in 1603 and there were shenanigans and skulduggery committed by locals and outsiders alike. Queen Bess has died and King James sits on the throne of England and Scotland.

Thomas Rushworth is now the man of the house being the older of the two boys. He is set to marry Agnes, in an arranged marriage, but a love story develops between them. This rollicking adventure paints a descriptive picture of the characters and the landscape they fill. You are kept in suspense ’til the final pages where one hopes good will triumph over evil.

Paul was educated at Charles Sturt University in New South Wales, Australia. He became a writer in 2015 when he embarked on a six-month project to produce a written family history for his children, Rachael, Christopher and Hayley.

This four hundred page book traced his family’s ancestry back to Haworth, Yorkshire where his ancestors had been living as copyholders or peasant farmers since 1590. His Great Grandfather James Rushworth Ist was a carpenter and the first to move away from the dales in the mid-1800s with his wife and nine children. Through this research, he developed a passion for writing and “Skulduggery” and the soon to be released “Winter of Red” is a continuation of this.

Rushworth-Brown is available for interviews and appearances. For booking presentations, media appearances, interviews, and/or book-signings contact mailto:[email protected] Find out more on his website: www.paulrushworthbrownskulduggerywinterofred.com/

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Novel Colonic Agonist Formulation Promising for Obesity

NEW YORK (Reuters Health) – A colonic release formulation of medium-chain fatty acids (MFCA) curbed appetite and boosted levels of the anorexigenic hormone PYY in a small placebo-controlled crossover trial involving obese adults.

“We have shown that two nutrient-sensing receptors, GPR84 and FFAR4, are expressed on human L-cells;” Dr. Madusha Peiris of Queen Mary University of London, UK told Reuters Health by email. “L-cells are found in high levels in the colon and they store and release the potent appetite-reducing hormones, PYY and GLP-1.”

“We also have shown that stimulating GPR84 and FFAR4 causes a synergistic release of PYY and GLP-1 from human colonic biopsies,” she said. “This was a surprising result.”

The clinical trial, reported in Gut, demonstrated that treating obese volunteers with a combination of nutrients that stimulated GPR84 and FFAR4 reduced calorific intake by increasing the levels of PYY in the blood, she explained. “This hormone travels from the gut to the brain to activate food control centers that tell us we are feeling ‘full.'”

In essence, she said, “We are mimicking gastric bypass surgery but without the risk of surgery.”

In a randomized crossover fashion, Dr. Peiris and colleagues had 20 volunteers come to the clinic on two separate days, separated by at least four weeks, to take combined GPR84 and FFAR4 agonists in colonic-release capsules or placebo before breakfast and lunch. Participants were not diabetic, had a mean age of 49, a mean BMI of 34.2, and had never undergone major gut surgery.

Active capsules contained 500 mg 3′3 diindolyl-methane (250 mg, Olympian Labs); 2100 mg alpha lino-lenic acid contained within perilla oil (500 mg, 90 LiCaps, Fairvital); and 2400 mg lauric acid (Sigma Aldrich).

Those who received the active treatment had reduced overall calorific intake and increased postprandial levels of PYY versus placebo. Specifically, the authors note, “there was no effect of MCFA capsules on subjective hunger ratings but modest yet significant effects on energy intake. This reduction in calorific intake of approximately 12% could result in weight loss of 12 kg over 24 weeks.”

Tissue analyses showed that GPR84 and FFAR4 receptors, among others, were coexpressed on human colonic enteroendocrine cells. Activation of GPR84 alone induced intracellular pERK, whereas FFAR4 selectively activated pCaMKII.

Further, coactivation of GPR84 and FFAR4 induced both phosphoproteins, and a superadditive release of GLP-1 and PYY.

Using a special preparation in a mouse model, the team found that nutrients and hormones convergently activated colonic afferent nerves via GLP-1, Y2 and 5-HT3 receptors.

Dr. Peiris said, “We will begin a 24-week trial in obese volunteers next year, where capsules will be given twice a day. This will allow us to assess weight loss as well as changes to those all-important appetite-reducing hormones, PYY and GLP-1. Upon successful completion of this study, we aim to have a product for clinical use by 2025.”

Dr. Kuldeep Singh, Director of the Maryland Bariatric Center at Mercy, commented in an email to Reuters Health, “This is an excellent study that shows it is possible to simultaneously and in an additive fashion increase the in vivo after-meal production of satiety hormones PYY and GLP-1. It is very promising as just recently GLP-1 agonists (liraglutide and simaglutide) have been approved by FDA (for diabetes) and have shown substantial weight loss, even in patients with no diabetes.”

“The risk profile will dictate the long-term use of these approaches; however, I believe this is very promising and exciting,” he said. “Only serious patients opt for surgery. Once a non-surgical method is introduced, I believe everybody will line up for that.”

SOURCE: https://bit.ly/2UXUvIh Gut, online June 3, 2021.

Author: By Marilynn Larkin
Read more here >>> Medscape Medical News

Novel Liver Dialysis Device May Safely Curb ACLF

An investigational liver dialysis device (DIALIVE) was associated with significantly greater survival of patients with acute-on-chronic liver failure (ACLF), compared with the standard of care in a multicenter randomized study.

Among 30 evaluable patients with ACLF from alcoholic cirrhosis randomized to treatment with the DIALIVE system or standard of care, two-thirds of patients assigned to DIALIVE had both survived and experienced resolution of ACLF by 28 days, compared with one-third of patients assigned to standard of care, reported Banwari Agarwal, MBBS, MD from the Royal Free Hospital in London at the meeting sponsored by the European Association for the Study of the Liver.

Different From MARS

The DIALIVE system differs from the Molecular Adsorbent Recirculating System (MARS) liver dialysis system in that DIALIVE removes and replaces albumin, including proinflammatory albumin, rather than filtering and recirculating it, he explained.

“It addresses systemic inflammation, which wasn’t quite the case with MARS,” he said in the question-and-answer portion of his presentation in a general session.

In patients with ACLF, the risk of 28-day mortality increases substantially as the grade of ACLF increases.

“ACLF, however, is potentially reversible, and the initial grade at presentation undergoes changes over time during the natural course of the illness, with some patients deteriorating, some improving, and some even achieving complete ACLF resolution. The final grade is reached by days 3-7, and it is this final grade which determines their future outcome trajectory. I therefore propose that ACLF resolution in itself is an important therapeutic target,” he said.

Study Details

Agarwal and coinvestigators from eight centers in six European countries enrolled patients with a history indicative of alcohol-related cirrhosis, at least one acute decompensation event, and progression to ACLF grades 1, 2, or 3a.

Patients with an international normalized ratio above 3 were excluded, as were those with more than three organ failures, uncontrolled infections, patients with primary respiratory organ failure, and those with hemodynamic instability refractory to volume resuscitation and low-dose vasopressors.

A total of 32 patients, of whom 30 were evaluable, were randomized to receive liver dialysis in three to five DIALIVE sessions lasting 8-12 hours each (15 evaluable patients) or to standard of care at participating institutions (15 patients).

The investigators looked at safety of the device (the primary endpoint) in all patients who received at least one DIALIVE treatment (safety population), and a modified safety population of patients who received at least three DIALIVE treatments.

The median patient age in each arm was 49 years, and all patients had alcoholic cirrhosis, with alcoholic hepatitis accounting for at least one decompensation event. In addition, about 25% of patients in each arm had decompensation with infections and/or sepsis as precipitating factors.

Safety

Serious adverse events on days 1-10 occurred in 11 of 17 patients in the DIALIVE arm, and in 8 in the standard-of-care arm. In the DIALIVE arm, there were seven treatment-related serious device events, three unexpected serious device events (anemia, septic shock, and hypotension), and one patient discontinued dialysis after having unsafe levels of thrombocytopenia.

Four patients in the DIALIVE arm died on study. The first two died on day 1 one from hypotension, coagulopathy, and multiorgan failure, and this prompted a change in the protocol mandating that DIALIVE be conducted only in an ICU setting with more invasive monitoring and more frequent lab analysis of clotting and other biochemical parameters. Of the two other patients in the DIALIVE arm who on died on study, one died from non-MI cardiac arrest on day 8, and one patient with ACLF grade 3 and a European Foundation for the study of chronic liver failure (CLIF)–ACLF score of 68 died from multiorgan failure.

“I must emphasize that even this very sick patient tolerated the device very, very well,” Agarwal said.

In the standard-of-care arm, two patients died from progressive liver failure on days 17 and 27, respectively, and one died on day 17 from bacterial infections, bleeding, and progressive liver failure.

There were eight instances of filters clotting out of 64 filters used in total, and four episodes of device deficiency, including two instances where tubing could not be disconnected from an Oxiris filter during setup of the DIALIVE circuit, requiring use of new DIALIVE kits; one use of an incorrect dialysis fluid; and one incorrect setup of the DIALIVE circuit.

Significant Improvements in Many Scores

In the DIALIVE group, there were significant improvements over baseline at day 10 in both liver scores (P < .05) and brain scores (P < .001). In contrast, in the standard-of-care group there were no improvements in individual organ scores, and respiration scores were significantly worse (P < .01).

DIALIVE was also associated with significant improvements in CLIF-C organ failure scores, compared with standard of care at day 5 and day 10 (P = .021 and .001, respectively); CLIF-C–ACLF scores at days 5 and 10 (P = .045 and .023); and Model for End-Stage Liver Disease scores at day 5 (P = .028).

In the DIALIVE group, ­40% of patients had ACLF resolution by day 5, and 66.7% had resolution by day 10. In the standard-of-care arm, 15% had resolution on day 5, and 33.3% had resolution on day 10. DIALIVE was also associated with a significantly faster median time to resolution, compared with standard of care (10 days vs. not reached; P = .0307). At 28 days, 10 of 15 evaluable patients were alive and had resolution of ACLF with DIALIVE versus 5 of 15 with standard of care (P = .0281).

Agarwal said that the data justify the implementation of late-phase clinical trials of the liver dialysis device.

“Hopeful” Findings

“It’s very early, but we’re really desperate in finding something to bridge to transplantation,” commented Tobias Boettler, MD, from the University of Freiburg (Germany), who was not involved in the study.

“I think this is very hopeful,” said Boettler, who moderated the briefing where Agarwal summarized the study findings.

In the question and answer following the talk in a general session, moderator Philip N. Newsome, MD, from University Hospitals Birmingham (England) asked whether patients who were not treated should have been included in the analysis.

Agarwal replied that “the whole idea behind this study was to understand what this device does to these patients, and how these patients react to this device, so really not looking at the efficacy.”

The study was supported by the European Union’s Horizon 2020 initiative. Agarwal received a study grant from the initiative, but had no other relevant disclosures. Boettler and Newsome had no disclosures relevant to the study.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Author: Neil Osterweil
This post originally appeared on Medscape Medical News

Review: Winds of Change – A Polished, Absorbing, Animal-Filled Visual Novel

Shall we get this out of the way up front? This game features ‘furry’ characters. If you’re already heading to the comments to issue a humorous barb, please re-examine your life. Winds of Change is an accomplished, heartfelt and enjoyable visual novel that does not deserve to be held up against the invented, ludicrous stigma of being furry. Righto, cheers. That’s that. Let’s get on with the review, then.

Visual novels can be difficult to critique as games; the meat of the experience is with the writing and your enjoyment thereof, so all that can really be covered elsewhere is the UI, performance and possibly visuals. If we come out of the gate, then, and say that Winds of Change has all the features you’d want from a visual novel married with a good, compelling story, that’s about all some of you will need.

You are ‘the Seer’, as in see-er. An interesting in medias res opening is revealed to be a flash forward; a premonition, such as a Seer is wont to have, the subject of which is the destruction of their home and a mystical artifact known as the Blade of Exodus. It’s an interesting way to introduce the player to the game — show them a pivotal, horrifying moment of destiny then go “right, get out of that.” And, of course, you essentially spend your time reading text, looking at the rather good character art and backgrounds and wondering where all this is going, and just what the nature of the mysterious ‘Triumvirate’ actually is.

There are dialogue choices to be made; extensive ones, too, because there’s an enormous amount of lore to be wrung out of the world and it’s a pleasure to dig into it, interrogating the characters to witness their many, many optional conversation strands that flesh out and add colour to the proceedings. It helps that the voice acting is both exhaustive and rather wonderful — there’s a thoroughly enjoyable sense of verisimilitude to the interactions, with earnest line deliveries that don’t feel overwrought or played ‘too big’.

It makes the game a treat to play at its chosen pace, which is good because you can switch on Auto mode to (yes) automatically skip to the next line in time with the voiceover. And you should, because it’s quite easy to accidentally skip dialogue if you’re blasting through, usually hitting the ‘A’ button skips to the end of the passage, but if there’s a conversation choice to select it’ll automatically skip past it, which is non-ideal. We’d really recommend letting the game play out at its own pace, though; there’s a lot of dialogue but it’s all there to service the characters and their relationships — both romantic and otherwise — and yes, it’s very much LGBT friendly. There are background stats to take into account, too, which affect the flow of the story. The game tells you directly when these come into play, which is a nice user-friendly way to inform the player they haven’t (yet) screwed anything up.

Breaking up the text are some very (very) light exploration elements, by which we mean you’re presented with a scene and able to move your cursor around it to investigate certain elements à la Phoenix Wright. These aren’t complex and essentially serve to add even more detail and intrigue to an already-rich story, but they do make for a nice — if brief — change of pace. Don’t worry about missing anything, either: the game will prompt you when your latest inspection of an item will trigger the next part of the story, allowing you to back off and dig deeper if you want to. You can also use these sections to chat to your current ‘party’ in a variety of optional discussions. There’s also a world map to explore and the ability to revisit areas with new party members to unlock more discourse, but this exposes one other issue in the game: it feels like there’s a fair bit of loading, considering the relatively static nature of the game.

There are side-quests too, but given the nature of the game these are going to fall flat if the story isn’t interesting and well told; we believe it is, as there’s very obviously a lot of passion and love for the characters and world imbued within Winds of Change, and it’s difficult not to appreciate. We didn’t see all of the content by any means, but our playthrough took a shade under twenty hours, using the autoplay function throughout in order to wring maximum enjoyment from the game’s voicework and pacing. Speed readers will naturally find it a shorter game.

As with all visual novels it will live and die by your interest in the characters and their story; we think there’s a good chance you’ll get into this one if you approach it knowing that there’s going to be a lot of text and dialogue — more even than most VNs — and that there’s little in the way of overt humour or any real tongue-in-cheek tone to ease up the somewhat intense storytelling.

Conclusion

This is thoroughly absorbing piece of fiction that manages to justify being a video game by virtue of skillfully integrated choices and missable content, making multiple playthroughs a potentially appealing prospect. The voice acting throughout is extremely impressively performed, the UI and controls are nearly perfect and the art is beautifully drawn, though we felt the characters could use a few more poses/expressions at times. Anyone interested in a ripping virtual novel yarn -. and who isn’t tediously prejudiced against any and all ‘furry’ content — will find a lot to love in Winds of Change.

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This post originally appeared on Nintendo Life | Reviews

Metallica: Kirk Hammett took inspiration from Stephen King novel for second album

Both Metallica and legendary novelist Stephen King have the same sort of themes as they both write about some of the deeper topics in life. This connection was not lost on Hammett, who previously spoke out about using King as inspiration for one of their biggest-selling albums to date.  

Hammett told the story on one of his blog posts where he revealed he found the inspiration for the band’s second album, Ride The Lightning.

He wrote: “One huge thing about my personal connection with Stephen King occurred when I was reading a chapter in The Stand.

“The chapter had a guy in prison who was waiting to Ride The Lightning, and I just thought: ‘Oh my God, what a cool collection of adjectives and nouns that is!’”

The Stand was King’s fifth novel and focussed on a worldwide pandemic wreaking havoc through the lands.

READ MORE: Winds of Winter: Stephen King feared George RR Martin ‘would die’

During the novel, as noted by Hammett, one of the characters – Lloyd Henreid – is in prison and about to be executed by electric chair.

This turn of phrase was enough to inspire Hammett into writing the incredible song Ride The Lightning. The guitarist went on to name the entire album after the the song.

Hammett went on: “I told [the band’s singer] James [Hetfield], he thought the same, and the rest is Metallica history!

“Pick up a copy of The Stand if you’re obsessive enough and find the chapter about a guy on death row where King actually writes the words.”

King has remained a fan of Metallica for years and most recently touched upon still listening to them.

The author revealed he fuels his creative process by listening to heavy metal.

Speaking to The Atlantic, King said: “I listen to music when I rewrite now. I don’t listen to music when I compose anymore. I can’t. I’ve lost the ability to multitask that way!

“[I listen to] Metallica, Anthrax. I still listen to those guys … There’s a band called the Living Things that I like a lot. Very loud group.”

King did, however, go on to add: “I never cared for Ozzy very much.”

He also confessed his love for the band back in 2016 on Twitter.

The writer told his 6.4 million followers: “I believe I’ll have a Heavy Metal Weekend, starting with Slayer, Sabbath, and Motorhead.”

He added: “Saving Metallica & [Judas] Priests for Sunday.”

SOURCE / SOURCE

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This post originally appeared on Daily Express :: Entertainment Feed

Novel Drug Approved by FDA for Some Bile Duct Cancers

A novel drug, infigratinib (Truseltiq), is now available in the United States for adults with previously treated unresectable bile duct cancer harboring a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

The agent is an orally administered, ATP-competitive tyrosine kinase inhibitor of FGFR.

It was granted an accelerated approval by the US Food and Drug Administration (FDA) on the basis of response rate data from a single arm, open label phase 2 trial, dubbed CBGJ398X2204. This trial involved 108 patients with locally advanced or metastatic cholangiocarcinoma — including 107 with stage IV disease, the FDA noted in a press release.

These types of bile duct cancers, which affect about 20,000 people in the United States and European Union each year, are aggressive and often diagnosed in later stages when treatment options are limited and prognosis is poor. The median 5-year survival rate is 9%, the drug’s maker, BridgeBio Pharma affiliate QED Therapeutics, and its partner, Helsinn Group, noted in their joint press release.

The FDA also approved the FoundationOne comprehensive diagnostic (CDx) genomic profiling test as the registrational companion CDx device for identifying patients with FGFR2 fusion or other rearrangement who might benefit from treatment with infigratinib.

FoundationOne CDx is a comprehensive genomic profiling (CGP) test for solid tumors, currently approved as a CDx test for 26 unique therapies. It is the only tissue-based CGP test approved as a companion diagnostic test for infigratinib, according to the device maker, Foundation Medicine

Details of Infigratinib Results

Patients enrolled in CBGJ398X2204 received infigratinib at a once-daily dose of 125 mg for 21 consecutive days followed by 7 days off therapy, in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 23%. One patient experienced complete response and 24 had partial response.

The duration of response was 5 months, and in eight of the 23 responders the response was maintained for 6 months or more.

The study results were reported at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium by lead investigator Milind Javle, MD, professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, Houston.

Adverse reactions occurring in at least 20% of patients included hyperphosphatemia, increased creatinine, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting.

“Serious risks include hyperphosphatemia and retinal pigment epithelial detachment and monitoring for these adverse reactions during treatment is recommended,” the FDA notes in its press release, adding that “[c]ontinued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).”

In addition to the pivotal second-line trial of infigratinib for bile duct cancer, QED Therapeutics is also enrolling patients in the phase 3 PROOF trial comparing the agent with gemcitabine plus cisplatin in the first-line setting.

Enrollment is also ongoing in trials looking at infigratinib for bladder and urinary tract cancers and achondroplasia.

The company has also launched ForgingBridges, a “comprehensive patient support program designed specifically to provide education, access and affordability resources for patients during their TRUSELTIQ journey.”

Sharon Worcester is an award-winning reporter for MDedge News, part of the Medscape Professional Network.

For more news, follow Medscape on Facebook, Twitter, Instagram, YouTube, and LinkedIn.

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This post originally appeared on Medscape Medical News Headlines

Novel IL-6 Antibody Slashes CRP up to 92% in High-risk ASCVD

Inhibition of interleukin (IL)-6 with ziltivekimab reduces multiple biomarkers of inflammation and thrombosis in patients at high atherosclerotic risk with moderate to severe chronic kidney disease (CKD) and elevated C-reactive protein, results of the phase 2 RESCUE trial show.

At 12 weeks, median levels of high-sensitivity C-reactive protein (hsCRP) were reduced by 77%, 88%, and 92% with 7.5 mg, 15 mg, and 30 mg doses of ziltivekimab, respectively, every 4 weeks, compared with a 4% reduction with placebo (P < .0001 for all).

Dose-dependent increases were also seen in the number of patients who achieved both a reduction in hsCRP of at least 50% and an on-treatment hsCRP of less than 2 mg/L (66%, 80%, 93% vs 4%; P < .001 for all).

Paul Ridker

“The magnitude of change with ziltivekimab on hsCRP was nearly twice as large in RESCUE as that previously observed in CANTOS, where canakinumab resulted in 15% to 20% reductions in event rates,” Paul Ridker, MD, MPH, Brigham and Women’s Hospital, Boston, said.

The results were reported at the American College of Cardiology 2021 Scientific Session (ACC.21) and published simultaneously in the Lancet.

The landmark CANTOS trial showed that targeting the IL-1 to IL-6 to CRP pathway of innate immunity with canakinumab (Ilaris), a monoclonal antibody directed at IL-1β, reduced hsCRP by 35% to 40% and reduced the risk for MI, stroke, and cardiac death independent of low-density-lipoprotein (LDL) lowering.

Clinical benefit was greater in those with robust IL-6 reductions, suggesting that IL-6 itself may be the primary target for atheroprotection, Ridker said. Further support has come from recent Mendelian analyses and murine models showing anti-IL-6 receptor antibodies slow atherosclerotic progression.

RESCUE focused on high-risk patients with CKD and an elevated hsCRP because this is a group with considerable unmet clinical need in which IL-6 correlates with the severity of renal impairment and level of atherosclerotic risk, he explained.

The 264 patients with stage 3 to 5 CKD and a hsCRP of at least 2 mg/L were randomly assigned to subcutaneous placebo or ziltivekimab at 7.5 mg, 15 mg, or 30 mg every 4 weeks for up to 24 weeks.

The median estimated glomerular filtration rate was 38 mL/min per 1.73 m2, median hsCRP was 5.7 mg/L, and median IL-6 level was 5.6 pg/mL. The patients’ median age was 66 years, and two-thirds were taking statins.

In addition to reductions in the primary endpoint of hsCRP, dose-dependent changes with 7.5 mg, 15 mg, and 30 mg ziltivekimab, compared with placebo, were seen in:

  • fibrinogen: –25%, –25%, –37% vs –2%
  • haptoglobin: –30%, –40%, –56% vs –3%
  • serum amyloid A: –40%, –50%, –42% vs +2%
  • secretory phospholipase A2: –27%, –41%, –49% vs 0%.

Interestingly, levels of lipoprotein(a) were also lowered (by 16%, 20%, 25% vs 0%). This is “very important because prior IL-6 inhibitors and other IL-6 drugs are known to elevate atherogenic lipids. We did not see that effect with ziltivekimab,” Ridker said. The ApoB:ApoA ratio was unchanged (0%, 0%, –5% vs –2%).

Perhaps equally important for cardiologists is the potential for adverse events with anti-inflammatory drugs, particularly IL-6 therapies, he noted. There was no evidence of grade 2, 3, or 4 sustained neutropenia or thrombocytopenia and no alanine aminotransferase or aspartate aminotransferase levels greater than three times the upper limit of normal.

Serious infections were reported in five patients in the placebo group, 11 in the ziltivekimab 7.5 mg group, five in the 15 mg group, and three in the 30 mg group.

“Ziltivekimab is an IL-6 ligand monoclonal rather than an IL-6 receptor inhibitor and it had been hypothesized that that might improve the specificity and therefore reduce the off-target issues and that seems to be holding up here,” Ridker told theheart.org | Medscape Cardiology. “It’s also a fully human monoclonal, so we had no injection-site reactions.”

“This is only a 24-week study and the numbers are relatively small, but the critical thing is we aren’t seeing an increase in liver dysfunction or neutropenia or thrombocytopenia compared to placebo,” he said. “And the lipids are stable. That’s very good news. So all these things point in the right direction that we can now embark on a large-scale outcomes trial.”

Novo Nordisk, which snapped up the drug as part of last year’s $ 725 million acquisition of France’s Corvida Therapeutics, is backing the double-blind cardiovascular outcomes ZEUS trial, which is evaluating ziltivekimab 15 mg in more than 6000 CKD patients with high-risk features similar to those in the pilot study.

Although the CANTOS results with canakinumab created a stir, its annual price tag of roughly $ 77,000 limits use outside its orphan drug designation to treat cryopyrin-associated periodic syndromes. Ziltivekimab, however, is being developed by Novo Nordisk specifically for atherosclerosis, Ridker said. “To their credit, they are going after a common disease, so they’re going to have to have it appropriated priced.”

Nephrologist Joel Topf, MD, Oakland University William Beaumont School of Medicine, Detroit, told theheart.org | Medscape Cardiology that ziltivekimab certainly has biological activity, but outcomes data are necessary to determine whether the “dramatic reductions in IL-6” will translate to better cardiovascular protection.

“I hope so,” he added. “My kidney patients have an unacceptably high CV disease burden and, despite great efforts with cardiac catheterization in ISCHEMIA-CKD, implantable cardiac defibrillators in ICD2, and statins in the 4D trial, we have not been able to move the needle.”

After the formal presentation, discussant Pradeep Natarajan, MD, Massachusetts General Hospital and Harvard University, Boston, congratulated Ridker on the results, and said: “I love that ZEUS is focusing on patients with CKD, a group with high biomarkers of inflammation, high cardiovascular disease risk, and often excluded from cardiovascular trials, often for competing risks.”

Natarajan observed that multiple inhibitors of the NLRP inflammasome are currently available or in development for cardiovascular disease, inhibiting the inflammasome itself or targeting IL-1β or IL-6, and asked about the relative strengths of targeting each of the pathways. “A related question: just like we target cholesterol through multiple different pathways, do you think there will be a role for all these different agents for inflammation?”

Ridker replied that there are oral agents that can attack the upstream NLRP3 that are a few years off in terms of moving into the atherosclerotic space, but they could run the risk of downstream adverse effects. IL-1β was shown to work in CANTOS, but it’s predominantly being developed as an oncologic agent because of its huge effects on lung cancer.

“IL-6 is likely to be the fundamental target and probably the target for why IL-1 inhibition in CANTOS worked. And that’s why focusing with this drug on IL-6 itself is what our chosen next step is going to be,” he said. “But Pradeep, you’re absolutely right. At the end of the day, we’re going to learn a lot about inflammation biology through these new trials and it’s a very exciting time for the cardiovascular community.

“My prediction would be that 5 to 10 years from now, we’re going to be giving everybody aggressive lipid lowering and aggressive inflammation lowering. We just have to figure out the right combinations,” he said.

The study was sponsored by Corvidia and Novo Nordisk. Ridker reported receiving research grants from Kowa, Novartis, Pfizer, AstraZeneca, the National Heart, Lung, and Blood Institute, and the National Cancer Institute; and serving as a consultant to Corvidia, Novo Nordisk, Inflazome, Novartis, Amgen, Merck, Jansen, Agepha, Flame, and CiviBio. He is also a coinventor on patents that are no longer active related to the use of inflammatory biomarkers in cardiovascular disease and diabetes.

American College of Cardiology 2021 Scientific Session. Presented May 17, 2021.

Lancet. Published online May 17, 2021. Abstract

Follow Patrice Wendling on Twitter: @pwendl. Follow ACC.21 coverage from theheart.org | Medscape Cardiology on Twitter and Facebook.

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This post originally appeared on Medscape Medical News Headlines

Novel Drug Offers Rapid Relief From Agitation in Serious Mental Illness

An investigational, orally dissolving film formulation of dexmedetomidine (BXCL501, BioXcel Therapeutics) may offer rapid relief from acute agitation related to schizophrenia or bipolar disorder (BD), results of two phase 3, randomized, placebo-controlled trials show.

Dr Leslie Citrome

For both disorders, BXCL501 showed “superiority over placebo” by meeting the primary endpoint of reduction of agitation as measured by the excited component of the Positive and Negative Syndrome Scale (PANSS), study investigator, Leslie Citrome, MD, MPH, department of psychiatry and behavioral sciences, New York Medical College, Valhalla, New York, told Medscape Medical News.

The findings were presented at the virtual American Psychiatric Association (APA) 2021 Annual Meeting.

Noninvasive Option

Acute agitation in patients with schizophrenia or BD is often encountered in emergency departments (EDs) and inpatient units. When nondrug tactics fail to calm the patient, drug options include injectable antipsychotics or benzodiazepines. BXCL501 is a thin, orally dissolving film for sublingual or buccal use.

“Dexmedetomidine is a highly-selective alpha-2a receptor agonist and we haven’t really had one of those before in psychiatry for this purpose. And we haven’t had much in the way of orally dissolving thin films that are absorbed in the oral mucosa so this represents an opportunity to provide a potential intervention that does not require an injection and yet could possibly be of use in people who are agitated,” Citrome said.

The study, known as SERENITY I, included 380 adults (mean age 45.6 years, 63% male) with schizophrenia, schizoaffective disorder, or schizophreniform disorder, and acute agitation in the emergency department (total score ≥ 14 on the PANSS-Excited Component (PEC) scale at baseline and a score ≥ 4 on at least one of the five PEC items).

Patients were randomly allocated to a single oral dose of BXCL501: 120 mcg, 180 mcg, or placebo. A total of 372 patients (97.9%) completed the study.

Mean PEC total score was 17.6 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -8.5 and -10.3 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.8 for placebo (P < .0001 vs placebo).

PEC response rates (≥ 40% reduction from baseline) were 80.6% and 89.6% with BXCL501 120 mcg and 180 mcg versus 47.6% with placebo (P < .0001 vs placebo).

Compared with placebo, significant improvement in the Clinical Global Impression-Improvement scale (CGI-I) was observed with both BXCL501 doses at 1 and 2 hours after dosing and in the Agitation and Calmness Evaluation Scale (ACES) at 2 hours postdosing.

The incidence of adverse events (AE) was 39.5%, 37.3%, and 15.1% with BXCL501 120 mg, 180 mg, and placebo groups.

All AEs were mild or moderate. The most common AEs with BXCL501 were somnolence, dizziness, dry mouth, hypotension, orthostatic hypotension, hypoesthesia, and paresthesia. No drug-related severe or serious AEs occurred.

Nipping It in the Bud

SERENITY II had a similar design. This study included 380 adults (mean age 48, 55% female) with bipolar I or II disorder and acute agitation in the ED (total score ≥ 14 on the PEC scale at baseline and a score ≥ 4 on at least one PEC item). A total of 362 (95.3%) of patients completed the study.

Mean PEC total score was 18 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -9.0 and -10.4 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.9 for placebo (P < .0001 vs placebo).

Bipolar patients also saw significant improvement on the secondary outcomes of CGI-I and ACES, with a similar adverse event profile as seen in patients with schizophrenia.

BXCL501 demonstrated “rapid, robust and clinically meaningful efficacy” in both patient populations and represents a “novel, non-invasive and well tolerated treatment of agitation,” the investigators conclude in their APA abstracts.

“Patients who are agitated are in psychic pain and they want relief from this psychic pain. We’re also worried that they might get worse and that agitation escalates to aggression potentially requiring restraints. We want to avoid that,” Citrome said.

“By nipping it in the bud with a pharmacological intervention, we can ease their psychic pain and we can manage a potentially dangerous situation. Offering an oral medicine that would work quickly would be ideal in my mind and patients might potentially be more accepting of that than an injection,” Citrome said.

Based on the SERENITY I and II data, BioXcel Therapeutics has submitted a new drug application to the US Food and Drug Administration.

Negotiation First, Medication Second 

Reached for comment, Samoon Ahmad, MD, professor, department of psychiatry, NYU Grossman School of Medicine, New York City, cautioned that, “when we talk about treating an agitated patient, medication is only part of the picture.”

“There is a negotiating process with the patient. Number one, you offer them an environment that is conducive to making them feel calm, safe and secure and that they are being listened to. Providing all of those things sometimes can be very helpful,” said Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York City.

“If someone starts throwing chairs at you or assaulting you, that is not really the time to negotiate a medicine; you basically have to restrain the patient, and many times give them intramuscular medicine,” Ahmad said.

He also noted that patients in the SERENITY trials had moderate-to-severe acute agitation.

“These are people you can potentially negotiate with. But again, when a patient crosses a certain line, you have to immediately do something and that could be intramuscular injection or something oral, which they may spit right in your face, which has happened numerous times,” Ahmad said.

“I don’t think intramuscular options will ever go away but an oral agent could be a useful tool as well,” said Ahmad, founder of the Integrative Center for Wellness in New York City.

He cautioned that clinicians are not going to be using this medicine in their offices. “If a patient walks in and is floridly psychotic, you will need to call 911. We’re really talking about its use either in the ED or acute inpatient setting,” Ahmad said.

American Psychiatric Association (APA) 2021 Annual Meeting. Presented May 1, 2021.

The SERENITY studies were funded by BioXcel Therapeutics. Several authors have financial relationships with the company. Ahmad disclosed no relevant financial relationships.

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Sunny Hostin Reveals The Inspiration Behind The Racy Sex Scenes

‘The View’ co-host talks to HL about celebrating Black joy, summer fun, and exploring colorism in her debut novel.

She’s often the voice of reason on The View. The one who backs her passionate takes with solid arguments, facts and receipts. But, if you leaf through Sunny Hostin’s debut novel, Summer on the Bluffs, you’ll discover something else. She knows how to write a sex scene that has the potential to make you blush and look at her with fresh eyes.

“I will tell you honestly, I blushed too,” the 52-year-old mom-of-two tells HollywoodLife. “I grew up in a very strict Catholic household, not a lot of boyfriends or anything like that. And I was having a little bit of trouble writing the sex scenes, but I wanted there to be sex scenes. And I also wanted the scenes to be centered around women and the pleasure of women, because I don’t see a lot of that. It worked for Bridgerton, right.”

Sunny Hostin
Sunny Hostin is the proud author of her first debut novel, ‘Summer on the Bluffs.’ (Miller Mobley)

But Sunny wrote Summer on the Bluffs – a novel about three African-American woman who are vacationing with their godmother Ama on Martha’s Vineyard – before the (excuse the cliché) bodice-ripping series became a Netflix hit. And she crafted her saucy sex scenes in the perfect way – with a group of her friends over a few glasses of wine.

“What I started to do when writing the book – believe it or not – is that, as I wrote groups of chapters, I invited some of my girlfriends over,” says Sunny, who also sometimes extended the invitation to her male friends. “We had almost a semi-writers’ room. I ordered food and we had wine flowing and I asked them to read the chapters.

“And one of my friends, Regina, said, ‘We should add this. How about adding this?’ Some other friends would say, ‘I don’t know. How about this?’ And that’s how the sex scenes got better and better and better. It’s sort of a group effort in many, many respects. And it was a group of women.”

Summer on the Bluffs
‘Summer on the Bluffs’ is the first part of Sunny’s three-book deal. (HarperCollins)

If the characters in Summer on the Bluffs seem familiar to readers, that’s because many of them were borrowed from Sunny’s real life. One of Ama’s goddaughters, Perry, for example, is an accomplished New York lawyer who is married to a talented doctor called Damon. As View fans know, Sunny – who is a former federal prosecutor – is happily married to Manny Hostin, an orthopedic surgeon.

However, in the book Damon has a wandering eye and a slightly roguish character. Is Manny worried that readers will confuse the two? “Oh, he’s worried,” Sunny says, chuckling. “He knows he’s not [like Damon], but he’s worried for sure.”

“It’s a fictional account,” Sunny adds. “But I definitely use my own experiences as a frame of reference for the story. So there is, if I’m being honest, just a little bit of people that I know, including my husband.”

Sunny uses Summer on the Bluffs to explore other truths in the Black and Latino communities, two worlds that she embodies as the daughter of a Puerto Rican mom and African-American dad. Like Dorothy West’s 1995 novel, The Wedding, which is set in 1950s Martha’s Vineyard, Summer shines a light on the exclusive Black beachfront community. While Black trauma appears, Black joy – affluence, professional accomplishments, art, music – is celebrated through the life experiences of the characters, starting with Ama who, in the book, is the first Black woman to have a seat on the New York Stock Exchange.

The uncomfortable parts of African-American culture are exposed too. Colorism, for example, is something that Sunny runs to in the book, rather than hide away from, through the pain of the character Olivia; the dark-skinned goddaughter who feels that her beauty is unseen.

“You have to tell the story of the African-American community in all its complexity. And part of that story, no question, is colorism, because I see it within my own friend group,” says Sunny who confesses that in social situations men have bypassed her model-like dark-skinned friends to talk to her, a biracial, light-skinned Afro-Latina. These “personal” and “hurtful” experiences have led to “difficult discussions” that have spilled over in some form into Summer.

Sunny Hostin, Joy Behar, Whoopi Goldberg, Meghan McCain
Sunny (left) with three of her fellow ‘View’ co-hosts, Joy Behar, Whoopi Goldberg and Meghan McCain. (ABC)

Whilst much is revealed in this book, Sunny (who, like her characters, vacations on Martha’s Vineyard each year) is already writing the second part of what is a three-novel series. If her stories make it on to the screen, The View co-host is already toying with casting ideas. “There is definitely a place for all of my crushes,” she says of Brit actors Idris Elba and Rege-Jean Page. “And I intend to definitely send them the book.”

As for Rege-Jean, she knows exactly who she wants the Bridgerton hunk to play – the character inspired by her real-life husband. “It would be incredible,” she says.

Author: Marissa Charles
This post originally appeared on Hollywood Life

Outlander book 9 release date ANNOUNCED: Diana Gabaldon novel to hit shelves this year

A lot has happened in the Outlander fandom since the last book in the series was released. Book eight in the Diana Gabaldon story, Written In My Own Heart’s Blood, quickly followed the release of the first season of the STARZ TV adaptation of the first book. The TV show boosted the novels’ fanbase, who in turn began asking the author when the highly anticipated ninth book would be hitting store shelves.

Today, Diana, alongside Penguin Random House, announced the release date of the upcoming book, Go Tell The Bees That I Am Gone. 

Go Tell The Bees That I Am Gone is due for release on November 23, 2021.

The book’s UK cover art has also been released, which fans can look at below. 

Its extensive and thrilling blurb delves into the highly-anticipated events of the novel, including the reunion of Claire and Jamie Fraser with their daughter, Brianna Fraser. 

She is joined by her husband, Roger MacKenzie, and their son, Jem – who was recently saved from being kidnapped in the previously released eighth novel. 

READ MORE: Outlander TV vs books: How was Claire Fraser changed from the books?

SCROLL DOWN TO READ THE SYNOPSIS FOR GO TELL THE BEES THAT I AM GONE

Go Tell The Bees That I Am Gone’s blurb reads: “The past may seem the safest place to be… but it is the most dangerous time to be alive…

“Jamie Fraser and Claire Randall were torn apart by the Jacobite Rising in 1743, and it took them twenty years to find each other again. Now the American Revolution threatens to do the same. It is 1779 and Claire and Jamie are at last reunited with their daughter, Brianna, her husband, Roger, and their children on Fraser’s Ridge. Having the family together is a dream the Frasers had thought impossible.”

However, it sounds like things aren’t going to remain as happy as they seem.

The Go Tell The Bees That I Am Gone synopsis continues: “Yet, even in the North Carolina backcountry, the effects of war are being felt. Tensions in the Colonies are great and local feelings run hot enough to boil Hell’s tea-kettle. Jamie knows loyalties among his tenants are split and it won’t be long until the war is on his doorstep.

The synopsis continues: “Brianna and Roger have their own worry: that the dangers that provoked their escape from the twentieth century might catch up to them. Sometimes they question whether risking the perils of the 1700s —among them disease, starvation, and an impending war—was indeed the safer choice for their family. Not so far away, young William Ransom is still coming to terms with the discovery of his true father’s identity—and thus his own—and Lord John Grey has reconciliations to make, and dangers to meet . . . on his son’s behalf, and his own.

“Meanwhile, the Revolutionary War creeps ever closer to Fraser’s Ridge. And with the family finally together, Jamie and Claire have more at stake than ever before.”

Go Tell The Bees That I Am Gone comes seven years after the release of Written In My Own Heart’s Blood.

Diana has been very secretive about what the new book will entail but previously explained where the title for the novel came from.

Writing on her website, the author explained its title was derived from a “very old Celtic custom”.

Diana said the custom suggests “you always tell the bees when someone is born, dies, comes or goes – because if you don’t keep them informed, they’ll fly away”.

This ominous passage has led to a number of fan theories, suggesting the book will involve characters dying, leaving, returning, or new arrivals and new births.

It has been presumed by fans that the Outlander TV show will also adapt the upcoming ninth book when its seasons catch up to it.

The TV show has been an enormous success for both TV network STARZ and author Diana.

Not only has it bolstered the already enormous fanbase of the series, the show has also won a collection of awards.

In recent years Outlander has won awards including a TV Choice Award for Most Exciting New Series and Best Fantasy Television Series at the Saturn Awards.

The show’s wonderful cast no-doubt help the campaign, with Jamie Fraser being played by Scottish heartthrob Sam Heughan.

Sam has reached headlines in recent months after being rumoured to be taking the role of James Bond in the next 007 movie.

He is currently in the upper echelons of the betting, after frontrunner and fellow period-drama actor Regé-Jean Page, who is best known for Netflix show Bridgerton.

Sam is joined on Outlander by Caitriona Balfe, who plays protagonist Claire Fraser.  

Go Tell The Bees That I Am Gone is due for release on November 23, 2021 from Century Publishing and is available for preorder now. 

This article originally appeared on Daily Express :: Entertainment Feed