Monthly Archives: April 2022

This is one of those bittersweet moments where I have the duty to share that our longtime editor Jake Slobe is stepping away from Clay & Milk to pursue other interests. Jakes been the primary news-sharer and storyteller of the Iowa entrepreneurial community for almost four years and we are all the better for his work. Personally, Im very happy for my friend Jake to have the opportunity to pursue other things while simultaneously being bummed about losing him from the Clay & Milk/Gravitate Coworking organization and our community overall.

This is Jakes last week as a full-time employee here but hes not going to disappear overnight. Hes agreed to stay on in a freelance capacity and help with the newsletter in the interim (woot!). Youll still see Jakes byline on stories (you can still email him tips and story leads at jake@clayandmilk.com) and were going to scale back the newsletter to three times per week rather than daily while we plan for the next evolution of Clay & Milk.

That evolution is the sweet part of an announcement like this, losing someone from the team who has been at the core forces us to put a real thought into what it is we do, how we can do it better and how we take things to a new level. Its the same thing weve done with every change in editor (were developing quite an alumni roster with Matt, Jami, Joey and now Jake!) weve had at Clay & Milk and its always exciting.

Do you have thoughts on what youd like to see in the next iteration of Clay & Milk? Id like to hear them (send a note!). While our mission to be the publication of record for all things tech, startup or entrepreneurial in Iowa wont ever change, how we go about always will.

Geoff WoodCo-Founder and Publisher

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The next evolution of Clay & Milk - Clay & Milk

Nature Timespiral: The Evolution of Earth from the Big Bang

Since the dawn of humanity, we have looked questioningly to the heavens with great interest and awe. Weve called on the stars to guide us, and have made some of humanitys most interesting discoveries based on those observations. This also led us to question our existence and how we came to be in this moment in time.

That journey began some 14 billion years ago, when the Big Bang led to the universe emerging from a hot, dense sea of matter and energy. As the cosmos expanded and cooled, they spawned galaxies, stars, planets, and eventually, life.

In the above visualization, Pablo Carlos Buddassi illustrates this journey of epic proportions in the intricately designed Nature Timespiral, depicting the various eras that the Earth has gone through since the inception of the universe itself.

Not much is known about what came before the Big Bang, but we do know that it launched a sequence of events that gave rise to the universal laws of physics and the chemical elements that make up matter. How the Earth came about, and life subsequently followed, is a wondrous story of time and change.

Lets look at what transpired after the Big Bang to trace our journey through the cosmos.

The Big Bang formed the entire universe that we know, including the elements, forces, stars, and planets. Hydrogen and massive dissipation of heat dominated the initial stages of the universe.

During a time span known as the Hadean eon, our Solar System formed within a large cloud of gas and dust. The Suns gravitational pull brought together spatial particles to create the Earth and other planets, but they would take a long time to reach their modern forms.

After its initial formation, the surface of the Earth was extremely hot and entirely liquid. This subsequent eon saw the planet cool down massively, solidifying some of the liquid surface and giving rise to oceans and continents, as well as the first recorded history of rocks.

Early in this time frame, known as the Archean eon, life appeared on Earth. The oldest discovered fossils, consisting of tiny, preserved microorganisms, date to this eon roughly 3.5 billion years ago.

The first era of the Proterozoic Eon, the Paleoproterozoic, was the longest in Earths geological history. Tectonic plates arose and landmasses shifted across the globeit was the beginning of the formation of the Earth we know today.

Cyanobacteria, the first organisms using photosynthesis, also appeared during this period. Their photosynthetic activity brought about a rapid upsurge in atmospheric oxygen, resulting in the Great Oxidation Event. This killed off many primordial anaerobic bacterial groups but paved the way for multicellular life to grow and flourish.

The Mesoproterozoic occurred during what is known as the boring billion stage of Earths history. That is due to a lack of widespread geochemical activity and the relative stability of the ocean carbon reservoirs.

But this era did see the break-up of the supercontinents and the formation of new continents. This period also saw the first noted case of sexual reproduction among organisms and the probable appearance of multicellular organisms and green plants.

In some respects, the Neoproterozoic era is one of the most profound time periods in Earths history. It bookends two major moments in the planets evolutionary timeline, with predominantly microbial life on one side, and the introduction of diverse, multicellular organisms on the other.

At the same time, Earth also experienced severe glaciations known as the Cryogenian Period and its first ice age, also known as Snowball Earth.

The era saw the formation of the ozone layer and the earliest evidence of multicellular life, including the emergence of the first hard-shelled animals, such as trilobites and archaeocyathids.

The Paleozoic is best known for ushering in an explosion of life on Earth, with two of the most critical events in the history of animal life. At its beginning, multicellular animals underwent a dramatic Cambrian explosion in aquatic diversity, and almost all living animals appeared within a few millions of years.

At the other end of the Paleozoic, the largest mass extinction in history resulted in 96% of marine life and 70% of terrestrial life dying out. Halfway between these events, animals, fungi, and plants colonized the land, and the insects took to the air.

The Mesozoic was the Age of Reptiles. Dinosaurs, crocodiles, and pterosaurs ruled the land and air. This era can be subdivided into three periods of time:

The rise of the dinosaurs began at the end of the Triassic Period. A fossil of one of the earliest-known dinosaurs, a two-legged omnivore roughly three feet long-named Eoraptor, is dated all the way back to this time.

Scientists believe the Eoraptor (and a few other early dinosaurs still being discovered today) evolved into the many species of well-known dinosaurs that would dominate the planet during the Jurassic period. They would continue to flourish well into the Cretaceous period, when it is widely accepted that the Chicxulub impactor, the plummeting asteroid that crashed into Earth off the coast of Mexico, brought about the end of the Age of Reptiles.

After the end of the Age of Dinosaurs, this era saw massive adaptations by natural flora and fauna to survive. The plants and animals that formed during this era look most like those on Earth today.

The earliest forms of modern mammals, amphibians, birds, and reptiles can be traced back to the Cenozoic. Human history is entirely contained within this period, as apes developed through evolutionary pressure and gave rise to the present-day human being or Homo sapiens.

Compared to the evolutionary timeline of the world, human history has risen quite rapidly and dramatically. Going from our first stone tools and the Age of the Kings to concrete jungles with modern technology may seem like a long journey, but compared to everything that came before it, is but a brief blink of an eye.

*Editors note: An earlier version of this article contained errors in the header graphic and an incorrect citation, and has since been updated.

This article was published as a part of Visual Capitalist's Creator Program, which features data-driven visuals from some of our favorite Creators around the world.

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Nature Timespiral: The Evolution of Earth from the Big Bang - Visual Capitalist

While every hotel customizes its offerings, one thing is abundantly clear contactlessguest experiences are here to stay.

Technological advancements were inevitable, and the pandemic gave hoteliers time to analyze and determine how technology could be best incorporated to overcome the challenges. All major hotel brands as well as independents now encourage guests to download their mobile apps which includes several features empowering them to get what they need and manage amenities with minimal human contact. While some features like contactless check-in and check-out, ordering food from the on-site restaurants, communicating with the front desk, or cashless payments are common, many apps have unique, customizable options.

Alma Resort, the independently owned and operated resort in Vietnams Cam Ranh peninsula, has launched the Alma Resort App, which offers menus, promotions and vouchers, as well as live stream broadcasts and information about events and COVID-19-related health and safety tips. Since Cam Ranh gets around 300 sunny days a year and is known for having Vietnams best weather, the hotel is planning to add a weather cam in real time that can be accessed on the app.

The app, which was put forward in a heads-of-department meeting by the resorts executive chef, was created by the hotel team within two months, said Almas Managing Director Herbert Laubichler-Pichler. Unlike major chains, the independent hotels always have to navigate technological change themselves as they dont have a head office to develop or recommend the latest equipment and software, Laubichler-Pichler said. And this can be difficult for the independent hotels when their staff on the ground such as, for example, the front office managers, are the users of the technology but are preoccupied with the guests and prioritizing their needs.

The good news, saidLaubichler-Pichler, is that the technologies required to power these apps is not expensive. As an independently owned and operated hotel, Alma Resort had the autonomy to invest in the app and develop it themselves which helped keep costs under control. The app cost no more than US$5,000 to develop. These technologies are not expensive; you dont have to spend hundreds of thousands of dollars. You also need to ensure that the technology is set up in a way so that it is not a money pit; you dont want to be continually spending a lot of money with a third-party every time you need to make an update to the app. You can realize ROI in many ways quite quickly after launching an app.

In spring 2021, Aqua-Aston Hospitality, Honolulu, Hawaii, introduced an app with an intelligent messaging platform in more than 20 of its managed hotels and resorts across Hawaii. It allows guests to communicate with associates in real-time without having to call or visit the front desk. For example, guests can send a message to the front desk about their arrival time and get information about guest amenities. Among other things, they can receive a copy of their folio, get fresh towels or arrange housekeeping service.

Since Aqua-Astons app uses text messaging system as a mode of communication between guests and associates, building the app was surprisingly affordable and utilizes a mode of communication that we all use in everyday life, said Mark DeMello, vice president of operations, Aqua-Aston Hospitality.

Besides providing remote check-in, mobile key, options to order food, temperature control, self-check-in and mobile payment methods, Virgin Hotels Lucy app also integrates the in-room entertainment system to provide casting, allowing guests to use their smartphones as the TV remote. Launched in 2015, the updated app now offers secure ID verification, cashless tipping facility, in-room lighting controls and access to custom fitness routines.

While guests at citizenM already had access to digital solutions like a check-in kiosk and an iPad to control their room settings before the pandemic, the introduction of a guest app during the pandemic across all its hotels has been a success and resulted in the highest guest satisfaction and most loyalty among the app users, said citizenM Hotels Chief Digital & Experience Officer Casper Overbeek.

Every day we see new opportunities, not because of tech, but because we want to adapt to customer needs, Overbeek said. We have launched a new paid subscription service. Our customer research showed that price security and availability are key pain points for the frequent traveler. With our new membership mycitizenM+ we solve those.

Charlestowne Hotels, Charleston, South Carolina, which was using contactless technology long before it became such an integral part of the industry, sends out a pre-registration email with an option for guests to add room requests or notes, a follow up email when the room is ready and a text message or email which contains the room key. A similar process takes place at checkout, where a folio can be reviewed electronically, charges confirmed and guest feedback submitted. Elaborating on the Charlestownes technological innovations, Director of Technology Max Spangler said in-room IoT devices, like Amazon Echo and Google Nest Hub, double up as virtual concierge as they are enabled to answer questions and streamline guest requests to appropriate departments.

The pre-arrival registration process has been the most popular and engaging with our guests. Automated guest communication and reservation management has also been well received, Spangler said.

Besides fulfilling the new-age travelers need for reduced human contact, these apps have helped reduce labor costs, especially at a time when the industry has been grappling with a severe labor crisis. The real benefit of contactless technology, Spangler said, is that it allows them to be more flexible with their staffing model.

We can be more agile when it comes to staff placement, hours worked during a shift, and hire a wider range of employees with skills that reach beyond knowledge for a particular method or system, Spangler explained. Flexibility for our team members, in a labor market as competitive as this, is paramount.

The technology also helps make staffs more productive, improve efficiency, and remove some of the mundane, repetitive tasks. At Charlestowne Hotels, the pre-arrival registration helps reduce phone volume and mobile key and text communication allows them to drastically reduce peak check-in times and corresponding volume.

When guests do arrive and decide to check in at the desk, our teams are fresher and more engaging with our guests than had they just managed a long queue of guests, Spangler added.

Besides the labor costs, a mobile key solution has also helped reduce other hard costs, like key cards. Spangler said integrating more contactless tech into Charlestowne hotels has resulted in an uptick in guest satisfaction and increased employee happiness. When we evaluate the contactless technology, the ROI is analyzed from the guest perspective are guests engaged and loyal, are guest scores up, is staff happier? Those are the items we quantity versus the costs of tech implementation.

For smaller and independent hotel brands like Alma Resort, it has been challenging to encourage guests to switch to the apps and use its features as many of them are still not used to the technology.

Our staff have spent a lot of time urging guests to download the app and helping to ensure that guests have downloaded it correctly, Laubichler-Pichler said.

With reduced travel and on-site presence due to lockdowns and travel restrictions, it has been difficult during the pandemic to implement all the emerging components of guests demands, said VirginHotels Vice President of Technology Jason Doebrich. At the same time, due to labor constraints and turnover, training on the new technologies and procedures has also been difficult. Supply chain issues have led to long lead times and delays on parts and resources, Doebrich added.

No more front desk?

Despite the proliferation of technology, hoteliers feel the hotel lobby can never be rendered redundant. Guests will still need and prefer access to a human and not a robot or an app to ask questions. Hotel apps can be cost-effective and convenient for travelers, but many guests will still want to sit in a restaurant and consult the waiter for the best available options before ordering a dish off the menu.

A warm greeting and a smile on arrival to a hotel are hallmarks of good old-fashioned hospitality, Laubichler-Pichler said. I think that the personal touch will further distinguish the high-end hotels from the budget ones in future.

Hotel lobbies still serve their purpose for guests who want a personal, high-touch experience. Irrespective of guests seeking a physical presence or a virtual one, Aston-Aquas front desk teams assist guests with their needs, DeMello said. The recently renovated lobby and refreshed arrival experience at our luxury condominium property, Aston Waikiki Beach Tower, provides guests with an enjoyable in-person check-in and check-out process. We installed two-sit down front desks and welcome guests with a sustainable strand shell lei, in addition to a cold Oshibori towel and glass of fresh juice.

Terming the apps as extra tools provided to team members and guests, Doebrich said the front desk is still widely used by many guests as the technologies are still in their formative years.

Technology is merely an enabler for creating a greater experience at citizenM hotels, Overbeek said. While the pandemic accelerated the digital innovations, it has also made the hotel industry aware of how much they need human touch. While citizenM guests have been checking in through check-in kiosks from the very first day, there is always an citizenM ambassador to welcome and help where needed, he explained. This will never change as it is key to our brand experience. We do study how we will further optimize the check-in experience through our app, but the welcoming smile will always be there.

Original post:

Evolution of the guest app HOTELSMag.com - HOTELS

Image source: Discovery Institute.

Magnetotactic bacteria are the fascinating stars of the new episode ofSecrets of the Cellwith Michael Behe, which premieres TODAY at 5 pm Pacific time/8 pm Eastern right here. These bugs could point the way to a treatment for cancerous tumors, thanks to their natural ability to maneuver by sensing the Earths magnetic field. Dr. Behe explains how. They owe this gift to a sophisticated manufacturing and quality-control process a code-driven factory, in effect, in each bacterium for the production of magnetosomes, forming the functional equivalent of a compass. A modern, human-built factory would be no less sophisticated.

Its true, says Behe,

some types of bacteria are harmful to humans. But countless others are superheroes of the microbial world. All this raises an obvious question. How did bacteria come to be so diverse and so ingenious?

Indeed, thats the question, and he details the steps that an unguided process would have to take to furnish these bacteria with the needed equipment. An intelligent agent with foresight and a plan could do it, step by step. But blind Darwinian evolution? Color me skeptical, says Professor Behe, a biochemist at Lehigh University and pioneer in the field of intelligent design.

Join us here as we learn about this and other micro-scale wonders that surely would have given Charles Darwin cause for reflection if he had known about them.

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Behe: Magnetotactic Bacteria and Other Micro-Wonders - Discovery Institute

Plenty has changed in the head and neck cancer field in the past 10 years. This time has allowed for key PD-1 inhibitors to gain FDA approval, de-intensification to come into the fold, and specifically, staging for human papillomavirus (HPV) status has evolved to aid oncologists in their prognosis.

Although there have been several negative trial results in recent larger studies, they have been hypothesis generating and have answered significant questions for the treatment of head and neck cancers. Going forward, they may help to generate practice-changing data and improve treatment options for the next 10 years.

In an interview with Targeted Oncology, Robert L. Ferris, MD, PhD, FACS, director, UPMC Hillman Cancer Center; Hillman Professor of Oncology; associate vice chancellor for cancer research; co-director for the Tumor Microenvironment Center; professor of otolaryngology, immunology, and radiation oncology, University of Pittsburgh; and co-physician editor in chief of Targeted Therapies in Oncology, elaborated on the significant progress in the head and neck cancer space, as well as potentially practice-changing results that will come with emerging agents, for Head and Neck Cancer Awareness Month.

Targeted Oncology: How has the field of head and neck cancer changed over the past 10 years?

Ferris: If you go back 10 years ago to 2012cetuximab [Erbitux] was felt to be just as effective as cisplatin. The RTOG 1016 [NCT01302834] study shows that's not the case.1 There's a superiority of [chemotherapy] over cetuximab for locally advanced disease. We had no FDA-approved PD-1 inhibitors, [but in the past 10 years] nivolumab [Opdivo] and pembrolizumab [Keytruda] are standard in second line and first line. We have the concept of de-intensification of therapy for good prognosis. HPV-positive disease [research] was getting started, and whether that was safe, and how to do that was launching clinical trials. The ECOG 3311 trial [NCT01898494] that we published a couple months ago,2 was just being designed in 2011 or 2012. The concept of de-intensification for HPV-positive, good-prognosis disease was a concept that was tested for the past 10 years, and is now beginning to show clinically relevant, practice-changing data to guide what the appropriate treatment intensity is for this new disease. I think we understood that HPV was a major and increasing subset 10 years ago. We understood that it had a better prognosis but had no impact on treatment. And in the past 10 years, the staging system AJCC [American Join Committee on Cancer] 8 came out,3 which changed the staging system and separated by HPV status. We began having de-intensification clinical trial results, which was just kind of a concept 10 years ago. I think [there has been] pretty substantial progress in 10 years. They have totally new and standard therapies for a good prognosis group of patients and have totally new FDA-approved agents in recurrent metastatic disease, but so far, we don't know how to use it in locally advanced disease.

De-intensification is here. Staging is here now based on HPV status, a different staging system, which didn't exist before. We used to stage it all the same, but now there's HPV-negative and HPV-positive staging, which is separate. Immunotherapy is approved, and cetuximab is inferior to cisplatin in locally advanced disease, though they were felt to be interchangeable 10 years ago.

What trials have been the most practice changing in recent years, and what do you think will be the next wave of practice-changing data?

There are the CheckMate 141 [NCT02105636] and KEYNOTE-048 [NCT02358031] trials that got PD-1 inhibitors, nivolumab and pembrolizumab, approved in the second line and the first line.4,5 [There is] RTOG 1016 for [chemoradiation for] locally advanced disease for non-surgical treatment of HPV-positive head neck cancer and then ECOG 3311 for transoral robotic surgery as de-intensification. I'd say those are probably the biggest. You could say, from a negative standpoint, that the JAVELIN 100 trial [NCT02952586],6 which showed no benefit of adding avelumab [Bavencio] in locally advanced disease wasn't practice changing, but it was impactful because the expectations were high. There is still pembrolizumab added to chemoradiation. [We are waiting for] the KEYNOTE-412 [NCT03040999] trial results, which was designed for high-risk locally advanced disease,7 like JAVELIN, to be reported. You could say that the phase 3 CheckMate 651 trial [NCT02741570],8 which was reported at ESMO [European Society for Medical Oncology], showed that nivolumab and ipilimumab [Yervoy] did not beat the EXTREME regimen [cetuximab, cisplatin/carboplatin, and fluorouracil followed by cetuximab maintenance] like the KEYNOTE-048 trial showed that pembrolizumab did alone. I think that was more of a trial design flaw than it was that nivolumab and ipilimumab doesn't work.

I would say the ones that are affirmative results that have changed practice are the CheckMate 141 and KEYNOTE-048 trials for the PD-1 inhibitors, RTOG 1016, showing superiority of cisplatin, and then the use of transoral robotic surgery, ECOG 3311, permitting omission of chemotherapy and reduced-dose radiation for surgically treated HPV-positive patients.

Obviously, I have a conflict of interest as I've been involved in a couple of those trials. But I think, if you asked someone who was not Bob Ferris, that they would say the same things.

What are some of the new targets that are of interest for the future of head and neck cancer?

In IO [immune oncology], LAG-3 inhibition has recently been approved for melanoma,9 and there's some promising data in head neck cancer. So, I think LAG-3 combined with PD-1 will be intriguing.

I don't know if CTLA-4 is dead. I think it's an active agent. It would be great to see some role for CTLA-4 targeting head and neck cancer. We've published on that recently and have a neoadjuvant trial in it.10 I think the [CheckMate 651 trial] was not as negative. It just barely missed and had great durability. So CTLA-4 and LAG-3 may still be pursued. LAG-3 is earlier in its development. The SMAC mimetic agent, xevinapant, that was [previously] called Debio 1143, is pretty promising and is being used on top of chemoradiation or in place of chemotherapy. So, xevinapant for particularly p53-mutated [malignancies is of interest].

PI3 kinase inhibitors have been pretty disappointing, despite the relatively frequent presence of activating PI3K alterations. I think the field would love to see that because we don't have a lot of oncogene activation, but PIK3CA is present, and yet the PI3 kinase inhibitors don't really seem all that active, particularly not in the mutated ones. The role of circulating tumor DNA, particularly for HPV-positive disease, which dovetails into the next phase of de-intensification, is actually monitoring tumor burden. I think that's an intriguing concept that is not a new target, but I think it's conceptually innovative.

What role would you say that drug sequencing of these therapies plays in head and neck cancer currently?

We think it matters now in the reverse way that we thought it mattered. It's sort of like the RTOG 91-11 trial [NCT04943445] for larynx cancer.11 That trial compared cisplatin chemoradiation given concurrently vs induction chemotherapy followed by radiation. If you looked at the early results, concurrent chemoradiation was the best at 2 years. That was the New England Journal of Medicine paper that Arlene A. Forastiere, MD, published in terms of preserving the larynx.12 If you follow down the road, because concurrent chemoradiation was so toxic, eventually the overall survival was better to give chemotherapy first and separate it from radiation. In the case of IO sequencing, IO therapy, again, the JAVELIN trial was designed concurrently, before, during, and with a year of maintenance of avelumab because the preclinical data seem to suggest that just giving IO separate before or after radiation or chemoradiation would not harness the synergy that now we think there's some biology and that it's actually potentially deleterious to give avelumab during chemoradiation because of the impact of it on the immune system.

We now have lung data from the PACIFIC trial [NCT02125461],13 showing that you can take a high-risk group after chemoradiation, give a year of durvalumab [Imfinzi], and they do fantastic. That analogous trial, called IMvoke010 [NCT03452137],14 giving atezolizumab [Tecentriq] after high-risk treated head and neck cancer, should report any time. Were all enthusiastic because since JAVELIN failed, that must mean that IMvoke010 will be positive. You say sequencing, I might say separation of concurrent agents, both of which have activity. We know that PD-1 and PD-L1 inhibitors work, and we know that chemoradiation works. So why, when you put them together, do you not get an added benefit, unless there's some interaction? If you go back to just treat with 1 and then treat with the other, you should get this plus that in terms of activity.

We have our oral abstract at ASCO [American Society of Clinical Oncology]. By pure coincidence, luck, and maybe a little bit of knowledge of the field, we designed a trial here, a relatively small, randomized, phase 2 trial that was just 40 mg/m2 or so in each arm of chemoradiation, concurrent with pembrolizumab or chemoradiation alone followed by pembrolizumab concurrently vs sequentially. Now that we know the JAVELIN trial failed results, we broke the code and put it in for ASCO, and the sequential data look better. This was started in 2015. We designed this trial so it started out as a biomarker trial [with 20 patients] in each arm, and I went back to Merck and got it doubled so we could at least look at some clinical end points. The 1-year progression-free survival rate, and we're getting 2-year and 3-year [progression-free survival rates], looks like sequentially separating them is better than concurrent treatment. We do think sequencing matters.

Currently, 2 immunotherapy agents are approved in HPV-positive and -negative related head and neck cancer. Can you address some of the research that is looking at immunotherapy in the definitive treatment setting in patients who don't have metastatic disease?

At present, there's no approved role for IO. There are trials using it in the pre-treatment stage, usually preoperatively: neoadjuvant for a month to 6 weeks, a single agent or in combination. There are post operative for post treatment with a year of maintenance that ECOG has, EA 3191 [NCT04671667].There are various trials testing in the local advanced setting, but none of them have shown any positive data yet that IMvoke010 already talked about. There's no role in the locally advanced setting for IO therapy outside of a clinical trial.

What are some of the emerging biomarkers in head and neck cancer that researchers are watching?

I would say that most folks are very enthusiastic. We've essentially failed adding anything to standard chemoradiation, and so this concept of xevinapant, adding a SMAC to a DNA damage pathway inhibitor [is promising]. The phase 2 data were very positive and very promising, and it wasn't by a little bit.15 You always expect a little fall off [in the curves] when you go to a phase 3, but this was a big enough phase 2, and it's substantially beneficial that I think the enthusiasm is there and there's a phase 3 running [NCT04459715]. I would say that folks are looking at that. There's also continued efforts at de-intensifying for HPV-positive disease in some ways, continuing to reduce radiation. There was an ASTRO [American Society for Radiation Oncology] with 36 Gy of radiation as opposed to the 50 Gy that we had in ECOG 3311. There's use of circulating tumor DNA to reduce adjuvant therapy. I think getting a little bit more personalized in selecting the best patients who are candidates for reduced doses and then finding ways to intensify therapy for the poor-prognosis HPV-negatives is a key area where we've made no progress in a few decades.

What would you say more community oncologists should know about how to treat head and neck cancers?

HPV is continuing to increase in frequency, primarily in the tonsil and the base of tongue. P16 is the surrogate biomarker to test for it, but don't use p16 unless the tumor is from the base of the tongue or the tonsil. It doesn't work in the oral cavity or the larynx, and we see community oncologists thinking that you just get p16 on every cancer of the head and neck. No. It's only a surrogate in the tonsil or base of tongue primary tumors. Also, you can get it from a neck needle biopsy so it can be useful to localize the primary tumor to the tonsil or the base of the tongue. [I want them to] know it does appear safe for good prognosis [for patients who are] HPV-positive to reduce the radiation and chemotherapy dose. National Comprehensive Cancer Network guidelines are being updated with that. PD-L1 testing is not required for second-line IO therapy, but it is helpful and required in the first line to decide whether to give pembrolizumab monotherapy or pembrolizumab plus chemotherapy. And at present, adding IO in the locally advanced setting does not have a role.

References

1. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial [published correction appears in Lancet. 2020 Mar 7;395(10226):784]. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X

2. Ferris RL, Flamand Y, Weinstein GS, et al. Phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: an ECOG-ACRIN cancer research group trial (E3311). J Clin Oncol. 2022;40(2):138-149. doi:10.1200/JCO.21.01752

3. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more personalized approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi:10.3322/caac.21388

4. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018;81:45-51. doi:10.1016/j.oraloncology.2018.04.008

5. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7

6. Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22(4):450-462. doi:10.1016/S1470-2045(20)30737-3

7. Machiels JP, Tao Y, Burtness B, et al. Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Future Oncol. 2020;16(18):1235-1243. doi:10.2217/fon-2020-0184

8. Argiris A, Harrington K, Tahara M, et al. Nivolumab (N) + ipilimumab (I) vs EXTREME as first-line (1L) treatment (tx) for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Final results of CheckMate 651. Ann Oncol. 2021;32(suppl_5):S1283-S1346. doi:10.1016/annonc/annonc741

9. FDA approves first LAG 3 inhibitor antibody Opdualag for metastatic melanoma. News release. BioSpace; March 22, 2022. Accessed April 25, 2022. https://bit.ly/3KgqB65

10. Jie HB, Schuler PJ, Lee SC, et al. CTLA-4 regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75(11):2200-2210. doi:10.1158/0008-5472.CAN-14-2788

11. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845-852. doi:10.1200/JCO.2012.43.6097

12. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091-2098. doi:10.1056/NEJMoa031317

13. Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial. J Thorac Oncol. 2021;16(5):860-867. doi:10.1016/j.jtho.2020.12.015

14. Wong D, Fayette J, Guo Y, et al. Abstract CT123: IMvoke010: Randomized Phase III study of atezolizumab as adjuvant monotherapy after definitive therapy of squamous cell carcinoma of the head and neck (SCCHN). Cancer Res. 2019;79(13_supplement):CT123. doi:10.1158/1538-7445.AM2019-CT123

15. Bourhis J, Sun X, Le Tourneau C, et al. 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus xevinapant or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck. Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

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Head and Neck Cancer Treatment Evolution Leads the Way for Future Developments - Targeted Oncology

The World Health Organizations (WHO) director-general is pressing countries to maintain COVID-19 surveillance and share information on its transmission and sequencing, saying reduced testing abroad makes us increasingly blind to patterns of transmission and evolution.

Speaking on Tuesday during a press conference, WHO Director-General Tedros Adhanom Ghebreyesus noted that while COVID-19 cases and deaths continue to decline, the world needed to welcome the news with some caution.

This makes us increasingly blind to patterns of transmission and evolution. But this virus wont go away just because countries stop looking for it. Its still spreading, its still changing, and its still killing, Tedros said.

The threat of a dangerous new variant remains very real and although deaths are declining, we still dont understand the long-term consequences of infection in those who survive, he added. When it comes to a deadly virus, ignorance is not bliss. WHO continues to call on all countries to maintain surveillance.

The development comes as White House officials have pressed for more money to be authorized by Congress for pandemic funding, though lawmakers have not been able to strike a deal yet.

During his first appearance speaking to reporters in the White House briefing room, COVID-19 response coordinator Ashish Jha on Tuesday warned that durable and effective vaccines potentially ready for the fall and winter as well as new, effective treatments could be jeopardized if administration officials are unable to secure more money for COVID-19.

The bottom line is that none of us can predict with any certainty where exactly this pandemic is going, what the virus is going to do next. All we can do is prepare. And thats what we need Congress to do, is to help us prepare and be ready for whatever eventuality comes, Jha said.

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WHO chief: World is 'increasingly blind' to COVID transmission, evolution - The Hill

If you wanted to look at how far Liverpool have come under the management of Jrgen Klopp, you only have to look at the competitions they have won and continue to compete for these days, compared with when he was first appointed. The German did remarkably well to guide the side he inherited to the League Cup and Europa League finals in 2016, but the Reds have far bigger targets in mind now.

But in terms of how they have advanced this far, clearly there have been many factors. Perhaps most importantly, the clubs recruitment has been outstanding over an extended period, with players brought in who fit perfectly with how Klopp wants his team to play.

But perhaps most vital of all has been an ability to turn what was arguably the Reds biggest weakness of their current managers reign into a strength. That takes serious hard work, and we have seen evidence of it in the recent victories over Everton and Villarreal.

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Much was said regarding Klopps style of heavy metal football when he was appointed and the impact of that was seen from day one. Theres a famous image of Adam Lallana almost collapsing in his managers arms when he was substituted in Klopps first game in charge, a 0-0 draw at Tottenham. The Reds were now a high pressing team and determined to prove that whether home or away.

However, opposition managers are not dumb. How do you stop a team that thrives on winning the ball high up the pitch to create goalscoring opportunities? Give them the ball and challenge them to break down your deep-lying defence.

Liverpool were repeatedly set this test in 2015/16 and then Klopps first full season at the helm, and repeatedly they failed it. In those two campaigns, the Reds had 10 league matches in which they had at least 70 per cent of the possession, and they won just three of them. Even then, one of the victories saw Hull City receive a first-half red card, so when playing against 11 men who had no interest in having the ball, Liverpool usually struggled.

But theres no interest in having the ball, and then theres what Everton served up at Anfield last weekend. The Reds recorded the second highest possession figure seen in a Premier League match since 2003/04 (when records began) in the latest edition of the Merseyside derby. Yet despite attempting 82.4 per cent of the total passes, Liverpool were still able to force six high turnovers.

These are defined by Opta as sequences that start in open play and begin 40m or less from the opponents goal, and they give a good indication of pressing in-or-just-outside the final third. While the Reds total of six against Everton was down on their seasonal average, it was a decent effort in light of Evertons play dead tactics. And more importantly, one of the high turnovers led to Liverpools opening goal.

The Blues were unable to play their way out of defence thanks to the close attention of multiple men in red, Fabinho recovered the ball and the sequence leading to the goal was underway. It was the seventh time Liverpool have scored from a high turnover in the league this season, more than any other team in the division. Klopps men may not have been as productive in an attacking sense from pressing high against Villarreal, but they still set a new benchmark for 2021/22 with their efforts.

Where once possession-averse teams confounded Liverpool, they can now have majority ownership of the ball and still win it back. This means it works from a defensive standpoint as well as from the more obvious attacking perspective, and that was very evident against Unai Emerys side.

Villarreal simply could not get out from the back, so swarmed were they by Liverpool players. The Spanish side completed just six open play passes into the final third all evening; Trent Alexander-Arnold alone was successful with three times as many. While they had been under pressure for much of their quarter-final tie with Bayern Munich, they were still able to break out and have a total of 16 shots in the 180 minutes. At Anfield, they had just one, and that from a set-piece situation.

The tables from five years ago have been well and truly turned for Liverpool. Where they were once clueless when having lots of possession, their opponents are now hopeless in both attacking and defensive terms when they do. Klopp famously once said that no playmaker in the world can be as good as a good counter-pressing situation, but his side have perhaps proved that no defensive midfielder can be as good going the other way either.

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Liverpool have discovered the ultimate playmaker to confirm Jrgen Klopp evolution is complete - Liverpool.com

NEW YORK This is what Jeff Gorton and, later, Kent Hughes clearly wanted all along.

As the Canadiens continued piling up lopsided losses under Dominique Ducharme in December, first with a roster decimated by COVID-19 but then after the pause to bring the outbreak under control, Ducharme kept his job. It was only when things got so bad that it was clearly becoming damaging five straight regulation losses in which the Canadiens gave up 33 goals and scored 12 did Gorton and Hughes step in, firing Ducharme and hiring Martin St. Louis, just about the most outside-the-box hire they could have made.

By that point the Canadiens were 8-30-7, and what was finally confirmed Wednesday night had seemed somewhat inevitable. No matter the new-coach bump the Canadiens would experience under St. Louis, the hole was too deep to avoid claiming the ultimate prize: last place in the NHL and the best odds at picking first at the draft Montreal is hosting in July.

A run of injuries for Arizona made this end goal tighter than it seemed it would be in February, but Montreal clinched finishing with the worst record in the NHL when the Coyotes erased a three-goal deficit and beat the Dallas Stars in overtime Wednesday, not long after the Canadiens had defeated the New York Rangers 4-3 on a last-minute goal by Jeff Petry.

The Canadiens win at Madison Square Garden was only their 15th regulation victory in 81 games this season. Think about that for a moment. And honestly, the Canadiens record under St. Louis at 13-19-4, a points percentage of .417 is not exactly great.

But Gorton and Hughes are scouting the world under-18 championships for a reason, because this draft pick is vitally important to the future of the Canadiens, a future they hope will look somewhat like the one the Rangers have created for themselves ever since Gorton embarked on a rebuild in New York in 2018.

The Rangers kept most of their best players out of the lineup Wednesday which takes some of the shine off this last-minute Canadiens win but when looking at the list of scratches that included basically the entire core of Artemi Panarin, Adam Fox, Mika Zibanejad, Chris Kreider and Jacob Trouba, it is worth noting that Gorton acquired every one of those players for the Rangers except for Kreider.

But the Rangers success this season is highly predicated on Kreider suddenly becoming a 52-goal scorer and winning the franchises first Mr. Ranger award before the game, an award named for the late Rangers great Rod Gilbert.

And Kreiders breakout season at age 30 he had never scored more than 28 goals before this year is highly relevant to what the Canadiens are trying to do and what role St. Louis will play in it.

Because though Gorton and Hughes are surely happy to have the best odds in the draft lottery this year, they have no intention of this becoming a regular occurrence.

When Kreider was an impending free agent approaching the 2020 trade deadline, Gorton signed him to a seven-year contract worth $6.5 million a year. The Canadiens were on the ice practicing that day, Feb. 24, 2020. When Brendan Gallagher came off the ice, I told him about the contract that took Kreider off the trade market.

What did he get? he asked.

Seven years, I responded.

No, Gallagher said, how much?

When told the AAV, Gallagher nodded his approval.

He and Kreider were seen at the time as very similar players with similar numbers and similar impact. Gallagher was a year away from his contract expiring and was likely to enter into negotiations that offseason. As it turns out, eight months later, Gallagher signed his six-year extension with the Canadiens.

And the AAV was exactly $6.5 million.

But now Gallagher is not performing, or at least not producing. In the game Wednesday, only Michael Pezzetta got less ice time than Gallaghers 12:27, and he was basically a nonfactor.

Gallagher is fully aware of how disappointing his season has been, how bad it looks in the first year of that contract, and he is determined to make things right this offseason with proper preparation and determination.

Saturday night in Ottawa, Gallagher was asked about trusting his shot a bit more and attempting more shots from distance than he normally has.

I still have to be around the net to score the majority of my goals, I know that, and I know I havent been scoring this year, Gallagher said. But its a good chance for me to grow my game a little bit. It doesnt mean Im forgetting about the success Ive had and where it was, but there are opportunities you can find to get in those areas. I had some good looks tonight, didnt beat the goalie.

St. Louis is asking Gallagher to adapt his game, to evolve. And that word evolve came up a lot Wednesday. Because St. Louis once played with Kreider in New York, and the player he sees now is not the player he played with in a Rangers uniform.

I think Chris has evolved as a player, St. Louis said. I think Chris always had a fastball, you know, coming down the wing and getting behind. I think hes learned a few other pitches now. Hes not just a fastball thrower. Hes evolved as a player, hes controlling his speed better. It allows him to process the game probably a little bit better and get into the right areas. Hes always been very good in front, so he hasnt lost that.

Theres probably one thing Kreids does better now than he did in the past is he probably manages his game way better from blue line to blue line, in terms of what kind of speed does he bring.

Controlling speed is something St. Louis is asking of a lot of players, but particularly Josh Anderson, whose speed is such an asset in his game. And if there is one player on the Canadiens who is most similar to Kreider in terms of playing style and size, it is Anderson.

I think its important that you need the speed, but to stay successful in this league I compare it to a baseball pitcher, if you only throw gas, eventually they just time it right and they hit home runs, St. Louis said. So thats why you need many different pitches. Im trying to address it with Josh, but still, you cant lose that speed. Its just knowing how to use it better, probably. And I think Kreids has done that.

Whats important for the Canadiens is that notion that players need to evolve over the course of their careers, something St. Louis understands better than most because he did that so well. He has already said the one thing he thought he did at an elite level as a player was get better. But not everyone can do that at the same level.

Gallagher will do it one way. Anderson another. And so will Jake Evans, who once said in Laval that he saw himself as a fourth-line checking centre in the NHL but acknowledged Wednesday he now sees himself as potentially more than that.

Maybe they see somebody do something they werent doing before, is it the coachs fault that the players doing X, Y and Z? St. Louis said. I think its part of it. You bring attention to certain details of their game that they need and certain thoughts that I want them to think of when theyre out on the ice.

But at the end of the day, its the players. Actually, its an art to be able to absorb and apply, and I think thats on the player. Its a little bit on me, too, in the sense that not everybody learns the same way, so I cant necessarily try to teach somebody one way and think its going to work with everybody. Im still figuring that part out. But for the most part, when guys are evolving as players, its really on them. As a coach, I think youre a facilitator in that sense, but its the player that has that responsibility to go and apply it.

The Canadiens will need St. Louis to lock down that ability to understand which players have a capacity to evolve and which dont, and it will be vitally important to the organization that he find a way for certain players to make a jump at least similar to the one Kreider made this season. No, neither Gallagher, Anderson nor Evans is likely to become a 50-goal scorer, but if they can adapt their games to become more consistent contributors, the Canadiens will be the big beneficiaries.

Because landing the first pick in the draft, or picking in the top three if someone else wins the lottery, is definitely a big thing for the organization. It can turn around what has been an objectively awful season, the worst season in the NHL.

But that one high-end prospect will not be enough. The Canadiens will need certain veterans to adapt and evolve into more productive versions of themselves next season. And even if the wins have not really been there much for St. Louis this season, he is a big part of that evolution.

(Photo of Brendan Gallagher: Bruce Bennett / Getty Images)

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Canadiens have best shot at the first draft pick, but the evolution of their veterans is almost as important - The Athletic

Google is quickly becoming the complete funnel for many of the searches and transactions we make online. When we first published this article in 2018, Google already made significant strides within the hotel and travel space and was in the process of adding even more features and functionalities.

According to a recent study by Similarweb (2022), as of October 2021, nearly 20% of keyword searches resulted in a search engine results page (SERP) feature on the results page. In January 2020, that percentage was lower than 5%. Hoteliers are no stranger to Googles SERP features like hotel listings, map packs, pricing tools, and ad-supported spaces. Ultimately, its Googles way of keeping its nearly 90% search market share within its search and buying ecosystem.

In this article, we are going to look at the updates Google has made over the past several years to its hotel and travel SERP results and features, and their effects on hotels and OTAs.

Back in October 2018, Google made a significant announcement that they would be rolling out a suite of design and functionality improvements to the hotel shopping experience. The gist of the announcement is that the information you can find within Googles own environment would rival that of TripAdvisor and other OTAs.

In doing so, Google put the finishing pieces on what has arguably become the most complete hotel shopping and booking system available. Within Googles hotel shopping ecosystem, youll find price comparisons, hotel details and overviews, Google reviews, reviews sourced from around the web, and hotel photos.

As a hotel, its on you to ensure the information on your hotel listing is accurate. Just in case you havent read our Google Business Profile for Hotels guide, Google Business Profile is going to be the place to start for any hotelier. By ensuring you have an optimized hotel listing, compelling photos, and are responding to guest reviews, you will put yourself in a position for success.

In 2018, Google rolled out a new search and filtering system to the search engine results page for hotel searches. In 2022, similar features still exist in addition to new hotel highlight icons and hotel listing callouts.

Data has already proven that a vast majority of hotel decisions begin with a search and, based on the ever-evolving hotel SERP tools, customers will continue to stay on Googles system for much longer as they slice and dice to find their perfect hotel.

Googles push to gather more and more reviews makes searches even more valuable. Back in 2018, Google was revealed as the number one online review site, outperforming Tripadvisor and other OTAs. Today, Google continues to be a leading source for hotel reviews. Now, searchers can get enough information from Google to validate a booking decision without having to visit Tripadvisor or an OTA.

Read the full article at TravelBoom

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The Evolution of Google Hotel Search Results - Hospitality Net

Evolution Theater Companys 2022 season begins this weekend with a rousing production of the fizzy, loving parody The Musical of Musicals: The Musical, with book by Eric Rockwell and Joanne Bogart, music by Rockwell, and lyrics by Bogart, directed by Joe Bishara.

Jonathan Collura, behind a piano on the side of the stage, leads the action as narrator and music director, offering wry commentary on the action while adroitly moving between rhythms and genres in a way thats as delightful as it is seamless. Matt Piper and Nat Harper play a series of young lovers (Pipers characters all named some variety of William and Harpers some shade of June). Tom Cardinal plays a landlord in each of the sketches, with variations on the name Jitter, standing for authority figures throughout the worlds of which were treated to a glimpse. Lisa Thoma covers all other adults the characters interact with, named withshades of Abby.

The unabashed delights of The Musical of Musicals come with the way Bogart and Rockwell stir together songs and wink at characters and themes across its five sketches, with a brief intro and outro. The opening sequence, Corn, takes its spine from Oklahoma and winks at the rest of the Rodgers and Hammerstein oeuvre, including a beautifully executed ballet with particularly strong work from Harper. Piper soars through the scores nods to the way R&H characters slide intoAmericana Opera, Looks like its time for a soliloquy, even as Cardinal and Thomas highlight the rough, lived-in rhythms that made that work so fresh and so often imitated.

The most arresting mash-up of elements for me was the Sondheim riff, A Little Complex, that slams Sweeney Todd and Company together with flashing hints of Sunday, Night Music, and a few others. Cardinal shines here and as Phantom Jitter in the hilarious Andrew Lloyd Webber poke Aspects of Junita in stellar showcases forhis rich voice and physical comedy.

The Kander and Ebb/Fosse sequence Speakeasy leads Chicago and Cabaret by the collar through a series of fun house mirrors, casting shadows of Spider Woman and other elements, again making excellent use of Harpers Dancing and the contrasting vocal textures of Harper, Piper, Cardinal, and especially Thoma in a show-stopping number.

One of the key elements that makes The Musical of Musicals as much fun as it is, is the sense of rough play. Anyone who loves something, like the art form of musicals, has just as passionate a list of things that drive us insane or widely beloved shows we hate and that acknowledgement, that grinning, playful sense of, Okay, this was ridiculous even before we turned the volume up, with exaggerated, extended leg movements in Jamie Markovich McMahons light choreography, with a raised eyebrow and a smirk from Collura, and with shared looks that nudge the elastic fourth wall but never quite break it.

The beauty of the voices and the fluid movements also keep the play grounded and amplify the cartoonish quality. Bisharas direction keeps things moving at a sometimes-breakneck pace but never gets frantic, never buries a joke. That fluidity has a perfect partner in Colluras encyclopedic knowledge of musical theater and the piano, moving between genres as easily as breathing. The Musical of Musicals is a delightful evening for people who love various stripes of musicals and have hated one or two.

The Musical of Musicals runs through May 7 at the Abbey Theater of Dublin, with performances at 7:30 p.m. Wednesday and Thursday,8 p.m. Friday and Saturday, and 2 p.m. Sunday. For tickets and more info, visit evolutiontheatre.org.

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Theater Review: Evolution Theatre Company Kicks Off 2022 Season With Bubbly 'Musical of Musicals' - Columbus Underground